Joined: 25 Jul 2005
Location: St. Pauls, Bristol, England
|Posted: Sun Aug 04, 2019 11:34 pm Post subject: GCMAF: Cancer immune boost, GC Macrophage Activating Factor
|Does the Immune System Naturally Protect Against Cancer?
The importance of the immune system in conferring protection against pathogens like viruses, bacteria, and parasitic worms is well established. In contrast, there is a long-lasting debate on whether cancer prevention is a primary function of the immune system. The concept of immunological surveillance of cancer was developed by Lewis Thomas and Frank Macfarlane Burnet more than 50 years ago. We are still lacking convincing data illustrating immunological eradication of precancerous lesions in vivo. Here, I present eight types of evidence in support of the cancer immunosurveillance hypothesis. First, primary immunodeficiency in mice and humans is associated with increased cancer risk. Second, organ transplant recipients, who are treated with immunosuppressive drugs, are more prone to cancer development. Third, acquired immunodeficiency due to infection by human immunodeficiency virus (HIV-1) leads to elevated risk of cancer. Fourth, the quantity and quality of the immune cell infiltrate found in human primary tumors represent an independent prognostic factor for patient survival. Fifth, cancer cells harbor mutations in protein-coding genes that are specifically recognized by the adaptive immune system. Sixth, cancer cells selectively accumulate mutations to evade immune destruction (“immunoediting”). Seventh, lymphocytes bearing the NKG2D receptor are able to recognize and eliminate stressed premalignant cells. Eighth, a promising strategy to treat cancer consists in potentiating the naturally occurring immune response of the patient, through blockade of the immune checkpoint molecules CTLA-4, PD-1, or PD-L1. Thus, there are compelling pieces of evidence that a primary function of the immune system is to confer protection against cancer.
Keywords: cancer immunosurveillance, primary immunodeficiency, cancer risk, organ transplantation, immunosuppressive drugs, HIV, NKG2D, checkpoint blockade
Lewis Thomas and Frank Macfarlane Burnet proposed the concept of immunological surveillance of cancer more than five decades ago (1–4). It was defined by Burnet as follows: “In large long-lived animals, like most of the warm-blooded vertebrates, inheritable genetic changes must be common in somatic cells and a proportion of these changes will represent a step toward malignancy. It is an evolutionary necessity that there should be some mechanism for eliminating or inactivating such potentially dangerous mutant cells and it is postulated that this mechanism is of immunological character” (1). More than 50 years after Burnet proposed his theory, the immunological scientific community remains largely divided with both proponents [e.g., Ref. (5, 6)] and opponents [e.g., Ref. (7, 8)] of the cancer immunosurveillance hypothesis. In fact, an opposite and very influential concept was proposed in 2001 by Frances Balkwill and Alberto Mantovani, who suggested that inflammatory immune cells and cytokines found in tumors may promote rather than suppress tumor growth (9, 10). Although, we are currently lacking convincing data illustrating immunological eradication of precancerous lesions in vivo, there are strong indications that a primary function of the immune system is indeed to prevent cancer. Here, I present eight types of evidence in support of the cancer immunosurveillance hypothesis.
Primary Immunodeficiency in Humans and Mice is Associated with Increased Cancer Risk
As Burnet himself pointed out, an implication of the cancer immunosurveillance hypothesis is that immunodeficiency should be associated with increased likelihood of neoplasia (1). Immunodeficiencies can be divided in two main types: primary (inborn) immunodeficiencies, which are caused by genetic defects and whose incidence is approximately 1:10,000 births; and secondary immunodeficiencies, which are induced by immunosuppressive medication or viral infection and which are much more common. In accordance with Burnet’s prediction, severe primary immunodeficiencies have been reported to be associated with increased risk of malignancy (11–14). For instance, patients with defective humoral immunity due to common variable immunodeficiency (CVID) had increased incidence of lymphoma and epithelial tumors of the stomach, breast, bladder, and cervix (12, 15). Selective immunoglobulin A (IgA) deficiency was associated with a high incidence of gastric carcinomas (15). Moreover, patients with X-linked immunodeficiency with hyper-IgM, caused by mutations in the CD40 ligand molecule, had a high incidence of tumors of the pancreas and liver (16). However, it remains unclear to what extent primary immunodeficiency in humans leads to increased cancer development, due to the relatively low number of patients investigated.
Gene-targeted mice, which selectively lack key components of the immune system have been extensively used to experimentally test the effect of well-defined primary immunodeficiencies on cancer development [reviewed in Ref. (17)]. Mice which lacked both T and B cells, due to a deficiency in the recombination-activating gene 2 (RAG2), were more susceptible to spontaneous and carcinogen-induced carcinomas (18). Mice lacking γδ T cells were highly susceptible to multiple regimens of cutaneous carcinogenesis (19). The cytokines interferon-α/β (IFN-α/β) and IFN-γ were shown to protect mice against spontaneous and carcinogen-induced malignancy (18, 20–22). Moreover, the molecule perforin, which is used by cytotoxic lymphocytes to kill target cells, was reported to be important for surveillance of spontaneous lymphoma (23). Collectively, the human and mouse data reveal a consistent association between primary immunodeficiency and increased incidence of various types of cancer.
Organ Transplant Recipients are More Prone to Cancer Development
A breakthrough in organ transplantation was the discovery of immunosuppressive drugs such as cyclosporine A, which prevent organ rejection by the adaptive immune system (24). Immunosuppressive medication is now standard treatment after organ transplantation. Life-long treatment of thousands of transplanted patients with immunosuppressive drugs was defined by Thomas as a “human experiment” to test the cancer immunosurveillance hypothesis (4). Already in 1973, an international registry-based study of renal-transplant recipients from 30 countries revealed that transplantation was associated with increased risk of developing cancer, in particular lymphoma (25). A large cohort investigation of cancer risk after organ transplantation was performed in the Nordic countries, in homogeneous populations with well-documented cancer incidence, on nearly 6000 kidney recipients (26). A two to fivefold excess risk was reported for cancers of the colon, larynx, lung, bladder, prostate, and testis. Strikingly high risks, 10-fold to 30-fold above normally expected levels, were observed for cancers of the lip, skin (non-melanoma), kidney, endocrine glands, cervix, and for non-Hodgkin’s lymphoma (26). Another large study of kidney transplantation in 200,000 patients from 42 countries reported that the risk of developing lymphoma was 12-fold higher for transplant recipients than that in a matched non-transplanted population (27). Notably, the majority of posttransplant lymphomas were associated with infection with Epstein–Barr virus (EBV), which primarily infects B cells and is known to cause B cell transformation (28). Thus, most lymphomas arising in transplant patients were likely to be a secondary event resulting from reduced antiviral immunity, rather than a direct effect of reduced antitumor immunity. However, lymphomas not associated with EBV infection have also been reported after transplantation (29). An investigation of 175,000 solid organ transplants in the USA revealed that increased cancer risk occurred not only after kidney transplantation but also after liver, heart, and lung transplantation (30). Risk was increased for 32 different malignancies, some related to known infections (e.g., anal cancer and Kaposi sarcoma) and others unrelated to infections (e.g., lung cancer and melanoma). The most common malignancies with elevated risk were non-Hodgkin lymphoma and cancers of the lungs (30).
Very high rates of non-melanoma skin cancers have been reported for Swedish (20–40%) and Australian (70%) populations 20 years after transplantation (31–33). Cutaneous types of human papillomaviruses have been suggested to be the cause of non-melanoma skin cancers such as squamous cell carcinoma in immunosuppressed patients, but the epidemiological pieces of evidence remain inconsistent (34). Strikingly, non-melanoma skin tumors in the renal-transplant population of Queensland, Australia, were reported to arise predominantly on chronically sun-exposed skin (head, neck, and distal limbs), strongly suggesting a causative role of ultraviolet (UV) light rather than oncogenic viruses (33). Thus, life-long treatment of organ transplant recipients with immunosuppressive drugs leads to increased risk of developing many different types of cancer, some related to known infections and others unrelated.
Immunosuppression Induced by Infection by Human Immunodeficiency Virus Type 1 leads to Elevated Risk for Cancer
The HIV-1 virus causes acquired immunodeficiency by selectively infecting and killing CD4+ T cells. Accordingly, HIV-infected patients, receiving or not antiviral treatments, possess reduced levels of CD4+ T cells compared to non-infected individuals. HIV-infected individuals have elevated risk for cancer linked to oncogenic viruses such as Kaposi sarcoma (caused by human herpes virus 8), Hodgkin’s and non-Hodgkin’s lymphoma (EBV), anal and cervical cancer (human papilloma virus), and liver cancer (hepatitis B and C viruses). Kaposi sarcoma, non-Hodgkin’s lymphoma and cervical cancer are particularly frequent and are considered as acquired immunodeficiency syndrome (AIDS)-defining cancers (35). However, several cancers that are not linked to oncogenic viruses, like lung cancer and multiple myeloma, are also more frequent in patients with HIV (35, 36). Lung cancer is the most common non-AIDS-defining cancer and a leading cause of mortality among HIV-infected individuals (37). For the majority of patients with lung cancer, malignant transformation is known to be caused by carcinogens present in cigarette smoke. Higher smoking rates have been reported for HIV-infected populations. After controlling for potential confounders including smoking, a large cohort study of veterans (with 37,000 HIV-infected patients and 75,000 healthy controls) concluded that HIV was an independent risk factor for incident lung cancer (37). Importantly, cancer incidence in HIV-infected individuals was found to be inversely related to CD4+ T cell counts in blood, which supports the association between immunosuppression and increased cancer risk (38). For instance, the risk of lung cancer was doubled by CD4+ T counts in the range of 350–499 cells per microliter blood compared to normal counts ≥500, and continued to increase as the CD4+ T cell count fell (38). Thus, acquired immunodeficiency by HIV infection, which selectively depletes CD4+ T cells, leads to increased risk of developing many different types of cancer, some related to known infections, and others unrelated.
Quantity and Quality of the Immune Cell Infiltrate in Human Primary Tumors Represent an Independent Prognostic Factor for Patient Survival
All solid tumors are infiltrated by a variety of immune cells. For many types of human cancers, an association has been reported between the type, density, and location of immune cells within the primary tumor and the clinical outcome [reviewed in Ref. (39)]. The number of intratumoral CD3+ T cells was shown to positively correlate with longer survival of patients with epithelial ovarian and colorectal cancers (40, 41). A high number of stromal CD4+ T cells were found to represent an independent positive prognostic factor in non-small cell lung cancer (42). Tumor-infiltrating CD8+ cytotoxic T cells were shown to predict clinical outcome in colon, lung, and breast cancers (42–45). Concurrent infiltration by both CD4+ and CD8+ T cells was reported to represent a favorable prognostic factor in esophageal squamous cell carcinoma and non-small cell lung cancer, suggesting that both cell types cooperate to fight cancer (46, 47). Among all CD4+ T cell subsets, Th1 cells seem to be particularly advantageous, as reported for colorectal, liver, and breast cancers (39, 40, 48, 49). In patients with gastrointestinal stromal tumors (GIST), the intratumoral density of CD3+ T cells and NKp46+ natural killer (NK) cells were found to represent two independent prognostic factors for progression-free survival (50). Notably, NK and T cells were detected in distinct areas of tumor sections, suggesting that both cell types contributed independently to GIST immunosurveillance (50). Furthermore, a high tumor infiltration by CD68+ macrophages was associated with prolonged survival in prostate, lung, and colon cancers (43, 51–54). Thus, for various types of human cancers, the quantity and the quality of the immune response within the primary tumor appear to represent an independent predictor for patient survival. This correlation between immunological data and clinical outcome strongly suggests that the immune system of the patient had naturally mounted an antitumor immune response before any treatment had started. The efficiency of this response presumably varies from patient to patient, thereby critically influencing survival.
Cancer Cells Harbor Mutations in Protein-Coding Genes that are Specifically Recognized by the Adaptive Immune System
Cancer cells originate from normal cells that have accumulated “driver” mutations, which either activate oncogenes by dominant gain of function or inactivate tumor suppressor genes by recessive loss of function. A typical tumor contains two to eight of these driver mutations (55). Cancer cells also accumulate “passenger” mutations, which do not contribute to tumorigenesis. Genome-wide sequencing studies have provided detailed information about somatic mutations in various types of cancers. For common solid tumors such as breast, colon, brain, and pancreas cancers, an average of 30–60 non-synonymous mutations in protein-coding genes was observed (56–59). Most of these mutations (95%) were single-nucleotide substitutions, whereas the remainder was deletions or insertions (55). Metastatic melanoma and non-small cell lung carcinoma, which represent two types of cancers caused by potent mutagens (UV light and cigarette smoke, respectively), had a higher mutation rate with ~150 mutations per tumor (60, 61). Pediatric tumors and leukemias had the fewest mutations with ~10 mutations per tumor on average (55). Thus, it is now established that tumor cells in most cancer types harbor numerous non-synonymous mutations in protein-coding genes.
Driver and passenger mutations, which alter the normal amino acid sequence of proteins, may potentially be recognized by the adaptive immune system. A number of studies have revealed that tumor-specific antigens created by mutations can be recognized either by the T cells or the B cells of the patient. For instance in melanoma, CD4+ T cells were found that recognized a tumor-specific antigen generated by a non-synonymous point mutation in the gene coding for triosephosphate isomerase (62). Another antigen recognized by CD4+ T cells in melanoma had been generated by a chromosomal rearrangement resulting in a fusion of a low density lipid receptor gene with a fucosyltransferase gene (63). In colorectal cancer with microsatellite instability phenotype, CD4+ T cells were identified that recognized a frameshift mutation in the transforming growth factor β receptor II (TGFβRII) (64). In a melanoma patient, the tumor suppressor p16INK4a with a point mutation was specifically recognized by cytotoxic CD8+ T cells (65). In non-small cell lung cancer, several CD8+ T cell epitopes created by point mutations have been reported (66–68). Moreover, in chronic myeloid leukemia, cytotoxic CD8+ T cells specific for a BCR-ABL fusion protein (resulting from the fusion of BCR and ABL genes) were found (69). Tumor-specific IgG antibodies are common in the serum of cancer patients, as revealed by serological identification of antigens by recombinant expression cloning (SEREX) technology (70). This powerful method has allowed the identification of over 2000 tumor antigens recognized by autologous IgG, including the p53 tumor suppressor modified by a point mutation (71). Collectively, these studies demonstrate that the adaptive immune system is able to detect cancer by specifically recognizing the mutated proteins of the malignant cells.
Cancer Cells Selectively Accumulate Mutations to Evade Immune Destruction
Recognition of cancer cells by tumor-specific CD8+ T cells is achieved by the presentation of antigenic peptides from mutated proteins on major histocompatibility complex (MHC) class I molecules on the surface of cancer cells. In order to avoid recognition and the resulting elimination by CD8+ T cells, cancer cells often mutate key genes of the MHC class I antigen presentation pathway. Downregulation of surface MHC class I molecules is a common feature of human cancer cells [reviewed in Ref. (72)]. Several mechanisms have been reported, including mutations in the β2-microglobulin gene, which is required for MHC class I molecule expression on the cell surface (73, 74). MHC haplotype loss in various human tumors was shown to be caused by complete or partial loss of chromosome 6, which harbor all MHC class I and class II genes (except for β2-microglobulin) (75). On the basis of its mutation pattern in cancer cells, β2-microglobulin was recently included in a list of 74 tumor suppressor genes (55). A recent study analyzed somatic point mutations in exon sequences from 4742 human cancers across 21 cancer types (76). Based on mutation frequency and pattern, 254 “cancer genes” were identified, including four genes belonging to the MHC class I antigen presentation pathway (β2-microglobulin, HLA-A, HLA-B, and TAP1), as well as the CD1D gene, which is involved in the presentation of lipid antigens to NK T cells (76). Hence, several mutations frequently observed in cancer cells are likely to result from selective pressure to evade the immune attack, in particular by cytotoxic CD8+ T cells and NK T cells.
Another strategy used by cancer cells to avoid the immune response consists of secreting immunosuppressive cytokines such as transforming growth factor β (TGF-β) and interleukin 10 (IL-10). In contrast to normal cells, which produce very little, malignant cells often secrete large amounts of TGF-β and IL-10 [reviewed in Ref. (77)]. Both cytokines have various effects on non-transformed cells present in the tumor mass, most notably the inhibition of immune cell functions. For several types of cancers, elevated serum levels of TGF-β or IL-10 have been reported to be associated with worse prognosis [reviewed in Ref. (77)]. Surprisingly, TGF-β can function both as a tumor suppressor and a tumor promoter, this duality being known as the TGF-β paradox. In early stage tumors, TGF-β is a potent inducer of growth arrest. In advanced stage malignant cells, TGF-β signaling pathways are severely dysregulated, and TGF-β promotes tumor growth [reviewed in Ref. (78)]. Thus, cancer cells often produce abnormally high levels of immunosuppressive cytokines, which strongly suggests that dampening immunity is a prerequisite for tumor growth.
Experiments with immunodeficient mice have demonstrated that the immune system may exert a strong selective pressure on the cancer cells. By using the chemical carcinogen methylcholanthrene, sarcomas were induced either in wild-type mice or in RAG2-deficient mice, which lack both T and B cells (18). When transplanted into RAG2-deficient mice, all sarcomas grew progressively with equivalent kinetics. In contrast, when the tumor cells were injected into immunocompetent wild-type hosts, all sarcomas from wild-type mice grew progressively, while 8 of 20 (40%) sarcomas from RAG2-deficient mice were rejected (18). These data strongly suggest that in wild-type mice, there was selection of tumor cells that were more capable of surviving in an immunocompetent host. This provides an explanation for the apparent paradox of tumor formation in immunologically intact individuals. Based on these findings, Robert Schreiber and coworkers introduced the term “cancer immunoediting,” which was further developed into a general theory, to describe the sculpting actions of the immune response on developing tumors in immunocompetent individuals (18, 79).
Lymphocytes Bearing the NKG2D Receptor are Able to Recognize and Eliminate Stressed Premalignant Cells
NK cells are innate lymphocytes that can kill malignant or infected cells. All NK cells and some T cells express the NKG2D molecule on the cell surface. NKG2D is an activating receptor, which serves as a major recognition receptor for detection and elimination of transformed cells (80). The ligands for NKG2D are self proteins that are poorly expressed by normal resting cells but upregulated on the surface of stressed cells. NKG2D ligands in humans include MICA, MICB, and six different ULBP proteins (81). In mice, NKG2D ligands include MULT1, five isoforms of RAE-1, and three isoforms of the H60 proteins (82). In humans, cells that express NKG2D ligands may be recognized and killed by either NK cells or γδ T cells in a process called lymphoid stress surveillance (83).
NKG2D ligands were shown to be upregulated in normal cells after treatment with DNA-damaging agents like ionizing radiations and UV light (84). It was concluded that the DNA damage response, which was known to arrest the cell cycle and enhance DNA repair, may also participate in alerting the immune system to the presence of potentially dangerous cells (84). Several studies suggested that expression of NKG2D ligands on transformed cells may be directly induced by oncogenes. For example, the BCR-ABL fusion oncogene was reported to control the expression of MICA in chronic myelogenous leukemia cells at the posttranscriptional level (85). Activation of the Ras oncogene was shown to upregulate the expression of RAE-1α/β in mouse cells, and ULBP1–3 and MICA/B in human cells (86). In a recent study, surface upregulation of NKG2D ligands by human epithelial cells in response to UV irradiation, osmotic shock, or oxidative stress, was shown to depend on the activation of the epidermal growth factor receptor (EGFR) (87). The EGFR pathway is frequently dysregulated in human cancer and it was proposed that activation of EGFR may regulate the immunological visibility of stressed premalignant cells (87). Surprisingly, several isoforms of RAE-1, like RAE-1ε, were found to be expressed not only by cancer cells, but also by some normal proliferating cells such as fibroblasts (88). The E2F transcription factor, which controls cell cycle entry, was shown to regulate RAE-1ε expression. These data suggest that NKG2D-bearing lymphocytes may control the proliferation of both normal and malignant cells (88).
MICA and MICB were found to be expressed by many, but not all, freshly isolated carcinomas of the lung, breast, kidney, ovary, prostate, colon, and liver (89, 90). Moreover, in vitro studies revealed that MICA and MICB contributed to the lysis of hepatocellular carcinoma cells by NK cells (90). The importance of NKG2D for cancer immunosurveillance in vivo gained support from experiments showing that cancer cells transfected with NKG2D ligands and injected into mice were rapidly rejected by NK cells and by CD8+ T cells (91, 92). Moreover, neutralization of NKG2D with blocking monoclonal antibodies rendered mice more susceptible to carcinogen-induced fibrocarcinoma (93). Gene-targeted mice deficient for NKG2D were shown to be more susceptible to the in situ development of prostate adenocarcinoma and B cell lymphoma (94). In humans, an association has been reported between polymorphisms of the NKG2D gene and susceptibility of developing liver and cervix cancers, supporting a protective role of NKG2D against these malignancies (95, 96). Thus, the expression of stress-induced endogenous molecules associated with cell transformation is used by the immune system to recognize and eliminate premalignant cells in mice and humans.
Promising Novel Strategy to Treat Cancer Consists in Potentiating the Naturally Occurring Immune Response of the Patient Through Blockade of Immune Checkpoint Molecules
Activation of a naïve T cell requires at least two signals: T cell receptor-mediated recognition of a cognate antigen (signal 1) and engagement of the costimulatory receptor CD28 (signal 2). Once activated, T cells upregulate on the cell surface two co-inhibitory molecules, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programed death 1 (PD-1). The function of these co-inhibitory molecules is to tightly regulate the immune response by containing excessive T cell activation. For the purpose of cancer immunotherapy, monoclonal antibodies have been generated to potentiate the ongoing antitumor immune response of the patient, through “immune checkpoint blockade” of CTLA-4, PD-1, or PD-1 ligand (PD-L1). The outcome of the initial clinical trials with these new treatments is remarkable (97).
In a phase 3, randomized trial, the CTLA-4 blocking antibody ipilimumab was shown to prolong survival of patients with previously treated metastatic melanoma by ~4 months (98). This was a breakthrough in the treatment of metastatic melanoma because no other therapy had previously been shown to prolong survival in a phase 3 controlled trial. Another phase 3 trial with previously untreated metastatic melanoma patients showed that the overall survival was significantly longer in the group receiving ipilimumab combined with the chemotherapy drug dacarbazine than in the group receiving dacarbazine plus placebo (11 vs. 9 months) (99). Moreover, higher survival rates after 3 years were observed in the ipilimumab–dacarbazine group compared to controls (21 vs. 12%) (99).
Although no phase 3 trial has yet been published based on PD-1 or PD-L1 blockade, phase 1 studies showed promising results. PD-1 checkpoint blockade was tested in a phase 1 trial on patients with several types of advanced cancer. Cumulative response rates (complete or partial responses) were 18% among patients with non-small cell lung cancer (14 of 76 patients), 28% among patients with melanoma (26 of 94 patients), and 27% among patients with renal-cell cancer (9 of 33 patients). Responses were durable, 20 of 31 responses lasting 1 year or more in patients with 1 year or more of follow-up (100). In a phase 1 trial with anti-PD-L1 blocking antibodies, an objective response (complete or partial response) was observed in 9 of 52 patients with melanoma, 2 of 17 with renal-cell cancer, and 5 of 49 with non-small cell lung cancer. Responses lasted for 1 year or more in 8 of 16 patients with at least 1 year of follow-up (101). Finally, combined treatment of advanced melanoma was performed with both anti-CTLA-4 and anti-PD-1 blocking antibodies in a phase 1 trial. The objective response rate for all 53 treated patients in the concurrent-regimen group was as high as 40% (102). Thus, immune checkpoint blockade represents a promising new strategy to treat advanced cancer in humans. The success of this approach, which is based on potentiating the ongoing, naturally occurring antitumor immune response of the patient, provides another piece of evidence that fighting cancer is indeed a primary function of the immune system.
As summarized in this review, the scientific literature over the past 50 years has provided strong support to the cancer immunosurveillance hypothesis. Thus, it appears that our immune system does not only naturally protect us against infectious non-self (pathogens) but also against malignant self (cancer). Many cell types belonging to both the innate (NK cells and macrophages) and the adaptive (T and B cells) immune systems seem to be involved in cancer control. Our current understanding on how the immune system fights cancer remains very fragmentary. There are pieces of evidence for two main strategies used by the immune system to distinguish cancer cells from normal cells. On one hand, the adaptive immune system recognizes altered (mutated) self proteins in malignant cells. On the other hand, NK cells and γδ T cells recognize stress-induced self molecules (NKG2D ligands) on transformed cells. Yet, cancer cells originate from normal cells and a main challenge for successful antitumor immunity is to restrain the destruction of normal cells (autoimmunity). In fact, a recent study suggested that autoimmune disease may occur as a result of an inaccurate antitumor immune response (103). Scleroderma is an autoimmune connective tissue disease in which patients make antibodies to a limited number of autoantigens, including the RNA polymerase III subunit, encoded by the POLR3A gene. In several patients who had both scleroderma and cancer, genetic alterations of the POLR3A locus were found in the malignant cells, suggesting that POLR3A mutations triggered an adaptive antitumor immune response, which cross-reacted with normal tissue, causing autoimmune disease (103).
Conflict of Interest Statement
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
I thank Inger Øynebråten for critical reading of the manuscript. This work was supported by grants from the Research Council of Norway, the Southern and Eastern Norway Regional Health Authority, the Norwegian Cancer Society, Anders Jahre fund, and Henrik Homans Minde fund.
1. Burnet FM. The concept of immunological surveillance. Prog Exp Tumor Res (1970) 13:1–27 [PubMed] [Google Scholar]
2. Burnet M. Cancer: a biological approach. III. Viruses associated with neoplastic conditions. IV. Practical applications. Br Med J (1957) 1:841–710.1136/bmj.1.5023.841 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
3. Thomas L. Discussion. In: Lawrence HS, editor. editor. Cellular and Humoral Aspects of the Hypersensitive States. New York: Hoeber-Harper; (1959). p. 529–32 [Google Scholar]
4. Thomas L. On immunosurveillance in human cancer. Yale J Biol Med (1982) 55:329–33 [PMC free article] [PubMed] [Google Scholar]
5. Senovilla L, Vitale I, Martins I, Tailler M, Pailleret C, Michaud M, et al. An immunosurveillance mechanism controls cancer cell ploidy. Science (2012) 337:1678–8410.1126/science.1224922 [PubMed] [CrossRef] [Google Scholar]
6. Smyth MJ, Godfrey DI, Trapani JA. A fresh look at tumor immunosurveillance and immunotherapy. Nat Immunol (2001) 2:293–910.1038/86297 [PubMed] [CrossRef] [Google Scholar]
7. Fuchs EJ, Matzinger P. Is cancer dangerous to the immune system? Semin Immunol (1996) 8:271–8010.1006/smim.1996.0035 [PubMed] [CrossRef] [Google Scholar]
8. Willimsky G, Blankenstein T. Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance. Nature (2005) 437:141–610.1038/nature03954 [PubMed] [CrossRef] [Google Scholar]
9. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet (2001) 357:539–4510.1016/S0140-6736(00)04046-0 [PubMed] [CrossRef] [Google Scholar]
10. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature (2008) 454:436–4410.1038/nature07205 [PubMed] [CrossRef] [Google Scholar]
11. Gatti RA, Good RA. Occurrence of malignancy in immunodeficiency diseases. A literature review. Cancer (1971) 28:89–9810.1002/1097-0142(197107)28:1<89::AID-CNCR2820280117>3.0.CO;2- Q [PubMed] [CrossRef] [Google Scholar]
12. Kinlen LJ, Webster AD, Bird AG, Haile R, Peto J, Soothill JF, et al. Prospective study of cancer in patients with hypogammaglobulinemia. Lancet (1985) 1:263–610.1016/S0140-6736(85)91037-2 [PubMed] [CrossRef] [Google Scholar]
13. Salavoura K, Kolialexi A, Tsangaris G, Mavrou A. Development of cancer in patients with primary immunodeficiencies. Anticancer Res (2008) 28:1263–9 [PubMed] [Google Scholar]
14. van der Meer JW, Weening RS, Schellekens PT, van Munster IP, Nagengast FM. Colorectal cancer in patients with X-linked agammaglobulinemia. Lancet (1993) 341:1439–4010.1016/0140-6736(93)90883-I [PubMed] [CrossRef] [Google Scholar]
15. Mueller BU, Pizzo PA. Cancer in children with primary or secondary immunodeficiencies. J Pediatr (1995) 126:1–1010.1016/S0022-3476(95)70491-4 [PubMed] [CrossRef] [Google Scholar]
16. Hayward AR, Levy J, Facchetti F, Notarangelo L, Ochs HD, Etzioni A, et al. Cholangiopathy and tumors of the pancreas, liver, and biliary tree in boys with X-linked immunodeficiency with hyper-IgM. J Immunol (1997) 158:977–83 [PubMed] [Google Scholar]
17. Swann JB, Smyth MJ. Immune surveillance of tumors. J Clin Invest (2007) 117:1137–4610.1172/JCI31405 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
18. Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ, et al. IFN gamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature (2001) 410:1107–1110.1038/35074122 [PubMed] [CrossRef] [Google Scholar]
19. Girardi M, Oppenheim DE, Steele CR, Lewis JM, Glusac E, Filler R, et al. Regulation of cutaneous malignancy by gammadelta T cells. Science (2001) 294:605–910.1126/science.1063916 [PubMed] [CrossRef] [Google Scholar]
20. Dunn GP, Bruce AT, Sheehan KC, Shankaran V, Uppaluri R, Bui JD, et al. A critical function for type I interferons in cancer immunoediting. Nat Immunol (2005) 6:722–910.1038/ni1213 [PubMed] [CrossRef] [Google Scholar]
21. Kaplan DH, Shankaran V, Dighe AS, Stockert E, Aguet M, Old LJ, et al. Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. Proc Natl Acad Sci U S A (1998) 95:7556–6110.1073/pnas.95.13.7556 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
22. Street SE, Trapani JA, MacGregor D, Smyth MJ. Suppression of lymphoma and epithelial malignancies effected by interferon gamma. J Exp Med (2002) 196:129–3410.1084/jem.20020063 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
23. Smyth MJ, Thia KY, Street SE, MacGregor D, Godfrey DI, Trapani JA. Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma. J Exp Med (2000) 192:755–6010.1084/jem.192.5.755 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
24. Calne RY, White DJ, Thiru S, Evans DB, McMaster P, Dunn DC, et al. Cyclosporin A in patients receiving renal allografts from cadaver donors. Lancet (1978) 2:1323–710.1016/S0140-6736(78)91970-0 [PubMed] [CrossRef] [Google Scholar]
25. Hoover R, Fraumeni JF., Jr Risk of cancer in renal-transplant recipients. Lancet (1973) 2:55–710.1016/S0140-6736(73)93256-X [PubMed] [CrossRef] [Google Scholar]
26. Birkeland SA, Storm HH, Lamm LU, Barlow L, Blohme I, Forsberg B, et al. Cancer risk after renal transplantation in the Nordic countries, 1964-1986. Int J Cancer (1995) 60:183–910.1002/ijc.2910600209 [PubMed] [CrossRef] [Google Scholar]
27. Opelz G, Dohler B. Lymphomas after solid organ transplantation: a collaborative transplant study report. Am J Transplant (2004) 4:222–3010.1111/j.1600-6143.2004.00451.x [PubMed] [CrossRef] [Google Scholar]
28. List AF, Greco FA, Vogler LB. Lymphoproliferative diseases in immunocompromised hosts: the role of Epstein-Barr virus. J Clin Oncol (1987) 5: 1673–89 [PubMed] [Google Scholar]
29. Leblond V, Davi F, Charlotte F, Dorent R, Bitker MO, Sutton L, et al. Posttransplant lymphoproliferative disorders not associated with Epstein-Barr virus: a distinct entity? J Clin Oncol (1998) 16:2052–9 [PubMed] [Google Scholar]
30. Engels EA, Pfeiffer RM, Fraumeni JF, Jr, Kasiske BL, Israni AK, Snyder JJ, et al. Spectrum of cancer risk among US solid organ transplant recipients. JAMA (2011) 306:1891–90110.1001/jama.2011.1592 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
31. Bouwes Bavinck JN, Hardie DR, Green A, Cutmore S, MacNaught A, O’Sullivan B, et al. The risk of skin cancer in renal transplant recipients in Queensland, Australia. A follow-up study. Transplantation (1996) 61:715–2110.1097/00007890-199603150-00008 [PubMed] [CrossRef] [Google Scholar]
32. Krynitz B, Edgren G, Lindelof B, Baecklund E, Brattstrom C, Wilczek H, et al. Risk of skin cancer and other malignancies in kidney, liver, heart and lung transplant recipients 1970 to 2008 – a Swedish population-based study. Int J Cancer (2013) 132:1429–3810.1002/ijc.27765 [PubMed] [CrossRef] [Google Scholar]
33. Ramsay HM, Fryer AA, Hawley CM, Smith AG, Harden PN. Non-melanoma skin cancer risk in the Queensland renal transplant population. Br J Dermatol (2002) 147:950–610.1046/j.1365-2133.2002.04976.x [PubMed] [CrossRef] [Google Scholar]
34. Schulz TF. Cancer and viral infections in immunocompromised individuals. Int J Cancer (2009) 125:1755–6310.1002/ijc.24741 [PubMed] [CrossRef] [Google Scholar]
35. Clifford GM, Polesel J, Rickenbach M, Dal Maso L, Keiser O, Kofler A, et al. Cancer risk in the Swiss HIV Cohort Study: associations with immunodeficiency, smoking, and highly active antiretroviral therapy. J Natl Cancer Inst (2005) 97:425–3210.1093/jnci/dji072 [PubMed] [CrossRef] [Google Scholar]
36. Shiels MS, Cole SR, Kirk GD, Poole C. A meta-analysis of the incidence of non-AIDS cancers in HIV-infected individuals. J Acquir Immune Defic Syndr (2009) 52:611–2210.1097/QAI.0b013e3181b327ca [PMC free article] [PubMed] [CrossRef] [Google Scholar]
37. Sigel K, Wisnivesky J, Gordon K, Dubrow R, Justice A, Brown ST, et al. HIV as an independent risk factor for incident lung cancer. AIDS (2012) 26:1017–2510.1097/QAD.0b013e328352d1ad [PMC free article] [PubMed] [CrossRef] [Google Scholar]
38. Guiguet M, Boue F, Cadranel J, Lang JM, Rosenthal E, Costagliola D. Effect of immunodeficiency, HIV viral load, and antiretroviral therapy on the risk of individual malignancies (FHDH-ANRS CO4): a Prospective Cohort Study. Lancet Oncol (2009) 10:1152–910.1016/S1470-2045(09)70282-7 [PubMed] [CrossRef] [Google Scholar]
39. Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer (2012) 12:298–30610.1038/nrc3245 [PubMed] [CrossRef] [Google Scholar]
40. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science (2006) 313:1960–410.1126/science.1129139 [PubMed] [CrossRef] [Google Scholar]
41. Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med (2003) 348:203–1310.1056/NEJMoa020177 [PubMed] [CrossRef] [Google Scholar]
42. Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund LT. Prognostic effect of epithelial and stromal lymphocyte infiltration in non-small cell lung cancer. Clin Cancer Res (2008) 14:5220–710.1158/1078-0432.CCR-08-0133 [PubMed] [CrossRef] [Google Scholar]
43. Kawai O, Ishii G, Kubota K, Murata Y, Naito Y, Mizuno T, et al. Predominant infiltration of macrophages and CD8(+) T Cells in cancer nests is a significant predictor of survival in stage IV nonsmall cell lung cancer. Cancer (2008) 113:1387–9510.1002/cncr.23712 [PubMed] [CrossRef] [Google Scholar]
44. Mahmoud SM, Paish EC, Powe DG, Macmillan RD, Grainge MJ, Lee AH, et al. Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J Clin Oncol (2011) 29:1949–5510.1200/JCO.2010.30.5037 [PubMed] [CrossRef] [Google Scholar]
45. Naito Y, Saito K, Shiiba K, Ohuchi A, Saigenji K, Nagura H, et al. CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res (1998) 58:3491–4 [PubMed] [Google Scholar]
46. Cho Y, Miyamoto M, Kato K, Fukunaga A, Shichinohe T, Kawarada Y, et al. CD4+ and CD8+ T cells cooperate to improve prognosis of patients with esophageal squamous cell carcinoma. Cancer Res (2003) 63:1555–9 [PubMed] [Google Scholar]
47. Hiraoka K, Miyamoto M, Cho Y, Suzuoki M, Oshikiri T, Nakakubo Y, et al. Concurrent infiltration by CD8+ T cells and CD4+ T cells is a favourable prognostic factor in non-small-cell lung carcinoma. Br J Cancer (2006) 94:275–8010.1038/sj.bjc.6602934 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
48. Budhu A, Forgues M, Ye QH, Jia HL, He P, Zanetti KA, et al. Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment. Cancer Cell (2006) 10:99–11110.1016/j.ccr.2006.06.016 [PubMed] [CrossRef] [Google Scholar]
49. Kristensen VN, Vaske CJ, Ursini-Siegel J, Van Loo P, Nordgard SH, Sachidanandam R, et al. Integrated molecular profiles of invasive breast tumors and ductal carcinoma in situ (DCIS) reveal differential vascular and interleukin signaling. Proc Natl Acad Sci U S A (2012) 109:2802–710.1073/pnas.1108781108 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
50. Rusakiewicz S, Semeraro M, Sarabi M, Desbois M, Locher C, Mendez R, et al. Immune infiltrates are prognostic factors in localized gastrointestinal stromal tumors. Cancer Res (2013) 73:3499–51010.1158/0008-5472.CAN-13-0371 [PubMed] [CrossRef] [Google Scholar]
51. Forssell J, Oberg A, Henriksson ML, Stenling R, Jung A, Palmqvist R. High macrophage infiltration along the tumor front correlates with improved survival in colon cancer. Clin Cancer Res (2007) 13:1472–910.1158/1078-0432.CCR-06-2073 [PubMed] [CrossRef] [Google Scholar]
52. Kim DW, Min HS, Lee KH, Kim YJ, Oh DY, Jeon YK, et al. High tumour islet macrophage infiltration correlates with improved patient survival but not with EGFR mutations, gene copy number or protein expression in resected non-small cell lung cancer. Br J Cancer (2008) 98:1118–2410.1038/sj.bjc.6604256 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
53. Shimura S, Yang G, Ebara S, Wheeler TM, Frolov A, Thompson TC. Reduced infiltration of tumor-associated macrophages in human prostate cancer: association with cancer progression. Cancer Res (2000) 60:5857–61 [PubMed] [Google Scholar]
54. Welsh TJ, Green RH, Richardson D, Waller DA, O’Byrne KJ, Bradding P. Macrophage and mast-cell invasion of tumor cell islets confers a marked survival advantage in non-small-cell lung cancer. J Clin Oncol (2005) 23:8959–6710.1200/JCO.2005.01.4910 [PubMed] [CrossRef] [Google Scholar]
55. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Jr, Kinzler KW. Cancer genome landscapes. Science (2013) 339:1546–5810.1126/science.1235122 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
56. Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science (2008) 321:1801–610.1126/science.1164368 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
57. Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, et al. An integrated genomic analysis of human glioblastoma multiforme. Science (2008) 321:1807–1210.1126/science.1164382 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
58. Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, et al. The consensus coding sequences of human breast and colorectal cancers. Science (2006) 314:268–7410.1126/science.1133427 [PubMed] [CrossRef] [Google Scholar]
59. Wood LD, Parsons DW, Jones S, Lin J, Sjoblom T, Leary RJ, et al. The genomic landscapes of human breast and colorectal cancers. Science (2007) 318:1108–1310.1126/science.1145720 [PubMed] [CrossRef] [Google Scholar]
60. Govindan R, Ding L, Griffith M, Subramanian J, Dees ND, Kanchi KL, et al. Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell (2012) 150:1121–3410.1016/j.cell.2012.08.024 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
61. Wei X, Walia V, Lin JC, Teer JK, Prickett TD, Gartner J, et al. Exome sequencing identifies GRIN2A as frequently mutated in melanoma. Nat Genet (2011) 43:442–610.1038/ng.810 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
62. Wang RF, Wang X, Atwood AC, Topalian SL, Rosenberg SA. Cloning genes encoding MHC class II-restricted antigens: mutated CDC27 as a tumor antigen. Science (1999) 284:1351–410.1126/science.284.5418.1351 [PubMed] [CrossRef] [Google Scholar]
63. Wang RF, Wang X, Rosenberg SA. Identification of a novel major histocompatibility complex class II-restricted tumor antigen resulting from a chromosomal rearrangement recognized by CD4(+) T cells. J Exp Med (1999) 189:1659–6810.1084/jem.189.10.1659 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
64. Saeterdal I, Bjorheim J, Lislerud K, Gjertsen MK, Bukholm IK, Olsen OC, et al. Frameshift-mutation-derived peptides as tumor-specific antigens in inherited and spontaneous colorectal cancer. Proc Natl Acad Sci U S A (2001) 98:13255–6010.1073/pnas.231326898 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
65. Wolfel T, Hauer M, Schneider J, Serrano M, Wolfel C, Klehmann-Hieb E, et al. A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. Science (1995) 269:1281–410.1126/science.7652577 [PubMed] [CrossRef] [Google Scholar]
66. Echchakir H, Mami-Chouaib F, Vergnon I, Baurain JF, Karanikas V, Chouaib S, et al. A point mutation in the alpha-actinin-4 gene generates an antigenic peptide recognized by autologous cytolytic T lymphocytes on a human lung carcinoma. Cancer Res (2001) 61:4078–83 [PubMed] [Google Scholar]
67. Hogan KT, Eisinger DP, Cupp SB, III, Lekstrom KJ, Deacon DD, Shabanowitz J, et al. The peptide recognized by HLA-A68.2-restricted, squamous cell carcinoma of the lung-specific cytotoxic T lymphocytes is derived from a mutated elongation factor 2 gene. Cancer Res (1998) 58:5144–50 [PubMed] [Google Scholar]
68. Karanikas V, Colau D, Baurain JF, Chiari R, Thonnard J, Gutierrez-Roelens I, et al. High frequency of cytolytic T lymphocytes directed against a tumor-specific mutated antigen detectable with HLA tetramers in the blood of a lung carcinoma patient with long survival. Cancer Res (2001) 61: 3718–24 [PubMed] [Google Scholar]
69. Clark RE, Dodi IA, Hill SC, Lill JR, Aubert G, Macintyre AR, et al. Direct evidence that leukemic cells present HLA-associated immunogenic peptides derived from the BCR-ABL b3a2 fusion protein. Blood (2001) 98:2887–9310.1182/blood.V98.10.2887 [PubMed] [CrossRef] [Google Scholar]
70. Sahin U, Tureci O, Schmitt H, Cochlovius B, Johannes T, Schmits R, et al. Human neoplasms elicit multiple specific immune responses in the autologous host. Proc Natl Acad Sci U S A (1995) 92:11810–310.1073/pnas.92.25.11810 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
71. Scanlan MJ, Chen YT, Williamson B, Gure AO, Stockert E, Gordan JD, et al. Characterization of human colon cancer antigens recognized by autologous antibodies. Int J Cancer (1998) 76:652–810.1002/(SICI)1097-0215(19980529)76:5<652::AID-IJC7>3.3.CO;2-9 [PubMed] [CrossRef] [Google Scholar]
72. Garrido F, Ruiz-Cabello F, Cabrera T, Perez-Villar JJ, Lopez-Botet M, Duggan-Keen M, et al. Implications for immunosurveillance of altered HLA class I phenotypes in human tumours. Immunol Today (1997) 18:89–9510.1016/S0167-5699(96)10075-X [PubMed] [CrossRef] [Google Scholar]
73. D’Urso CM, Wang ZG, Cao Y, Tatake R, Zeff RA, Ferrone S. Lack of HLA class I antigen expression by cultured melanoma cells FO-1 due to a defect in B2m gene expression. J Clin Invest (1991) 87:284–9210.1172/JCI114984 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
74. Perez B, Benitez R, Fernandez MA, Oliva MR, Soto JL, Serrano S, et al. A new beta 2 microglobulin mutation found in a melanoma tumor cell line. Tissue Antigens (1999) 53:569–7210.1034/j.1399-0039.1999.530607.x [PubMed] [CrossRef] [Google Scholar]
75. Jimenez P, Canton J, Collado A, Cabrera T, Serrano A, Real LM, et al. Chromosome loss is the most frequent mechanism contributing to HLA haplotype loss in human tumors. Int J Cancer (1999) 83:91–710.1002/(SICI)1097-0215(19990924)83:1<91::AID-IJC17>3.0.CO;2-4 [PubMed] [CrossRef] [Google Scholar]
76. Lawrence MS, Stojanov P, Mermel CH, Robinson JT, Garraway LA, Golub TR, et al. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature (2014) 505:495–50110.1038/nature12912 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
77. Lippitz BE. Cytokine patterns in patients with cancer: a systematic review. Lancet Oncol (2013) 14:e218–2810.1016/S1470-2045(12)70582-X [PubMed] [CrossRef] [Google Scholar]
78. Principe DR, Doll JA, Bauer J, Jung B, Munshi HG, Bartholin L, et al. TGF-beta: duality of function between tumor prevention and carcinogenesis. J Natl Cancer Inst (2014) 106:djt369.10.1093/jnci/djt369 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
79. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol (2002) 3:991–810.1038/ni1102-991 [PubMed] [CrossRef] [Google Scholar]
80. Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, et al. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science (1999) 285:727–910.1126/science.285.5428.727 [PubMed] [CrossRef] [Google Scholar]
81. Groh V, Bahram S, Bauer S, Herman A, Beauchamp M, Spies T. Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium. Proc Natl Acad Sci U S A (1996) 93:12445–5010.1073/pnas.93.22.12445 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
82. Raulet DH, Gasser S, Gowen BG, Deng W, Jung H. Regulation of ligands for the NKG2D activating receptor. Annu Rev Immunol (2013) 31:413–4110.1146/annurev-immunol-032712-095951 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
83. Shafi S, Vantourout P, Wallace G, Antoun A, Vaughan R, Stanford M, et al. An NKG2D-mediated human lymphoid stress surveillance response with high interindividual variation. Sci Transl Med (2011) 3:113ra124.10.1126/scitranslmed.3002922 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
84. Gasser S, Orsulic S, Brown EJ, Raulet DH. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature (2005) 436:1186–9010.1038/nature03884 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
85. Boissel N, Rea D, Tieng V, Dulphy N, Brun M, Cayuela JM, et al. BCR/ABL oncogene directly controls MHC class I chain-related molecule A expression in chronic myelogenous leukemia. J Immunol (2006) 176:5108–1610.4049/jimmunol.176.8.5108 [PubMed] [CrossRef] [Google Scholar]
86. Liu XV, Ho SS, Tan JJ, Kamran N, Gasser S. Ras activation induces expression of Raet1 family NK receptor ligands. J Immunol (2012) 189:1826–3410.4049/jimmunol.1200965 [PubMed] [CrossRef] [Google Scholar]
87. Vantourout P, Willcox C, Turner A, Swanson CM, Haque Y, Sobolev O, et al. Immunological visibility: posttranscriptional regulation of human NKG2D ligands by the EGF receptor pathway. Sci Transl Med (2014) 6:231ra249.10.1126/scitranslmed.3007579 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
88. Jung H, Hsiung B, Pestal K, Procyk E, Raulet DH. RAE-1 ligands for the NKG2D receptor are regulated by E2F transcription factors, which control cell cycle entry. J Exp Med (2012) 209:2409–2210.1084/jem.20120565 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
89. Groh V, Rhinehart R, Secrist H, Bauer S, Grabstein KH, Spies T. Broad tumor-associated expression and recognition by tumor-derived gamma delta T cells of MICA and MICB. Proc Natl Acad Sci U S A (1999) 96:6879–8410.1073/pnas.96.12.6879 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
90. Jinushi M, Takehara T, Tatsumi T, Kanto T, Groh V, Spies T, et al. Expression and role of MICA and MICB in human hepatocellular carcinomas and their regulation by retinoic acid. Int J Cancer (2003) 104:354–6110.1002/ijc.10966 [PubMed] [CrossRef] [Google Scholar]
91. Cerwenka A, Baron JL, Lanier LL. Ectopic expression of retinoic acid early inducible-1 gene (RAE-1) permits natural killer cell-mediated rejection of a MHC class I-bearing tumor in vivo. Proc Natl Acad Sci U S A (2001) 98:11521–610.1073/pnas.201238598 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
92. Diefenbach A, Jensen ER, Jamieson AM, Raulet DH. RAE1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Nature (2001) 413:165–7110.1038/35093109 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
93. Smyth MJ, Swann J, Cretney E, Zerafa N, Yokoyama WM, Hayakawa Y. NKG2D function protects the host from tumor initiation. J Exp Med (2005) 202:583–810.1084/jem.20050994 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
94. Guerra N, Tan YX, Joncker NT, Choy A, Gallardo F, Xiong N, et al. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Immunity (2008) 28:571–8010.1016/j.immuni.2008.02.016 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
95. Chen D, Juko-Pecirep I, Hammer J, Ivansson E, Enroth S, Gustavsson I, et al. Genome-wide association study of susceptibility loci for cervical cancer. J Natl Cancer Inst (2013) 105:624–3310.1093/jnci/djt051 [PubMed] [CrossRef] [Google Scholar]
96. Melum E, Karlsen TH, Schrumpf E, Bergquist A, Thorsby E, Boberg KM, et al. Cholangiocarcinoma in primary sclerosing cholangitis is associated with NKG2D polymorphisms. Hepatology (2008) 47:90–610.1002/hep.21964 [PubMed] [CrossRef] [Google Scholar]
97. Couzin-Frankel J. Breakthrough of the year 2013. Cancer immunotherapy. Science (2013) 342:1432–310.1126/science.342.6165.1432 [PubMed] [CrossRef] [Google Scholar]
98. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med (2010) 363:711–2310.1056/NEJMoa1003466 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
99. Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med (2011) 364:2517–2610.1056/NEJMoa1104621 [PubMed] [CrossRef] [Google Scholar]
100. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med (2012) 366:2443–5410.1056/NEJMoa1200690 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
101. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med (2012) 366:2455–6510.1056/NEJMoa1200694 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
102. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med (2013) 369:122–3310.1056/NEJMoa1302369 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
103. Joseph CG, Darrah E, Shah AA, Skora AD, Casciola-Rosen LA, Wigley FM, et al. Association of the autoimmune disease scleroderma with an immunologic response to cancer. Science (2014) 343:152–710.1126/science.1246886 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
"The maintenance of secrets acts like a psychic poison which alienates the possessor from the community" Carl Jung
Joined: 25 Jul 2005
Location: St. Pauls, Bristol, England
|Posted: Sun Aug 04, 2019 11:51 pm Post subject:
|The NHS appear to kill 200,000 a year
We have heard that the MHRA ruthlessly stopped the production of GcMAF in England, 9 months ago on the 28th January 2015.
GcMAF is the body’s way of curing cancer, a human protein all of us make, and a human right; it has no side effects. It is the best treatment known for tumour cancers, which is 90% of them, and 50 other diseases. People with disease can’t make it, and need external GcMAF to cure their diseases. It was discovered in 1990, and the MHRA has conspired to conceal it from the public since then.
300 scientists have written over 150 scientific research papers on GcMAF, and Immuno Biotech Ltd had supplied 11,000 people, with fabulous results before the MHRA closed them down.
As the regulatory agency the MHRA’s remit is to support new treatments; they should have helped Immuno Biotech Ltd (IBL) to get the product into the NHS as soon as possible.
But they abused their position, to protect the profits of the big pharmaceutical companies that they illegally represent. They have big pharma on their board.
Instead of making a telephone call to arrange a meeting, the MHRA raided IBL’s Cambridge laboratory with 8 police, 4 in bullet proof vests, interrogated and terrorised the two female scientists who were on duty for eight hours. They were so traumatised they could not work for months afterwards.
They closed Immuno Biotech’s bank accounts using the illegal compliance system (see Legal abuse above), and the company was forced to cease trading.
They closed the CEO’s bank accounts and left him penniless. They are now doing that to members of his family.
On their website they published 18 fraudulent misrepresentations about IBL’s excellent sterility record.
Thirty Three major persecutions, no prosecution for almost 4 years
To avoid prosecuting Immuno Biotech, and its a simple case, the MHRA have persecuted them with 33 attacks, wasting millions in public money:
The MHRA’s Andrew Graham committed perjury and fraudulent misrepresentation in his witness statement to Canterbury Crown court to obtain a Restraint Order (RO). One lie is that all IBL’s benevolent income is proceeds of crime.
The Restraint Order closed Immuno Biotech and its bank accounts and left them penniless.
18 fraudulent misrepresentation about IBL’s excellent sterility on the MHRA website
Forced Wickham Laboratories Ltd to retrospectively downgrade the independent part of IBL’s sterility results
The RO closed their team of four scientists, who had been carrying out scientific research into many diseases, including those of the brain, publishing the results in 33 research papers and winning scientific awards.
The RO forced them to jump through hoops to keep saving lives on a smaller scale overseas.
It got their clinics closed; they were saving 4 lives per clinic every month – those people are now dying.
Got their 3 doctors fired.
The MHRA carried out 14 raids on IBL with 100 officers, traumatising their staff, some more than once.
Arrested 5 staff.
The MHRA contacted France, who arrested David Halsall; he is still in a French prison with no hope of getting out. The French then put out a European Arrest Warrant for David Noakes and his girlfriend, a biomedical scientist. If they are extradited they too will will be in an appalling French prison for up to 2.4 years awaiting trial. He’s 64 with high blood pressure now 190/110, He has diabetes, and will probably not make it. French prisons and human rights are appalling. And the MHRA won’t have to prosecute – a perfect solution for them.
The MHRA have put David in a number of prison cells, the latest Wandsworth Prison, they’ve put him on bail twice at the same time, with strict bail conditions.
Staff now have to watch patients dying because the MHRA has closed them down and they can’t treat them.
All 27 staff were forced to leave.
The RO and the MHRA have made their lives a living hell. Two staff have had mental breakdowns.
This persecution, and the MHRA’s criminal killing of 110,000 a year, are not reasonable actions. The are the actions of psychopaths. Some of those responsible are Ian Hudson, Gerald Heddell, Archibald Cox, Jeff Clements, and Andrew Graham. None of these are fit for public office, and should face prosecution for the deaths they cause. Their salaries really are proceeds of crime.
By denying the public an excellent treatment, GcMAF, that saves lives, the MHRA have committed a crime against humanity. 160,000 people a year die unnecessarily in Britain from cancer; 110,000 could be saved.
Finally the MHRA are prosecuting 5 people for “Making a medicine without a licence” on November 19th 2018 at Southwark Crown Court London. This is a strict liability charge, meansing you can only plead guilty and cannot have a jury.
In the EU nation of Britain, judges illegally subject us to corpus juris, not common law; the ignore the British Constitution. You really are guilty, and may never get the chance to prove you are innocent. Innocent unless proven guilty has gone.
Judge Heather Norton
The MHRA chose Canterbury Court, and its senior judge Heather Norton, to seize all of IBL’s assets and to close its bank account with a Restraint Order. Why did the MHRA chose Canterbury, miles away from its bases in Manchester and London? Did they know they could control a judge, or get a biased one?
Judge Heather Norton ignored the obvious multiple perjuries in Andrew Graham’s witness statement on behalf of the MHRA. The most obvious of which was “David Noakes has evaded income tax in the UK.” He then states David’s address as Fort George, Guernsey. As Andrew Graham and Heather Norton know full well, Guernsey is an indepenent nation and its residents do not pay UK income tax. (And David had just voluntarily paid £110,000, the maximum tax cap, in a payment to the Inland Revenue of Guernsey for one year’s income tax.) Judge Heather Norton went along with this perjuries.
The Judge ignored the fact that 11 public bodies have reported the MHRA is corrupt – see this website’s home page.
Norton also ignored the fact that the two active directors of the MHRA, Ian Hudson, Chairman, and Gerald Heddell, who closed IBL down, are from Big Pharma (Glaxo Smith Kline) in a deadly conflict of interest. It should have been obvious to the dumbest of judges that these men were closing IBL down to protect GSK’s profits. But Judge Heather Norton is not dumb.
It should have been evident to Judge Heather Norton that the guilty parties are the MHRA, who are conspiring with others to defraud the NHS and the British government of £9 Billion annually for drugs that kill, and cause 200,000 deaths as a result.
And it must have been clear to her that IBL, who were using GcMAF, the body’s way of curing cancer without side effects, at one percent the cost of chemotherapy, are a benevolent, honest and philanthropic company.
Judge Heather Norton is clearly either biased and corrupt, or incompetent. But she knows what she’s doing; she’s not incompetent.
By making it impossible for IBL to make progress and get GcMAF into the NHS, Judge Heather Norton’s dishonesty is one of the major causes of 300,000 deaths: The three hundred thousand people who have died unnecessarily of cancer since she first intervened two and a half years ago.
She also is not fit to hold any public office, and should resign.
And be prosecuted for corruption, causing her to have a part in killing 300,000 people.
If you know of other examples of good treatments denied to the British public by the MHRA, please tell us in the posts below.
To disband the MHRA – Sign the Petition here
https://www.change.org/p/house-of-commons-to-disband-the-medicines-and -healthcare-products-regulatory-agency-mhra-a-corrupt-government-body- charged-with-protecting-patients-from-avoidable-harm-in-the-national-h ealth-service-and-in-public-health
ianHudsonIan Hudson, CEO GeraldHeddellGerald Heddell, Director
In a deadly conflict of interest, MHRA directors Ian Hudson and Gerald Heddell are from Glaxo Smith Kline, the world’s second largest pharmaceutical company.
The Medicines and Healthcare Regulatory Agency or MHRA protects the monopolies of the billion dollar pharmaceuticals (who charge, eg. £40,000 for a round of chemotherapy poison), and ruthlessly close down inexpensive, effective treatments wherever it can. Ten public bodies state they are corrupt (see below). The MHRA kills around 200,000 British people a year, and 12,000 have signed the above petition to close them down.
Their crime is a £9 Billion drug fraud; conspiring to defraud the NHS and the British government of £9 Billion, while concealing inexpensive treatments that work, causing 200,000 deaths as a result, the worst kind of fraud.
Its murder for profit. To kill without conscience or remorse requires a psychopathic mentality. Which MHRA board directors are psychopaths?
MHRA3254editDemonstration outside the MHRA’s offices, Victoria, London, 5th July 2016
MHRA Board Hijacked
The MHRA has been hijacked; its board has been infiltrated and is controlled by Big Pharma. This corrupt board has no right to be in charge. They abuse their positions to make the MHRA do the exact opposite of what it was intended for, which was to protect the British from Big Pharma.
Paul Flynn MP, Newport: What credibility does the MHRA have?
Recent events have proven that it is not a watchdog; it is a pussycat that purrs in front of the pharmaceutical industry and does what it is told. It has an incestuous relationship with the big pharmas and has a close association with the Association of the British Pharmaceutical Industry. It has a disgraceful recent record. We can look with gratitude to the work not of the Medicines and Healthcare products Regulatory Agency in protecting the public, but to people such as Sarah Boseley of The Guardian for her exposé of the organisation, to the television programme “Panorama” and to Richard Brook of Mind, who courageously resigned from the MHRA in disgust at its activities.
It is a matter of enormous importance that, in recent history, the regulator is not protecting the 25,000 people who suffered heart attacks and the 7,000 who died from taking a painkilling drug for arthritics that was withdrawn by Merck Sharpe and Dohme in September, after being promoted by the regulator.
The MHRA, the UK Drug Safety Agency, Falsified Vaccine Safety Data – Millions of Children At Serious Risk
Glaxo Smith Kline’s (GSK) Cervarix HPV vaccines for cervical cancer: The MHRA systematically tampered with 6000 reports of adverse reactions to declare the vaccine safe…………The MHRA’s Director Gerald Heddell and CEO Ian Hudson are both ex GSK.
https://childhealthsafety.wordpress.com/2012/10/25/new-research-shows- how-gardasil-and-cervarix-vaccines-can-silently-kill-your-daughters-an d-sons/
House of Commons Health Select Committee Report of 2005
“In view of the failings of the MHRA, we recommend a fundamental review.”
MHRA: Regulators’ trail of deception has been exposed
Andrew Miller, the chairman of a parliamentary select committee, has said that a “trail of deception” has been exposed in the system.
http://www.telegraph.co.uk/news/health/9629337/Faulty-medical-implants -investigation-Regulators-trail-of-deception-has-been-exposed-says-cha irman.html
MHRA under fire amid calls for shake-up of regulatory system:
The scandal of device regulation in the UK
Horton said: “The MHRA’s mission is ‘to enhance and safeguard the health of the public by ensuring that medicines and medical devices work and are acceptably safe’. The MHRA is, by its own admission, unable to fulfil this mission.
MHRA, The Seroxat killer: Parmjit Dhanda, MP, Gloucester
is asking the Government why they allowed Dr Ian Hudson, the MHRA CEO, to take part in the European Medicines Evaluation Agency (EMEA)’s review of Seroxat, an antidepressant. As well as working as worldwide safety director for GSK – the manufacturers of Seroxat (Paxil, Paroxetine)– from 1999 until 2001, Dr Hudson acted as witness for the defence in a trial in which Seroxat was accused of triggering a man’s violent and suicidal behaviour.
MHRA conceals Seroxat causes suicide
“The MHRA had information in its possession for more than a decade that high doses of the anti-depressant Seroxat (Paroxetine) can lead to aggression and thoughts of suicide. But instead of revealing the truth to the 17,000 people taking high doses and the other half-million Britons on a safer dose, the MHRA sat on its findings. Astonishingly, I was actually threatened with legal action by Professor Kent Woods, chief executive of the MHRA, if I revealed this.”
MHRA shreds all its data: Doctor Ben Goldacre, in his book Bad Pharma – Page 80.
The MHRA had shredded all its data on the SSRI antidepressants Fluoxetine and Paroxetine (which cause depression and suicide) even though they had seen many scandals with hidden data. Paroxetine was the largest investigation the MHRA had ever conducted; after 4 years criminal charges were considered against its manufacturer, GSK. But MHRA directors Ian Hudson and Gerald Heddell are both from GSK; the criminal charges never happened.
The MHRA is GlaxoSmithKline, Aventis Pasteur, Merck, Sharpe and Dohme
A Sunday Express investigation found that nearly a third of the 181 experts who sit on the Medicines Control Agency (MCA, now the MHRA) committees are linked to Glaxo Smith Kline, Aventis Pasteur or Merck, Sharpe and Dohme……The MCA has continued to endorse the triple measles, mumps and rubella (MMR) jab despite concerns linking it to autism and stomach disorders. But the extent of the MCA members’ financial ties to MMR manufacturers raises questions about potential conflicts of interest.
Licensed drugs are the number 4 killer of mankind
The MHRA’s big brother, the USA’s FDA, admits drugs, ie those the FDA and MHRA license, kill scores of thousands. That’s what happens when the regulator is controlled by the drug companies. The MHRA conceal this.
The MHRA is infltrated by Big Pharma
“By infiltration the pharmaceutical companies have take over completely the regulation of pharmaceutical medicines in the UK. The most powerful of the groups involved is the Medicines and Healthcare Regulatory Agency, (MHRA), like the CDC, the agency responsible for licensing.” Martin Walker, author, Dirty Medicine.
The MHRA is criticised for failing to adequately regulate implants
with grim consequences for some patients. While the board contains retired senior executives from AstraZeneca and Merck Sharp & Dohme, it includes no one from a patient group, or any other body representing people whose health could be damaged by its decisions.
The web of unelected bodies functions as a kind of shadow government, drafting and enforcing policies, disbursing money, regulating – or failing to regulate – business, quietly, unobtrusively, without effective public scrutiny or restraint. When it is unbalanced, crawling with conflicts of interest, it makes a nonsense of democracy.
Even the courts know the MHRA is corrupt
The MHRA has never successfully prosecuted a company since it was established nearly 10 years ago. (It seems judges won’t accept evidence from so corrupt a source.)
http://www.theguardian.com/business/2012/jul/08/pharma-misbehaviour-gs k-fine -see last paragraph.
The BBC’s Panorama programme is equally damning:
BBC Panorama – The Great Implant Scandal | 26th November
Parliamentary Early day motion 1197; 14th March 2013
That this House calls for reform of the weak Medicines and Healthcare Products Regulatory Agency (MHRA) that is funded by the pharmaceutical industry and repeatedly fails the public interest; is appalled that the 20,000 victims of birth defects arising from the use of sodium valproate (Epilim) have been denied legal aid while American parents have already received compensation; recalls that there were 2,000 victims of Thalidomide in the UK and only 20 in the US; congratulates the US regulator, the Food and Drug Administration that revealed that 60,000 deaths had resulted from the use of the anti-arthritis drug Vioxx while no alarm was registered here because of the MHRA’s defective system of reporting drug side-effects; commends the US’ massive fine on Glaxo Smith Kline of $3.5 billion for suppressing negative results of drug trials while no action has been taken here for identical misdemeanours; and believes that the UK should be protected by a fully independent regulatory authority liberated from financial dependence on the pharmaceutical industry.
This was signed by 15 MP’s including Jeremy Corbyn. If they had carried the motion though, countless thousands of lives would have been saved.
Prince Charles personally wrote at least seven letters to the MHRA, the Medicines and Healthcare products Regulatory Agency shortly before they relaxed the rules governing labelling of such herbal products, it was reported that Charles had personally lobbied the Health Secretary, Andy Burnham, regarding greater provision of alternative treatments in the NHS. In 2016, Charles said in a speech that he used homeopathic veterinary medicines to reduce antibiotic use at his farm.
Cancer Survival Rates in Britain are worst of Western Europe
The Daily Telegraph on the 26.09.15 effectively proved what a disaster the MHRA is for the UK. The European Journal of Cancer did a study on 20 million EU patients.
Jeremy Hunt is the Minister of Health ultimately in charge of the MHRA. He allows Big Pharma to control all his health departments, not just the MHRA. That’s far worse than just slovenly or incompetent. He’s responsible for 200,000 unnecessary deaths every year. He should resign.
His contact details are:
Department of Health,
London, SW1A 2NS
Tel: 020 7210 4850
http://data.gov.uk/organogram/department-of-health gives us:
Dame Una O’Brien, Permanent Secretary 020 7210 4850
Tamara Finkelstein, COO 020 7210 4850
Marion Furr Director, Ministerial Business and Parliamentary accountability. 020 7210 4850
MHRA Head office
151 Buckingham Palace Road
MHRA telephone 020 3080 6000 Fax: 0203 118 9803 firstname.lastname@example.org
MHRA Press office 020 3080 7651 Out of hours: 07770 446 189 email@example.com
"The maintenance of secrets acts like a psychic poison which alienates the possessor from the community" Carl Jung
Joined: 25 Jul 2005
Location: St. Pauls, Bristol, England
|Posted: Tue Aug 06, 2019 12:06 pm Post subject:
|Biomedical Researcher Lynda Thyer Traumatized by Extradition Threat, Narrowly Escapes Kidnap Attempt as Cancer Cure GcMAF is Demonized by MHRA and Pharmaceutical Establishment Protecting Chemo Drug Profits
Posted on June 13, 2019 by Ramola D | Leave a comment
–Ramola D/Posted 6/13/2019
https://everydayconcerned.net/2019/06/13/biomedical-researcher-lynda-t hyer-traumatized-by-extradition-threat-narrowly-escapes-kidnap-attempt -as-natural-remedy-gcmaf-effective-in-cancer-treatment-is-demonized-by -mhra-and-pharmaceutical-estab/
British biomedical research scientist Lynda Thyer who has helped many hundreds of patients recover from late-stage cancer in her work with David Noakes at ImmunoBioTech using GcMAF, a naturally occuring protein in the human body and part of the immune system, and who, along with David Noakes, CEO, and nine others has been wrongfully hounded and persecuted in recent times by the MHRA (Medicines & Healthcare Products Regulatory Agency), Britain’s Health and Regulatory Agency, is recovering from cardiac complications brought on by the extreme trauma and anxiety associated with a baseless order of extradition in London and is currently in need of public witness protection for protection of life and safety, reports Neelu Berry, retired pharmacist, rights advocate and friend and supporter.
Issued an order by the Kent Police European Liaison Unit to appear at Heathrow June 11 to be extradited to France where a French judge was waiting to prosecute her, despite a note on Friday from her solicitor permitting an extension of 10 days, which however was not recognized by Kent Police who sent her railway tickets, Lynda Thyer made her way, Neelu Berry reports, to Heathrow Airport, early Tuesday 11 June 2019 morning for the Extradition Fraud, through sheer State Terrorism.
At Reading she collapsed on the train, an ambulance was called, and ECG found normal but she was advised she is unfit to fly for 5 days. She was arrested and released. She continued her journey to Heathrow where she was advised that French Police would meet her on Wednesday. Intending to sleep on a bench, friends she spoke to asked others in London to reach out to help her recover, where it was decided she would be more comfortable to rest for the 5 no-fly days.
Extrajudicial Kidnap and Feared Whistleblower Disappearance/Assassination Attempt with Redbridge Ambulance: Secret Surveillance and Profound Invasion of Privacy
This terrifying saga rooted in intimidation and threat from unlawful and out-of-control “authorities” does not end there. Accepting an offer to stay at a friend’s home, Lynda Thyer arrived at the undisclosed safehouse at 9:45 pm. Around 10:15 pm, very suspiciously, two ambulance crew-women with walkie talkies knocked repeatedly and violently at the front door for 20 minutes. An uncalled-for ambulance was parked outside for no reason for two hours until midnight, then drove off. An unmarked car with rear lights on was seen between 10.30 pm and 1 am across the road to the left of the Green, also parked for no reason for over two hours. Neelu Berry notes it is possibly of the Secret Service which has followed Lynda from the airport on a tag.
Uncalled-for ambulance in front of home, unknown car parked across–both for 2 hours at night, June 11, 2019.
Why would an ambulance show up unasked at a private residence? Why would it park and stay for two hours outside that residence despite no communications from the residents?
Ms. Berry reports this matter, noting that the stress of impending extradition has been taking its toll on Lynda Thyer. “Last Saturday 8th June her heart stopped and she was resuscitated causing severe bruising… This was an Extra-Judicial Kidnap and Assassination attempt after Lynda had a resuscitation in Truro and an ECG at Reading Station when she collapsed on her way to Heathrow Airport.”
Lynda Thyer: Recent Resuscitation, June 8, 2019
Neelu Berry states firmly that Lynda needs to recover before she is able to instruct her lawyers, and adds: “A call is being made to the public for Witness Protection.”
This attempt by Kent Police to force an extradition by intimidation has also been carried out in direct contravention of the ruling on May 27, 2019 by the British Common Law Court with a 12-person jury held by John Smith which annulled the fraudulent extradition order from Judge Supperstone, and denounced the criminal coercion, malfeasance in public office, unlawful court orders, fraud, legal deception, and the “threat of unlawful detention to protect vested interests.” from Judge Supperstone.
This was also an act of malicious prosecution in supporting the claims of the French prosecutor, notes the ruling, targeting innocent people, acting for vested business interests and “maintaining the monopoly of judicial and pharmaceutical systems.”
Newsbreak 27: Lynda Thyer Extradition Moved, MHRA Corruption, GcMAF Cancer Cure Withheld
The whole matter of this wrongfully demanded extradition was discussed recently at Newsbreak 27 on Ramola D Reports as also earlier on a round-table podcast, and recent interviews with David Noakes, Lynda Thyer, and Neelu Berry where the highly questionable nature of the demand was made clear.
Breaching matters of jurisdiction, High Court Judge Supperstone has essentially ruled that Lynda Thyer should prepare for extradition to France based on a French judge and prosecutor seeking to prosecute her on wrongful charges at the behest of the marauding Big Pharma-run MHRA which has sought to destroy Immuno BioTech and all involved in healing cancer naturally with GcMAF. David Noakes points out that this is fraudulent and corrupt, given that GcMAF is a lifesaving remedy and has provenly saved thousands of lives.
“If put in the NHS, GcMAF will save 120,000 lives a year. That’s the thing they want to prevent, so to do that there, they came out with a 26-year jail sentence for me–they wanted me to serve 14 years in England and 12 in France and they then got the French lawyer–OCLAESP is the even more corrupt MHRA equivalent in France so their judge GODAUD came up with nine fraudulent completely false charges completely out of his own head and of course they have no evidence of this because it is fake.
So Judge Supperstone should have rejected the extradition for Lyn and me because the charges are fake, and then of course also the jurisdiction is England; we had twenty-seven staff in England and only one part-time member of staff in France, poor David Halsall has already spent five months in a French jail without charges so that’s what happened. So now they want to send Lynn, they can’t send me because I’m serving a sentence in England, they will send Lynn to France for a 12- year sentence so there are some odd things going on.”
Biased and Defamatory Mainstream Media Coverage Against GcMAF, David Noakes, Lynda Thyer, Immuno BioTech Team Ignores the Science & Facts
While mainstream media coverage as by the BBC of the court, MHRA, and police persecution of David Noakes, ImmunoBioTech, Lynda Thyer and others associated with the manufacture and distribution of GcMAF has been remarkably biased if not positively opaque on the true natural healing powers of GcMAF, its actual profile as a natural protein rather than a manufactured drug requiring MHRA licensing, and the accomplishments of ImmunoBioTech in assisting in the recovery of 9000 patients from 50 diseases with GcMAF, including 800 late-stage cancer patients from cancer, it appears to this reporter as also to others that these journalists are essentially propping up both the MHRA and a corrupt pharmaceutical industry protecting cancer drug profits: their denunciation of David Noakes as a quack peddling a “wonder drug” cure, and their mischaracterization of GcMAF as a “blood plasma product” in the face of tremendous evidence to the contrary speaks volumes.
Primarily one-sided and declarative of a blanket refusal to examine the scientific backing, as David Noakes points out, it is absolutely astonishing to note that both the BBC and the British courts who prosecuted David Noakes in November 2018, imprisoning him for six months after a misguided attorney-advised plea-bargain let them wrongfully label him “guilty of money-laundering and charges of selling an unlicensed product,” have completely failed to look at the vast scientific documentation on GcMAF, detailing its nature as a bodily-created protein, its curative immune-system profile, and its numerous benefits. Hundreds of scientists have supported GcMAF in research papers, studies, and conferences; numerous scientists and doctors in different disciplines including oncology have used GcMAF successfully to treat their patients.
Excerpts from a few summaries and papers detailing scientific study of GcMAF:
“GcMAF is the body’s way of curing cancer, a human protein all of us make, and a human right; it has no side effects. It is the best treatment known for tumour cancers, which is 90% of them, and 50 other diseases. People with disease can’t make it, and need external GcMAF to cure their diseases. It was discovered in 1990, and the MHRA has conspired to conceal it from the public since then.
300 scientists have written over 150 scientific research papers on GcMAF, and Immuno Biotech Ltd had supplied 11,000 people, with fabulous results before the MHRA closed them down.”– MHRACorrupt.st/gcmaf
“We had 4 scientists, the most senior being Professor Marco Ruggiero MD, 7 doctors, two ultrasound staff, 4 nurses, and admin staff, when the MHRA closed us down.
GcMAF successfully treats all tumour cancers, which is 90% of cancers
75% of terminal stage IV patients lives saved in our clinics.
The American National Library of Medicine, or Pubmed has 70 GcMAF papers peer reviewed for the second time.”– GcMAF, The Cancer Cure the World Has Waited For/gcmaf.se
“Dr. Yamamoto studied GcMAF in 16 patients with metastatic prostate cancer with excellent results. Nagalase activity declined to normal, and there was no evidence of tumor recurrence over 7 years of observation.”– Cancer Immunotherapy from Dr. Yamamoto by Jeffrey Dach, Op Ed News 7/3/2013
“Clinical trials using first-generation GcMAF in patients with metastatic breast cancer (7), prostate cancer (, and metastatic colorectal cancer (9) have been conducted. Cancer did not recur over a four- to seven-year period in all those administered weekly doses of 100 mg of GcMAF for seven to 19 weeks.”– Clinical Experience of Integrative Cancer Immunotherapy with GcMAF, Toshio Inui, MD, of the Saisei Mirai Clinic in Kobe, Japan; Anticancer Research Vol. 33 no. 72917-2919
“Further, DBP-maf (Vitamin D Binding Protein), as well as being directly antiangiogenic activates macrophages which can then infiltrate solid tumors. This proposed amplification of the antiangiogenic effect of DBP-maf may explain the currently observed potency of this molecule as an anti-tumorigenic therapy.” —Vitamin D Binding Protein-Macrophage Activating Factor (DBP-maf) Inhibits Angiogenesis and Tumor Growth in Mice; Neoplasia.Vol. 5, No. 1, January 2003, pp. 32 –40
The Raids Over Licensing Issue: Does GcMAF Need to be Licensed, as a Natural Remedy?
Neelu Berry, a UK-trained pharmacist notes that GcMAF, contrary to MHRA implications, is not a licensable drug: it is neither synthetic nor manufactured chemically, as cancer chemotherapy drugs are, but a natural substance found in the body. When produced in the laboratory, Lynda Thyer notes, it is made with natural means such as fermentation and becomes a natural remedy supporting the body; as such, it would not be required to be subject to licensing or regulation of any kind.
https://youtu.be/_9n95-mEAEM“Natural remedies do not require licenses,” affirms Neelu Berry. Prosecution by the MHRA has been based on the “unlicensed” nature of the product sold by GcMAF, a focus in much of the derogatory BBC and other mainstream media coverage.
“Before the mainstream media can justify participating in this criminal cover-up that’s going on,” says Neelu Berry, “there would have to be evidence of harm, people would have to be screaming out about things that went wrong, but there’s nobody.” David Noakes notes the MHRA actually did find one lone patient who said GcMAF did not work for her, but this patient confided to him that she did not approve what the MHRA was doing to him and his company, plus, it is profoundly significant that she did not in any way report “harm” from GcMAF.
But is it even likely that the MHRA would license GcMAF if they could or should? The MHRA has conducted highly invasive and aggressive raids on ImmunoBiotech facilities and offices in Cambridge, Guernsey, and Lausanne–14 raids with 100 officers, confiscating computers, flasks of GcMAF, one vial of Vitamin D binding protein (DBP) used in the creation of Goleic, the product containing GcMAF which was made by Immuno Biotech, clamped down on the bank accounts of David Noakes and staff, terrorized scientists and staff in extended interrogation processes, and essentially destroyed the livelihood and lives of the professionals healing cancer patients at Immuno Biotech.
This article by Ben Porter, Corrupt Guernsey, covering the raids in Guernsey on Immuno BioTech offices as well as other raids details the trail of destruction caused by MHRA playing concerned regulator but in actuality swooping in to destroy the lives of caregivers.
Additionally, the seizure of GcMAF and the closing of laboratories and offices instigated and executed by MHRA in conjunction with local police has caused the deaths of a number of patients who had been recovering from cancer with GcMAF treatments after their supply was stopped. Details on these matters can be found here.
One-Sided Coverage With Information Solely From MHRA Ensures That MPs are Kept in the Dark
A former journalist himself who has worked for the BBC and editor of six newspapers, writing 30 articles a month at one time, David Noakes notes that a very basic tenet of journalism, of checking both sides for a story, is flouted in such abysmally biased coverage: “They get all their information from the MHRA. No-one ever comes to us, no-one cross-references–all the journalists are lousy. Even the BBC, Cancer Research UK, the Parliamentary Library–even Matt Hancock the Health Minister gets his information only from the MHRA.”
“The media are assassins,” says Neelu Berry, cutting no corners. “They are responsible for the ongoing deaths of 200,000 people a year. The publishers have to be held accountable. And the entire behavior of the Health Ministry proves that the UK is a dictatorship, it’s not a democracy.”
Both David Noakes and Neelu Berry stress that the MHRA is already responsible for millions of deaths from cancer and other diseases which GcMAF could have treated and cured fully–by MHRA withholding this miracle cure for decades. Autism is one of the diseases that has responded favorably to GcMAF. Dr. Jeff Bradstreet, well-known doctor and researcher, who was killed in the prime of his life, at the peak of his research and effective work with autism patients using GcMAF, David Noakes states, had healed 2000 autism patients. Outstanding autism results–complete cessation of symptoms–have been observed, David Noakes says, within one week of daily GcMAF administering.
“Dr Jeffrey Bradstreet has now treated over 2,000 autistic children with GcMAF and the results are well established. In 15% GcMAF makes no difference. 85% improve, if only a little, and of them 15% have their autism eradicated. In all 3,000 children have been treated with GcMAF with similar results.”–Autism
Neelu Berry states: “We’ve got different levels here. Because of the crimes that have already been committed by the MHRA, who are responsible for these two million murders since the 1980s (when it was called the Medicines Control Authority), the damage has already been done, the crimes have already been committed, the claims are already known about, so the question is: is the MHRA fit for purpose–No.”
Neelu Berry, describing liability
“What can the Health Minister do here–start with the natural remedy, then go to the synthetics. Here they have shut down the entire saving of 200,000 people a year–that is a massive crime the MHRA has committed. Not only did it deny the GcMAF, but it actually went out and shut it down–and caused all these crimes to be committed against these geniuses so that in itself proves the MHRA was acting as a gatekeeper to deny humanity the natural remedies that are given to us by God. They acted against God, that’s treason.”
“So you know there’s a lot of serious criminals running the MHRA and the Health Service–and that is the issue now, we don’t require these policies that deny natural remedies in the Health Service. The people want natural remedies and it’s common sense to have to start with the natural. Most diseases can be cured simply with natural remedies that have been excluded, that have been demonized by the MHRA, and that’s where the MHRA have made themselves extinct, the Health Service is now extinct because of its addiction to profit, addiction to toxic synthetic drugs and its addiction to excluding the natural remedies.”
Excluding natural remedies and imposing synthetic drugs which offer unpleasant modalities of treatment essentially constitutes fraud. The nature of the revolving door between regulatory agency MHRA and Big Pharma, the fact that police and pharmaceutical company CEOs and not scientists and unbiased researchers sit on the Board of MHRA was covered in podcasts by David Noakes and Neelu Berry and also discussed here by journalist Iaian Davis.
An immense fraud has been pulled off, it appears by the pharmaceutical industry and the regulatory agencies on humanity, by denying access to simple natural cures of all kinds, not just GcMAF, but all the other natural remedies for cancer too, which exist in naturopathy, homeopathy, and various traditional systems of medicine.
“Chemotherapy is a poison,” notes David Noakes, “You can lose your eye, liver, any organ–half the people who die of cancer don’t die of cancer, they die of the chemotherapy, and they die in horrific pain.”
The public can assist in the protection of Lynda Thyer and David Noakes and really the protection and furtherance of GcMAF as an acknowledged and readily available remedy for cancer by making calls and emails to MPs, providing them scientific information from PubMed (collected at the sites mentioned in the podcast, gcmaf.se, mhracorrupt.st, gsy.st). Also see the excellent articles by Ben Porter, Iain Davis, and Scott Tips, linked below, for further information. Coverage at this site will continue, and as Neelu Berry urges, all cancer and other patients healed with the use of GcMAF are especially urged to come forward to give their testimonials.
GcMAF, Nagalase, Vaccines, Autism & Cancer Cures, & Holistic Doctors Being Killed: What is the Connection?
Looking Closer At The Sudden Deaths of Several Holistic Doctors & the GcMAF/Nagalase & Cancer/Autism & Vaccine Connections
Richard Presser: Dr Rima Laibow interviews David Noakes and exposes the Big Pharma fingerprints in the GcMAF/Nagalase health bombshell
GcMAF & Immune System Health/Nagalase in Vaccines/An Update
Common Law Court Order May 27, 2019 Annulling Judge Supperstone’s Extradition Order
Instead of a Medal They Gave Him Prison by Scott C. Tips
GcMAF – The Persecution of David Noakes and Lyn Thyer by Iaian Davis
Corrupt Guernsey by Ben Porter
For more information on GcMAF, please visit these sites:
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Visit these pages for further evidence of healthcare provider persecution:
"The maintenance of secrets acts like a psychic poison which alienates the possessor from the community" Carl Jung