Anti-CTLA-4 therapy may have mechanisms similar to those occurring in inherited human CTLA4 haploinsufficiency

Bakács, Tibor; Mehrishi, J.N.

doi:10.1016/j.imbio.2014.11.019

Cited by 12 publications

(16 citation statements)

References 11 publications

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“…They therefore hypothesized that the anti-CTLA-4 therapy may have mechanisms similar to that occurring in inherited human CTLA4 haplo-insufficiency. 31 This theoretical proposition is consistent with the finding that inherited human CTLA4 haploinsufficiency plays a critical quantitative role for CTLA-4 in governing T and B lymphocyte homeostasis. 58 This proposition has since been validated by two new genetic diseases of CTLA-4 checkpoint insufficiency.…”

Section: Iatrogenic Ctla-4 Blockade Turns Physiologic Autoimmunit Ysupporting

confidence: 85%

“…We have predicted that ICIs cannot be restricted to the targeted antitumour T cell population because the anti‐CTLA‐4 mAb blockade induces an uncontrolled T cell activation . This prediction has been confirmed in many thousands of patients.…”

Section: Proof‐of‐principle Of Low‐dose Ici Therapy Has Been Demonstrmentioning

confidence: 95%

“…Since the anti‐CTLA‐4 immune checkpoint blockade cannot be restricted to the targeted tumour‐specific T cell population, such that this blockade induces an uncontrolled pan T cell activation, tolerance to healthy self‐tissues will be compromised. They therefore hypothesized that the anti‐CTLA‐4 therapy may have mechanisms similar to that occurring in inherited human CTLA4 haplo‐insufficiency …”

Section: Iatrogenic Ctla‐4 Blockade Turns Physiologic Autoimmunity Inmentioning

confidence: 99%

“…We would suggest that the widespread, dose-dependent irAEs of ipilimumab can best be explained by the view that all T cells possess self-reactivity. [27][28][29][30][31] The 'tonic' signal 1 (TCR signal), generated by positively selecting self-peptide/major histocompatibility complex (MHC), promotes activation and homeostatic survival of T cells in the periphery. Furthermore, there is evidence for control of such tonic TCR signals by co-inhibitors.…”

Section: Blockade Induces An Uncontrolled T Cell Activationmentioning

confidence: 99%

“…In addition, a systemic grade IV anaphylactic reaction and a fatal case of tumour mass liquefaction were also reported. 62 Thus, the theory that anti-CTLA-4 therapy has a similar mechanism to that occurring in inherited human CTLA4 haploinsufficiency 31 clinical phenotypes of the genetic and iatrogenic CTLA-4 insufficiencies. Since the CTLA-4 receptor blockade cannot achieve long-lasting cancer regressions without breaking the physiologic tolerance to healthy self-tissues, a therapeutic paradigm shift is required.…”

Section: Ctl A4 Gene Insufficiency Are Eerily Similar To That Of the mentioning

confidence: 99%

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Exploiting autoimmunity unleashed by low‐dose immune checkpoint blockade to treat advanced cancer

Bakács¹,

Moss²,

Kleef³

et al. 2019

Scand J Immunol

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As a result of the cancer immunotherapy revolution, more than 2000 immuno‐oncology agents are currently being tested or are in use to improve responses. Not unexpectedly, the 2018 Nobel Prize in Physiology or Medicine was awarded to James P. Allison and Tasuku Honjo for their development of cancer therapy by the blockade of co‐inhibitory signals. Unfortunately, manipulation of the co‐inhibitory receptors has also resulted in a safety issue: widespread iatrogenic immune‐related adverse events (irAEs). Autoimmunity is emerging as the nemesis of immunotherapy. Originally, it was assumed that CTLA‐4 blockade selectively targets T cells relevant to the antitumour immune response. However, an uncontrolled pan T cell activation was induced compromising tolerance to healthy self‐tissues. The irAEs are very similar to that of a chronic graft‐versus‐host‐disease (GVHD) reaction following allogeneic bone marrow transplantation (BMT). We hypothesized that ipilimumab induced a graft‐versus‐malignancy (GVM) effect, which eradicated metastatic melanoma in a minority of patients, but also involved an auto‐GVHD reaction that resulted in widespread autoimmunity in the majority. Therefore, we argued for a profound theoretical point against the consensus of experts. The task is not to desperately put the genie back in the bottle by immune‐suppressive treatments, but instead to harness the autoimmune forces. In this way, the same goal could be achieved by an antibody as by the adoptive transfer of alloreactive donor lymphocytes, but without severe GVHD. The proof‐of‐principle of a low‐dose‐combination immune checkpoint therapy, consisting only of approved drugs and treatments, was demonstrated in 111 stage IV cancer patients.

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Section: Iatrogenic Ctla-4 Blockade Turns Physiologic Autoimmunit Ysupporting

confidence: 85%

Section: Proof‐of‐principle Of Low‐dose Ici Therapy Has Been Demonstrmentioning

confidence: 95%

Section: Iatrogenic Ctla‐4 Blockade Turns Physiologic Autoimmunity Inmentioning

confidence: 99%

Section: Blockade Induces An Uncontrolled T Cell Activationmentioning

confidence: 99%

Section: Ctl A4 Gene Insufficiency Are Eerily Similar To That Of the mentioning

confidence: 99%

See 3 more Smart Citations

Exploiting autoimmunity unleashed by low‐dose immune checkpoint blockade to treat advanced cancer

Bakács¹,

Moss²,

Kleef³

et al. 2019

Scand J Immunol

Self Cite

View full text Add to dashboard Cite

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Significant association between tumor mutational burden and immune-related adverse events during immune checkpoint inhibition therapies

Kerepesi

Bakács²,

Moss³

et al. 2020

Cancer Immunol Immunother

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More than 2000 immuno-oncology agents are being tested or are in use as a result of the cancer immunotherapy revolution. Manipulation of co-inhibitory receptors has achieved tumor eradication in a minority of patients, but widespread immunerelated adverse events (irAEs) compromised tolerance to healthy self-tissues in the majority. We have proposed that a major mechanism of irAEs is similar to a graft-versus-malignancy effect of graft-versus-host disease. To verify our hypothesis, we retrieved post-marketing data of adverse events from the U.S. Food and Drug Administration Adverse Event Reporting System. A significant positive correlation was revealed in 7677 patients between the reporting odds ratio of irAEs during immune checkpoint inhibitor therapy and the corresponding tumor mutational burden across 19 cancer types. These results can be interpreted to mean that the ICI drugs unleashed T cells against "altered-self," self, and tumors resulting in better overall survival. Keywords Immune-related adverse event • Immune checkpoint inhibition • Tumor mutation burden • Graft-versus-host disease • FAERS Abbreviations AE Adverse event FAERS Food and Drug Administration Adverse Event Reporting System GVHD Graft-versus-host disease GVM Graft-versus-malignancy ICI Immune checkpoint inhibitor irAE Immune-related adverse event NSCLC Non-small cell lung carcinoma ROR Reporting odds ratio TMB Tumor mutation burden Electronic supplementary material The online version of this article (

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A Patient with CTLA-4 Haploinsufficiency Presenting Gastric Cancer

et al. 2015

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Cytotoxic T-lymphocyte-antigen 4 (CTLA-4) is an essential negative regulator expressed on regulatory T cells (Tregs) and activated T cells. Germline heterozygous mutations in CTLA4 lead to haploinsufficiency of CTLA-4, resulting in the development of an autosomal dominant immune dysregulation syndrome with incomplete penetrance. We report here a Japanese patient with this disorder who has a novel heterozygous single nucleotide insertion, 76_77insT (p. L28SfsX40), in the CTLA4 gene. Peripheral blood mononuclear cells from the patient showed decreased frequency of CTLA-4(high) cells in CD4(+)FOXP3(+) cells following CD3/CD28 stimulation. The patient experienced hypogammaglobulinemia, recurrent pneumonia, esophageal candidiasis, cytomegalovirus-positive chronic gastritis, chronic and severe diarrhea, and type 1 diabetes mellitus. Moreover, the patient developed multifocal gastric cancer, histologically poorly and well-differentiated adenocarcinomas, associated with chronic atrophic gastritis and intestinal metaplasia. Previously, 23 symptomatic cases with heterozygous CTLA4 mutations have been reported. Including the case presented here, 3 of the 24 cases (12.5%) developed gastric cancer. Notably, 2 of 3 patients presented similarly multifocal adenocarcinomas associated with atrophic gastritis and intestinal metaplasia. Predisposition to gastric cancer has been also reported in CVID patients. These clinical observations suggest that gastric cancer is a disease commonly associated with autosomal dominant immune dysregulation syndrome due to CTLA4 mutation.

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Anti-CTLA-4 therapy may have mechanisms similar to those occurring in inherited human CTLA4 haploinsufficiency

Cited by 12 publications

References 11 publications

Exploiting autoimmunity unleashed by low‐dose immune checkpoint blockade to treat advanced cancer

Exploiting autoimmunity unleashed by low‐dose immune checkpoint blockade to treat advanced cancer

Significant association between tumor mutational burden and immune-related adverse events during immune checkpoint inhibition therapies

A Patient with CTLA-4 Haploinsufficiency Presenting Gastric Cancer

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