Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients
F. Stephen Hodi,Marcus O. Butler,Darryl A. Oble,Michael V. Seiden,Michael V. Seiden,Frank G. Haluska,Andrea Kruse,Suzanne MacRae,Marybeth Nelson,Christine Canning,Israel Lowy,Alan J. Korman,David B. Lautz,Sara Russell,Michael T. Jaklitsch,Nikhil H. Ramaiya,Teresa C. Chen,Donna Neuberg,James P. Allison,Martin C. Mihm,Glenn Dranoff +20 more
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TLDR
It is shown that periodic infusions of anti-CTLA-4 antibodies after vaccination with irradiated, autologous tumor cells engineered to secrete GM-CSF (GVAX) generate clinically meaningful antitumor immunity without grade 3 or 4 toxicity in a majority of metastatic melanoma patients.Abstract:
Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) functions as a negative regulator of endogenous and vaccine-induced antitumor immunity. The administration of fully human anti-CTLA-4 blocking monoclonal antibodies to advanced-cancer patients increases immune-mediated tumor destruction in some subjects. Nonetheless, patients that respond also frequently manifest serious inflammatory pathologies, raising the possibility that the therapeutic and toxic effects of CTLA-4 blockade might be linked. Here we show that periodic infusions of anti-CTLA-4 antibodies after vaccination with irradiated, autologous tumor cells engineered to secrete GM-CSF (GVAX) generate clinically meaningful antitumor immunity without grade 3 or 4 toxicity in a majority of metastatic melanoma patients. The application of this sequential immunotherapy to advanced ovarian carcinoma patients also revealed that tumor destruction and severe inflammatory pathology could be dissociated, although further refinements are required to increase clinical responses and to minimize toxicity in this population. The extent of therapy-induced tumor necrosis was linearly related to the natural logarithm of the ratio of intratumoral CD8(+) effector T cells to FoxP3(+) regulatory T cells (Tregs) in posttreatment biopsies. Together, these findings help clarify the immunologic and clinical effects of CTLA-4 antibody blockade in previously vaccinated patients and raise the possibility that selective targeting of antitumor Tregs may constitute a complementary strategy for combination therapy.read more
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Padmanee Sharma,James P. Allison +1 more
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Guidelines for the Evaluation of Immune Therapy Activity in Solid Tumors: Immune-Related Response Criteria
Jedd D. Wolchok,Axel Hoos,Steven J. O'Day,Jeffrey S. Weber,Omid Hamid,Céleste Lebbé,Michele Maio,Michael Binder,Oliver Bohnsack,Geoffrey M. Nichol,R. Humphrey,F. Stephen Hodi +11 more
TL;DR: Systematic criteria, designated immune-related response criteria, were defined in an attempt to capture additional response patterns observed with immune therapy in advanced melanoma beyond those described by Response Evaluation Criteria in Solid Tumors or WHO criteria.
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FOXP3 + regulatory T cells in the human immune system
Shimon Sakaguchi,Makoto Miyara,Makoto Miyara,Cristina M. Costantino,Cristina M. Costantino,David A. Hafler,David A. Hafler +6 more
TL;DR: Recent findings regarding human TReg cells are discussed, including the ontogeny and development of TReg cell subsets that have naive or memory phenotypes, the unique mechanisms of suppression mediated by TRegcell subsets and factors that regulateTReg cell lineage commitment.
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Immune Checkpoint Blockade in Cancer Therapy
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References
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Consensus coding sequences of human breast and colorectal cancers
Tobias Sjöblom,Sian Jones,D. Williams Parsons,Laura D. Wood,Jimmy Lin,Thomas D. Barber,Diana Mandelker,Bert Vogelstein,Kenneth W. Kinzler,Victor E. Velculesu +9 more
TL;DR: In this paper, the authors analyzed 13,023 genes in 11 breast and 11 colorectal cancers and found that individual tumors accumulate an average of 90 mutant genes but only a subset of these contribute to the neoplastic process.
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Lymphoproliferative Disorders with Early Lethality in Mice Deficient in Ctla-4
Paul Waterhouse,Josef M. Penninger,Emma Timms,Andrew Wakeham,Arda Shahinian,Kelvin P. Lee,Craig B. Thompson,Henrik Griesser,Tak W. Mak +8 more
TL;DR: Although CTLA-4-deficient T cells proliferated spontaneously and strongly when stimulated through the T cell receptor, they were sensitive to cell death induced by cross-linking of the Fas receptor and by gamma irradiation, and is vital for the control of lymphocyte homeostasis.
Journal ArticleDOI
Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4
Elizabeth A. Tivol,Frank Borriello,A N Schweitzer,W P Lynch,Jeffrey A. Bluestone,Arlene H. Sharpe +5 more
TL;DR: In this article, the authors showed that CTLA-4-deficient mice rapidly develop lymphoproliferative disease with multiorgan lymphocytic infiltration and tissue destruction, with particularly severe myocarditis and pancreatitis, and die by 3-4 weeks of age.
Journal ArticleDOI
Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation.
TL;DR: It is reported that the Treg cells that control intestinal inflammation express the same phenotype (CD25+CD45RBlowCD4+) as those that control autoimmunity, suggesting that Treg cell function contributes to the immune suppression characteristic of CTLA-4 signaling.
Journal ArticleDOI
Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer
Eiichi Sato,Sara H. Olson,Jiyoung Ahn,Brian N. Bundy,Hiroyoshi Nishikawa,Feng Qian,Achim A. Jungbluth,Denise Frosina,Sacha Gnjatic,Christine B. Ambrosone,James L. Kepner,Tosin Odunsi,Gerd Ritter,Shashikant Lele,Yao-Tseng Chen,Haruo Ohtani,Lloyd J. Old,Kunle Odunsi +17 more
TL;DR: It is concluded that intraepithelial CD8+ TILs and a high CD8-/Treg ratio are associated with favorable prognosis in epithelial ovarian cancer.
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