Intestinal toxicity to CTLA-4 blockade driven by IL-6 and myeloid infiltration
Yifan ZhouYusra B. MedikBhakti PatelDaniel ZamlerSijie ChenThomas ChapmanSarah SchneiderElizabeth M. ParkRachel L. BabcockTaylor T. ChrisikosLaura M. KahnAllison M. DyevoichJosué E. PinedaMatthew C. WongAditya K. MishraSamuel CassAlexandria P. CogdillDaniel H. JohnsonSarah JohnsonKhalida WaniDebora Alejandra LedesmaCourtney W. HudgensJingjing WangM.A. Wadud KhanChristine B. PetersonAron Y. JoonWeiyi PengHaiyan S. LiReetakshi AroraXiming TangMaria Gabriela RasoXuegong ZhangWai Chin FooMichael T. TetzlaffGretchen E. DiehlKaren Clise-DwyerElizabeth M. WhitleyMatthew M. GubinJames P. AllisonPatrick HwuNadim J. AjamiAdi DiabJennifer A. WargoStephanie S. Watowich
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Abstract:
Immune checkpoint blockade (ICB) has revolutionized cancer treatment, yet quality of life and continuation of therapy can be constrained by immune-related adverse events (irAEs). Limited understanding of irAE mechanisms hampers development of approaches to mitigate their damage. To address this, we examined whether mice gained sensitivity to anti-CTLA-4 (αCTLA-4)–mediated toxicity upon disruption of gut homeostatic immunity. We found αCTLA-4 drove increased inflammation and colonic tissue damage in mice with genetic predisposition to intestinal inflammation, acute gastrointestinal infection, transplantation with a dysbiotic fecal microbiome, or dextran sodium sulfate administration. We identified an immune signature of αCTLA-4–mediated irAEs, including colonic neutrophil accumulation and systemic interleukin-6 (IL-6) release. IL-6 blockade combined with antibiotic treatment reduced intestinal damage and improved αCTLA-4 therapeutic efficacy in inflammation-prone mice. Intestinal immune signatures were validated in biopsies from patients with ICB colitis. Our work provides new preclinical models of αCTLA-4 intestinal irAEs, mechanistic insights into irAE development, and potential approaches to enhance ICB efficacy while mitigating irAEs.Keywords:
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<p>PDF file - 2088KB, Supplementary Figure 2. Therapeutic blockade at 2 weeks post-intracranial injection (wpic.) against CTLA-4, PD-L1 and IDO selectively changes the T cell phenotype in established brain tumors.</p>
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Meeting abstracts Therapies targeting T cell immune checkpoints such as CTLA4 and PD1/PDL1 axis have shown considerable promise in the therapy of human cancer. Combination therapy with dual immune checkpoint blockade (ICB) was recently shown to be highly active in melanoma. While signaling via both
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Engagement of the ICOS pathway markedly enhances efficacy of CTLA-4 blockade in cancer immunotherapy
Cytotoxic T lymphocyte antigen-4 (CTLA-4) blockade with a monoclonal antibody yields durable responses in a subset of cancer patients and has been approved by the FDA as a standard therapy for late-stage melanoma. We recently identified inducible co-stimulator (ICOS) as a crucial player in the antitumor effects of CTLA-4 blockade. We now show that concomitant CTLA-4 blockade and ICOS engagement by tumor cell vaccines engineered to express ICOS ligand enhanced antitumor immune responses in both quantity and quality and significantly improved rejection of established melanoma and prostate cancer in mice. This study provides strong support for the development of combinatorial therapies incorporating anti–CTLA-4 and ICOS engagement.
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Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a key inhibitory regulator for priming phase in T cell adaptive immunity against cancer. CTLA-4 blockade monotherapy or combination therapy with PD-1 blockade induces T cell activation and shows clinical activity in melanoma patients. Anti-CTLA-4 antibody is the first drug for immune checkpoint blockade and has been clinically used over the past decades. Several clinical characteristics and biomarkers in cancer immunotherapy were identified during developing CTLA-4 blockade therapy for mela- noma patients. Further roles of CTLA-4 blockade in other cancers are still to be determined. Well-designed clinical trial considering immune biology and findings from translational re- search is warranted to emerge potential efficacy of CTLA-4 blockade in cancer treatment.
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Supplementary Tables 1-2 from Tumor Vaccines Expressing Flt3 Ligand Synergize with CTLA-4 Blockade to Reject Preimplanted Tumors
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<p>PDF file - 2088KB, Supplementary Figure 2. Therapeutic blockade at 2 weeks post-intracranial injection (wpic.) against CTLA-4, PD-L1 and IDO selectively changes the T cell phenotype in established brain tumors.</p>
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Supplementary Figures 1-6 from Tumor Vaccines Expressing Flt3 Ligand Synergize with CTLA-4 Blockade to Reject Preimplanted Tumors
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