Abstract 195P
Background
The systemic immunological effects of combining anti-CTLA4 therapy with PD-(L)1 blockade remain incompletely characterized, despite the widespread use of this combination in treating various solid tumors. We investigated the additive impact of anti-CTLA4 on peripheral immune signatures in patients undergoing PD-(L)1 blockade, using serial blood samples from a cohort of patients receiving checkpoint inhibitor therapy for advanced solid tumors.
Methods
We prospectively collected serial blood specimens from adult patients receiving treatment with anti-PD(L)1 alone or in combination with anti-CTLA4 therapy for advanced, unresectable solid tumors at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. We performed in-parallel analysis of peripheral blood mononuclear cells (PBMC) using Cytometry by Time-of-Flight (CyTOF), and plasma cytokines using Luminex immunoassay on specimens collected at baseline and early on treatment (month 1 or 2).
Results
Our study cohort included 109 patients [anti-PD(L)1 alone, n=58, in combination with anti-CTLA4, n=51]. As compared to single-agent anti-PD(L)1, combination therapy was associated with a greater expansion of CD4+ helper subsets, including Th17 (adjusted p=0.039) and Treg (adjusted p=0.018) after multivariable and multiple testing adjustment. In patients receiving anti-CTLA4, Th17 populations demonstrated an acquired non-classical Th1-like phenotype characterized by upregulation of the Th1-related transcription factor T-BET (p=0.04). Assessment of the peripheral cytokine signatures showed an increase in Th1-associated cytokines in combination ICI recipients, particularly the IFNg inducible cytokines MIG (adjusted p=0.021), IP-10 (adjusted p=0.021).
Conclusions
Our results confirm prior reports that anti-CTLA4 therapy is associated with augmentation of Th17 cell subsets but show that anti-CTLA4 may also contribute to a Th1-like program as a result of lineage plasticity.
Legal entity responsible for the study
Johns Hopkins, Genentech/Roche.
Funding
F. Hoffmann-La Roche Ltd.
Disclosure
M. Baretti: Financial Interests, Personal, Other, Personal Fees: AstraZeneca, Incyte. G.S. Chandler: Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche. R. Mohindra: Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd. E.M. Jaffee: Financial Interests, Personal, Other: Abmeta; Financial Interests, Personal, Other, Personal Fees: Genocea, Achilles, DragonFly, Candel Therapeutics, Carta, NextCure; Financial Interests, Personal and Institutional, Research Grant: Lustgarten, Genentech, Break Through Cancer; Financial Interests, Institutional, Research Grant: AstraZeneca. W.J. Ho: Financial Interests, Personal, Royalties: Rodeo/Amgen; Financial Interests, Personal and Institutional, Research Grant: Sanofi, NeoTX, Circle Pharma; Financial Interests, Personal, Speaker, Consultant, Advisor: Exelixis. M. Yarchoan: Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, Exelixis, Genentech, Replimune, Hepion, Lantheus; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, Exelixis, Genentech, Incyte; Financial Interests, Personal, Officer: Adventris Pharmaceuticals. All other authors have declared no conflicts of interest.
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