791 Immune checkpoint blockade enhances cyclophosphamide induced anti-tumor immunity in a preclinical melanoma model

• DOI: 10.1136/jitc-2022-sitc2022.0791
• Publication Date: 2022-11-08T01:09:05Z
• Authors: Mariam George; Allison Betof; Taha Merghoub; Linda Hamadene; Daniel Hirschhorn; Alan Houghton; Jedd Wolchok
• Keywords: Immune checkpoint

<h3>Background</h3> Immune Checkpoint Blockade (ICB) with anti- programmed cell death protein (PD)-1 and anti-cytotoxic T lymphocyte associated (CTLA)-4 have had immense success in cancer treatment. However, primary acquired resistance to these therapies limits their clinical benefit. Accumulating evidence indicates that chemotherapeutic agents such as Cyclophosphamide (CTX) can induce anticancer immunity improves the efficacy of ICBs when used combination. A combination strategy reorchestrate anti-tumor immune response could magnify benefit ICBs. CTX is an alkylating agent which directly tumoricidal induces immunomodulatory properties. preferentially depletes subsets (such regulatory cells) leads homeostatic proliferation cells. We hypothesized addition treatment will augment changes induced by including but not limited cells reset receptor (TCR) repertoire favor tumor antigen-specific The murine melanoma model, B16-F10, known be refractory ICBs, particularly anti-PD-1, it only modestly slows growth. <h3>Methods</h3> Mice were given a single dose one day prior starting ICB (anti-PD-1 and/or anti-CTLA-4) regimen. <h3>Results</h3> progression B16-F10 compared or alone significantly prolongs survival mice. Further, PD-1 anti-CTLA-4 increased number activated proliferating CD8+ infiltrating lymphocytes (TILs). This increase cytotoxic was accompanied decrease Tregs, further augments control. Additionally, we observed significant highly cytolytic population CD4+ double positive TILs. depletion abrogates therapeutic effect triple suggesting dependent. control (CTX+ + extends other models namely, MC38 (colon adenocarcinoma) 4T1 (mammary carcinoma). <h3>Conclusions</h3> Our results suggest anti-CTLA-4, potent combinatorial approach prime promote robust These findings form basis for investigations understanding mechanisms are inform design future interventions combine chemotherapy.