Journal Article

Cyclophosphamide enhances the antitumor potency of GITR engagement by increasing oligoclonal cytotoxic T cell fitness

Hamadene, Linda, Maniyar, Rachana, Suek, Nathan, Hirschhorn, Daniel, Betof Warner, Allison, Liu, Cailian, Mangarin, Levi M.B., Rizzuto, Gabrielle A., Merghoub, Taha, Wolchok, Jedd D., Budhu, Sadna, Cohen, Adam D., Houghton, Alan N., Chow, Andrew

2021

Overview

Only a subset of cancer patients responds to checkpoint blockade inhibition in the clinic. Strategies to overcome resistance are promising areas of investigation. Targeting glucocorticoid-induced tumor necrosis factor receptor–related protein (GITR) has shown efficacy in preclinical models, but GITR engagement is ineffective in controlling advanced, poorly immunogenic tumors, such as B16 melanoma, and has not yielded benefit in clinical trials. The alkylating agent cyclophosphamide (CTX) depletes regulatory T cells (Tregs), expands tumor-specific effector T cells (Teffs) via homeostatic proliferation, and induces immunogenic cell death. GITR agonism has an inhibitory effect on Tregs and activates Teffs. We therefore hypothesized that CTX and GITR agonism would promote effective antitumor immunity. Here we show that the combination of CTX and GITR agonism controlled tumor growth in clinically relevant mouse models. Mechanistically, we show that the combination therapy caused tumor cell death, clonal expansion of highly active CD8 + T cells, and depletion of Tregs by activation-induced cell death. Control of tumor growth was associated with the presence of an expanded population of highly activated, tumor-infiltrating, oligoclonal CD8 + T cells that led to a diminished TCR repertoire. Our studies show that the combination of CTX and GITR agonism is a rational chemoimmunotherapeutic approach that warrants further clinical investigation.

• Publisher: American Society for Clinical Investigation,American Society for Clinical investigation
• Subject: Animal models / Animals / Antibodies / Antigens / Antitumor activity / CD8 antigen / Cell activation / Cell death / Cell proliferation / Chemotherapy / Clinical trials / Combination therapy / Cyclophosphamide / Cyclophosphamide - pharmacology / Cyclophosphamide - therapeutic use / Cytotoxicity / Effector cells / Flow cytometry / Glucocorticoid-Induced TNFR-Related Protein - metabolism / Humans / Immune checkpoint inhibitors / Immunogenicity / Immunology / Immunoregulation / Immunosuppressive Agents - pharmacology / Immunosuppressive Agents - therapeutic use / Immunotherapy - methods / Lymphocytes / Lymphocytes T / Melanoma / Mice / Mutation / Oncology / Proteins / T cell receptors / T-Lymphocytes, Regulatory - immunology / Tumor necrosis factor-TNF / Tumors