Anti-PD-1 Antibody Therapy Potently Enhances the Eradication of Established Tumors By Gene-Modified T Cells

By Liza B. John, Christel Devaud, Connie P. M. Duong, C. Yong, P. Beavis, N. Haynes, Melvyn T. Chow, M. Smyth, M. Kershaw, P. Darcy. Clinical Cancer Research, 2013

670 citations recorded by the source corpus.

Purpose: To determine the antitumor efficacy and toxicity of a novel combination approach involving adoptive T-cell immunotherapy using chimeric antigen receptor (CAR) T cells with an immunomodulatory reagent for blocking immunosuppression. Experimental Design: We examined whether administration of a PD-1 blocking antibody could increase the therapeutic activity of CAR T cells against two different Her-2+ tumors. The use of a self-antigen mouse model enabled investigation into the efficacy, mechanism, and toxicity of this combination approach. Results: In this study, we first showed a significant increase in the level of PD-1 expressed on transduced anti-Her-2 CD8+ T cells following antigen-specific stimulation with PD-L1+ tumor cells and that markers of activation and proliferation were increased in anti-Her-2 T cells in the presence of anti-PD-1 antibody. In adoptive transfer studies in Her-2 transgenic recipient mice, we showed a significant improvement in growth inhibition of two different Her-2+ tumors treated with anti-Her-2 T cells in combination with anti-PD-1 antibody. The therapeutic effects observed correlated with increased function of anti-Her-2 T cells following PD-1 blockade. Strikingly, a significant decrease in the percentage of Gr1+ CD11b+ myeloid-derived suppressor cells (MDSC) was observed in the tumor microenvironment of mice treated with the combination therapy. Importantly, increased antitumor effects were not associated with any autoimmune pathology in normal tissue expressing Her-2 antigen. Conclusion: This study shows that specifically blocking PD-1 immunosuppression can potently enhance CAR T-cell therapy that has significant implications for potentially improving therapeutic outcomes of this approach in patients with cancer. Clin Cancer Res; 19(20); 5636–46. ©2013 AACR.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/14d3d935e9d7a49426c8f0afe9f7f84d2bcf1d8a

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Citations in the corpus

Generation of knock-in primary human T cells using Cas9 ribonucleoproteins (2015, background): “Deletion of genes that encode key immune checkpoints such as PD-1 could prove useful for these efforts (12, 13).”
Multiplex genome editing to generate universal CAR T cells resistant to PD1 inhibition (2016, background): “Disruption of PD1 in CAR T cells leads to enhanced antitumor efficacy Given the robust anti-tumor efficacy of PD1 antagonists in multiple clinical trials, and that combination therapy with CAR T cells and PD1 antagonists have enhanced antitumor activity in preclinical models (25), we next tested whe”
The Principles of Engineering Immune Cells to Treat Cancer (2017, background): “…with checkpoint inhibitors makes a great deal of sense, and initial Cell 168, February 9, 2017 733 trials appear promising, where PD-1 or PD-L1 antagonists are being co-administered with engineered T cells (Chong et al., 2016), based on synergy observed in pre-clinical models (John et al., 2013).”
Mesothelin-specific Chimeric Antigen Receptor mRNA-Engineered T cells Induce Anti-Tumor Activity in Solid Malignancies (2013, background): “A recent study has shown a promising potential in combining CAR T-cell therapy with checkpoint blockade (22).”