A Chimeric Switch-Receptor Targeting PD1 Augments the Efficacy of Second-Generation CAR T Cells in Advanced Solid Tumors
- 14 March 2016
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 76 (6), 1578-1590
- https://doi.org/10.1158/0008-5472.can-15-2524
Abstract
Chimeric antigen receptor (CAR)–modified adoptive T-cell therapy has been successfully applied to the treatment of hematologic malignancies, but faces many challenges in solid tumors. One major obstacle is the immune-suppressive effects induced in both naturally occurring and genetically modified tumor-infiltrating lymphocytes (TIL) by inhibitory receptors (IR), namely PD1. We hypothesized that interfering with PD1 signaling would augment CAR T-cell activity against solid tumors. To address this possibility, we introduced a genetically engineered switch receptor construct, comprising the truncated extracellular domain of PD1 and the transmembrane and cytoplasmic signaling domains of CD28, into CAR T cells. We tested the effect of this supplement, “PD1CD28,” on human CAR T cells targeting aggressive models of human solid tumors expressing relevant tumor antigens. Treatment of mice bearing large, established solid tumors with PD1CD28 CAR T cells led to significant regression in tumor volume due to enhanced CAR TIL infiltrate, decreased susceptibility to tumor-induced hypofunction, and attenuation of IR expression compared with treatments with CAR T cells alone or PD1 antibodies. Taken together, our findings suggest that the application of PD1CD28 to boost CAR T-cell activity is efficacious against solid tumors via a variety of mechanisms, prompting clinical investigation of this potentially promising treatment modality. Cancer Res; 76(6); 1578–90. ©2016 AACR.Keywords
Other Versions
This publication has 55 references indexed in Scilit:
- Chimeric Antigen Receptor–Modified T Cells for Acute Lymphoid LeukemiaNew England Journal of Medicine, 2013
- Chimeric Antigen Receptor–Modified T Cells in Chronic Lymphoid LeukemiaNew England Journal of Medicine, 2011
- A novel high‐affinity human monoclonal antibody to mesothelinInternational Journal of Cancer, 2011
- Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunityThe Journal of Experimental Medicine, 2010
- Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen–specific CD8+ T cell dysfunction in melanoma patientsThe Journal of Experimental Medicine, 2010
- Tumor-infiltrating NY-ESO-1–specific CD8 + T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancerProceedings of the National Academy of Sciences of the United States of America, 2010
- Case Report of a Serious Adverse Event Following the Administration of T Cells Transduced With a Chimeric Antigen Receptor Recognizing ERBB2Molecular Therapy, 2010
- PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumorsProceedings of the National Academy of Sciences of the United States of America, 2010
- Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domainsProceedings of the National Academy of Sciences of the United States of America, 2009
- Molecular regulation of T‐cell anergyEMBO Reports, 2008