A Chimeric Switch-Receptor Targeting PD1 Augments the Efficacy of Second-Generation CAR T Cells in Advanced Solid Tumors
2016; American Association for Cancer Research; Volume: 76; Issue: 6 Linguagem: Inglês
10.1158/0008-5472.can-15-2524
ISSN1538-7445
AutoresXiaojun Liu, Raghuveer Ranganathan, Shuguang Jiang, Chongyun Fang, Jing Sun, Soyeon Kim, Kheng Newick, Albert Lo, Carl H. June, Yangbing Zhao, Edmund K. Moon,
Tópico(s)Immunotherapy and Immune Responses
ResumoAbstract 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.
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