Chimeric antigen receptor (CAR) T-cells may elicit responses in solid cancers by inducing cancer cell death and the release of tumor antigens that could stimulate T-cell activity, according to research presented at the 2017 ASCO Annual Meeting (June 2-6, 2017; Chicago, IL).
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CAR T-cells have proven therapeutic value and have produced significant responses in hematological malignancies. However, efficacy data for CAR T-cells in solid tumors are limited, due to poor in vivo persistence and heterogeneous expression of the CAR target on tumors. Researchers speculate that CAR T-cells may demonstrate a “vaccine” effect by catalyzing tumor cell disintegration and subsequent release of tumor antigens that could promote tumor-specific T-cell activity.
Rebecca H Kim, MD, University of Pennsylvania (Philadelphia, PA) and colleagues conducted a study to test the efficacy of CAR T-cells in solid tumors. Researchers sampled 6 patients with pancreatic ductal adenocarcinoma to receive mRNA-transfected mesothelin-redirected CAR T-cells (CARTmeso) intravenously for 3 doses every week. Additionally, 5 patients with pancreatic ductal adenocarcinoma, 5 with ovarian carcinoma, and 5 with mesothelioma received lentiviral-transduced CARTmeso intravenously, with or without cyclophosphamide preconditioning.
Blood samples were collected at baseline and various times after treatment. Researchers used genomic DNA identified from the blood samples or from pre-infused CAR T-cell product for deep sequencing of the T-cell receptor beta chain. Researchers defined a T-cell receptor beta clone as having expanded from baseline to various times after treatment if it showed at least a 2-fold change from baseline.
Results of the analysis showed that while mRNA CARTmeso cells persisted in vivo for less than 24 hours, therapy-induced clonal T-cell expansion was observed in all 6 patients after 14 days.
Three patients exhibited contraction of their expanded T-cell receptor beta clones after 28 days.
Similarly, lentiviral-transduced CARTmeso induced expansion of T-cell receptor beta clones, both present and not present in the infused CAR T-cell product. “However, with [cyclophosphamide] preconditioning, clonal expansion seen after [lentiviral-transduced] CARTmeso therapy was predominately restricted to clones detected in the CAR T-cell product,” the authors wrote.
Study findings imply that patients with advanced solid tumors may benefit from CARTmeso, which stimulates clonal expansion of endogenous T-cells. This “vaccine”-like effect has the potential for therapeutic implications.
“There are a few ongoing trials in Asia looking at [CARTmeso] as well as multiple trials looking into lung and ovarian cancers.” Dr Kim told Journal of Clinical Pathways.—Zachary Bessette
