Cancer Immunol Res July 1 2013 1 (1) 1-1; DOI:10.1158/2326-6066.CIR-13-0077
Chimeric antigen receptor–expressing T cells (CAR-T cells) represent a promising, novel form of adoptive immunotherapy to overcome tolerance to cancer. Using an intermittent dosing schedule of autologous CAR-T cells electroporated with mRNA encoding a hybrid single chain molecule comprising the extracellular domain of murine monoclonal antibody against human mesothelin and the human transmembrane and cytoplasmic T-cell signaling domains, Maus and colleagues characterized and reported a serious adverse event that occurred in one of four patients receiving repeated modified T-cell infusions, with proposed modifications to address and minimize future adverse occurrence.
The therapeutic potential of CTLA-4 blockade is evident in the ability of anti-CTLA-4 antibody to induce regression of established tumors. In an elegant set of experiments using a panel of murine immunoglobulin in various isotypes, Selby and colleagues delineated the mechanism of action of CTLA-4 blockade. Anti-CTLA-4 promotes antitumor activity by a selective reduction of intratumoral T-regulatory cells along with concomitant activation of T-effector cells.
To decrease therapy-induced autoimmunity due to on-target toxicity against normal tissues, Lanitis and colleagues developed a trans-signaling CAR-based immunotherapy strategy in which the T-cell activation signal is physically dissociated from the costimulatory signal in two CARs of differing antigen specificity. Their findings show that this dual-specificity, trans-signaling CAR approach can potentiate the therapeutic efficacy of CAR-T cells against cancer while minimizing parallel reactivity against normal tissues bearing single antigen.
Using paraffin-embedded specimens from 49 patients diagnosed with various stages of Merkel cell carcinoma (MCC), Lipson and colleagues found PD-L1 expression in approximately 50% of these rare tumors. PD-L1+ carcinomas were invariably associated with immune infiltrates and the presence of Merkel cell polyomavirus DNA. These findings suggest that an endogenous immune response, perhaps directed in part to MCC-related antigen, promotes PD-L1 expression in the tumor microenvironment and provide a rationale for investigating therapies blocking PD-1/PD-L1 for patients with MCC.
IL-6+/+ MDSC dampened the induction of TH1 cells and CD4+ T-cell cognate help for CD8+ T cells, and temporal blockade of IL-6 activity at the T-cell priming phase restored TH1 cell differentiation. Tsukamoto and colleagues identify Gr-1+ MDSC as a source of IL-6 in tumor-bearing mice and show that IL-6+/+ MDSC-sensitized CD4+ T cells were less potent in mounting antitumor immune responses. In the aggregate, these results suggest that MDSC-derived IL-6 contributes to the dysfunction of host antitumor responses.