Vabilo na predavanje »Expanding the therapeutic index of adoptive T cell therapy for solid cancer«, ki ga bo imel Daniel J. Powell Jr., Ph.D.

The advent of CAR T cell therapy has revolutionized treatment of certain types of hematologic malignancies, yet achieving similar efficacy against solid tumors in the absence of significant toxicities remains a challenge. Our recent clinical trial results indicate that infused CAR T cells can infiltrate solid tumors and mediate modest tumor regression, yet creating curative therapy will first necessitate a better understanding of the limits of therapy and the mechanisms of resistance. To begin to address this issue, our research efforts have focused on maximizing the tumor antigen targeting capabilities of T cell products; identifying and overcoming mechanisms of immune suppression and resistance; and recruiting endogenous cells to participate in, and extend the breadth of, the immune response to cancer. Deep phenotypic and transcriptional analysis of naturally occurring, tumor infiltrating T cells (TILs) is now illuminating the requirements of effective T cell immunotherapy, serving as a guidepost for improving T cell product potency. With this understanding, tumor-reactive TILs can now be enriched directly from tumors for clinical application and synthetic biology can be applied to instill endogenous antitumor T cells with supraphysiological properties that bolster functional activity. Still, once administered to patients, CAR T cells and TILs need to contend with the hostile and immunosuppressive tumor microenvironment. As such, our ongoing efforts are focused on disentangling the suppressive cellular and acellular constituents of the microenvironment to better understand the major contributors to immune suppression in solid tumors. While myeloid cells in tumors have the potential to have pro-inflammatory activity and deliver positive costimulatory signals to T cells, myeloid cells are easily corrupted and repolarized to a suppressive phenotype by the tumor microenvironment yet durable deletion or reprogramming of these cells remains a challenge. Our recent work has identified a biomarker of suppressive myeloid cells in tumors in mice, which can be targeted by CAR T cells, and this work is now being extended to human tumor studies. Further, we find that the acellular milieu of tumors and their surrounding fluid has properties that can either improve or limit CAR T cell activity, which may be capitalized upon to create a more favorable microenvironment into which CAR T cells can be administered. Addressing such gaps in knowledge is central to the development of clinically actionable, synthetic biology approaches that overcome these immunologic hurdles, mitigate toxicity and bolster the effectiveness of adoptive T cell therapy against solid tumors.