Engineering smarter T cells

Abstract
The emergence of immune-oncology as the first broadly successful strategy for metastatic cancer will require clinicians to integrate this new pillar of medicine with the pillars of chemotherapy, radiation and targeted small molecule compounds. Chimeric antigen receptor (CAR) T cells have proven that engineered immune cells can serve as a powerful new class of cancer therapeutics. Adoptive immunotherapy retargeting T cells to CD19 via a chimeric antigen receptor (CAR) is an investigational treatment capable of inducing complete tumor regression of B-cell malignancies when there is sustained survival of infused cells. Clinical experience has helped to define the major challenges that must be met to make engineered T cells a reliable, safe, and effective platform that can be deployed against a broad range of tumors. The emergence of synthetic biology approaches for cellular engineering is provides the field with a broadly expanded set of tools for programming immune cells. In this presentation, I will discuss how these tools could be used to design the next generation of smart T cell precision therapeutics.
In solid tumors, we have observed antitumor activity in patients with ovarian cancer, pancreatic ductal adenocarcinoma, pleural mesothelioma and glioblastoma following infusion of CAR T cells expressing scFv specific for mesothelin or EGFRvIII. However, this approach has not yet resulted in complete tumor eradication. Using genome edited T cells, it may be possible to enhance and prolong the activity of T cells that have disrupted immune and metabolic checkpoints. In preclinical studies, we show that TCR-specific T cells have enhanced antitumor activity following disruption of TCR alpha and beta genes and the PD1 gene using CRISPR/Cas9. This approach is just entering a clinical trial. These findings provide insights into the immunobiology of effector T cells and demonstrate the potential of multiplexed CRISPR/Cas9 genome editing to synthetically enhance the efficacy of immunotherapy.

 

Biosketch
Carl June is the Director of the Center for Cellular Immunotherapies at the Perelman School of Medicine, and Director of the Parker Institute for Cancer Immunotherapy at the University of Pennsylvania. He maintains a research laboratory that studies various mechanisms of lymphocyte activation that relate to immune tolerance and adoptive immunotherapy for cancer and chronic infection. In 2011, his research team published findings detailing a new therapy in which patients with refractory and relapsed chronic lymphocytic leukemia were treated with genetically engineered versions of their own T cells. The treatment has also now also been used with promising results to treat children with refractory acute lymphoblastic leukemia. He has published more than 350 manuscripts and is the recipient of numerous prizes and honors, including election to the Institute of Medicine in 2012 and the American Academy of Arts and Sciences in 2014, the Paul Ehrlich and Ludwig Darmstaedter Prize (shared w J. Allison), the Novartis Prize in Immunology (shared w Z. Eshaar and S. Rosenberg), the Karl Landsteiner Memorial award, and a lifetime achievement award from the Leukemia and Lymphoma Society.