Though tumor targeting using chimeric receptors (CAR) engineered to bind tumor-associated surface proteins such as CD19 in B cells have demonstrated remarkable efficacy in cancer, this therapy has hit a glass ceiling w.r.t. initial and durable remissions. Inclusion of a costimulatory domain in the CAR design have solved much of limited clinical efficacy issues, some challenges remained. We have recently demonstrated that T cell-intrinsic mechanisms solved part of the glass ceiling conundrum in leukemia, we recently demonstrated that primary chronic lymphocytic leukemia cells elicit a blunted response of second generation CAR T cells, even when using normal donor CAR-engineered T cells. In my talk I will highlight our discoveries in T cell- and tumor-intrinsic determinants of anti-CD19 CAR T cell responses in this disease.
1. Classify the Chimeric Antigen Receptor (CAR)-engineered T cells have dramatically altered the clinical outlook for many blood cancers
2. Identify that with the discovery of costimulation as a critical component of an effective T cell responses and the inclusion of such domains in CAR design we have overcome previous significant roadblocks, but encountered new challenges along the way
3. Recognize the part of what explains response and resistance to this therapy is T cell-intrinsic; however, even the most efficacious CAR showed ineffective against primary tumor cells
4. Summarize the highlights of some of our discoveries in elucidating T cell- and tumor-cell-intrinsic determinants of CAR T cell efficacy