Tumor infiltrating lymphocytes (TIL) consist of immune cells enriched in the tumor microenvironment. These cellular populations often contain tumor reactive T cells which mediate tumor cell killing and represent a potential therapeutic opportunity for treating cancers. Interestingly, tumors are also frequently infiltrated with B cells that can provide co-stimulation to T cells, resulting in significantly enhanced TIL expansion and a more favorable differentiation phenotype. It has been shown that ex vivo expansion and adoptive transfer of tumor infiltrating lymphocytes can induce durable responses in melanoma patients. While FDA approval is anticipated, there are still challenges to overcome for widespread implementation of this therapy, which are linked to the undefined nature of the drug product and interpatient variability in response to treatment.
The goal of this project is to unveil the molecular and cellular factors that condition the number and quality of ex vivo expanded TILs, in order to systematically design standardized production protocols. Previously, Shari Pilon-Thomas and her collaborators determined that melanoma infiltrating B cells include naïve and memory lymphocytes that respond to CD40 agonism by increasing the expression of activation markers. They have identified CD83 and IL27 as potential mediators of this effect and will test this hypothesis through functional in vitro and in vivo experiments. In addition, they will test the hypothesis that other tumors that are naturally infiltrated with B cells can also yield better TILs through CD40 stimulation. They will establish a proof of concept using melanoma TIL and PDX models, and then validate the results using bladder cancer and renal cell carcinoma tumors.
The knowledge obtained through this project will allow the investigators to reduce interpatient variability by defining key elements that stimulate T cell growth. Developing strategies to better define and standardize the composition and expansion process of human TILs will facilitate the implementation of TIL therapy beyond melanoma. Successful completion of this project will provide rationale for immediate clinical translation.