Abstract 1150: CD70 HIT T cells overcome tumor antigen heterogeneity in renal cell carcinoma

CAR T cells have revolutionized the treatment of hematologic malignancies but have not yet achieved the same curative or deep responses for solid tumors like renal cell carcinoma (RCC). One of the major reasons for this lack of clinical success is the heterogeneous expression of target tumor antigens in solid tumors. In order to better understand the limitations of CAR T cell therapy in the solid tumor setting, we utilized two clear cell RCC patient-derived xenograft models (PDX), which replicate CD70 and carbonic anhydrase IX (CAIX) heterogeneity of expression seen in patient kidney tumor samples. We evaluated individual CD70 CAR T or CAIX CAR T cells in PDX-bearing NSG mice and showed only partial tumor clearance. This was not due to lack of tumor infiltration since we observed trafficking to tumor sites with in vivo T cell and tumor imaging. Even with a dual targeting approach combining CD70 and CAIX CAR T cells to increase tumor coverage, we did not eradicate the kidney tumors. By analyzing the tumor antigen profiles of relapsing kidney tumors, we found that the CD70 and CAIX positive populations were cleared but detected a residual CD70 and CAIX double-negative population. Based on transcriptomic and proteomic analyses of these residual populations, we detected CD70 expression, which suggested that these CD70/CAIX double negative populations did in fact, have ultra-low CD70 expression which was not at a level high enough to be eliminated by CD70 CAR T cells. This key finding revealed that CD70 expression was not present or absent but rather present in a spectrum ranging from high to very low. Based on this fundamental observation, we hypothesized that a highly sensitive HLA-independent T cell receptor (HIT receptor) may be used to target this ultra-low CD70 population. Indeed, treatment with CD70 HIT T cells resulted in complete and long-lasting tumor cures in both PDX models. Our findings show that we can overcome the major challenge of tumor antigen heterogeneity in RCC because apparent CD70-negative tumor populations retain CD70 expression and can be targeted by a highly sensitive HIT T cell. This represents a significant advance for the development of a potentially effective cellular therapy for RCC, which may be applicable to other aggressive CD70-positive tumors like ovarian and pancreatic cancers. Our findings underscore the critical importance of assessing antigen expression in a quantitative manner to determine if antigens are truly absent or present at very low levels, in which case they may be responsive to an engineered antigen-sensitive immune cell as afforded by the HIT receptor. Citation Format: Sophie A. Hanina, Michael Lopez, Huiyong Zhao, Rajasekhar Vinagolu, Ritesh Kotecha, A Ari Hakimi, John H. Healey, Jorge Mansilla-Soto, Michel Sadelain. CD70 HIT T cells overcome tumor antigen heterogeneity in renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1150.