Development Of Dual-Targeted Fine-Tuned Immune Restoring (Dfir) Car T Cell Therapy For Clear Cell Renal Cell Carcinoma (Ccrcc).

Abstract Clear cell renal cell carcinoma (ccRCC) is the major type of RCC and is among the 10 most common cancers in both men and women. Treatment of RCC has improved dramatically over the last decade, however, a curative treatment for advanced RCC remains rare. Chimeric Antigen Receptor (CAR) T cell therapy is a new type of “living drug”. The FDA approval of CAR-T cell therapies have ushered this new type of cellular immunotherapy into mainstream cancer therapy for hematologic malignancies. To date, these results have not been translatable to solid tumors due to inefficient homing of CAR-T cells, the immunosuppressive tumor microenvironment (TME), and on-target off-tumor toxicities due to shared antigens on normal tissues. Carbonic anhydrase IX (CAIX) is a therapeutic target against ccRCC that is under the control of HIF1α and becomes overexpressed on the surface of ccRCC cells because of VHL inactivation. The first anti-CAIX CAR-T study using the 1st generation G250-CD3 CAR-T cells plus IL-2 to treat patients with metastatic ccRCC was terminated due to hepatitis that developed after CAR-T cell infusions. The on-target off-tumor side effects were attributed to low expression of CAIX on healthy bile duct cells. To translate CAR-T cell therapy to ccRCC, we designed dual-targeted fine-tuned immune restoring (DFIR) CAR-T cells. The DFIR-CAR T cells secreted immune checkpoint inhibitor (ICI) monoclonal antibodies at the tumor site and exhibited superior efficacy and safety profiling. Increased efficacy is achieved through anti-CD70/CAIX dual-targeting CAR which allows the CAR-T cell activation in response to either antigen to mitigate solid tumor heterogeneity. Elevated safety is addressed through fine-tuned CARs which have the affinities of the scFv targeting moieties tailored so that they are activated only by high density tumor associated antigens (TAAs) but not the same antigens expressed at physiologic levels on normal tissues. The ICI payloads act globally on the TME, not only to prevent CAR-T cell exhaustion but also to restore anti-tumor activity of the educated tumor infiltrated lymphocytes (TILs) that have accumulated in the TME. In summary, our DFIR CAR-T cell therapy holds the promise to achieve cures of ccRCC by killing heterogenous ccRCC cells, mitigating against on-target off-tumor toxicity, reversing TME immunosuppression and restoring host anti-tumor immunity. We believe that DFIR-CAR T cells are ready to be translated to the clinic upon completion of pre-IND studies. Citation Format: Yufei Wang, Alicia Buck, Marion Grimaud, Sreekumar Kodangattil, Cecile Razimbaud, Atef Fayed, Matthew Chang, Aedin Culhane, David A. Braun, Toni K. Choueiri, Catherine J. Wu, Kevin S. Wei, Leo L. Chan, Brandon P. Piel, Elena V. Ivanova, Cloud P. Paweletz, David A. Barbie, Rebecca Jennings, Miriam Ficial, Maura Aliezah Sticco-Ivins, Sabina Signoretti, Gordon J. Freeman, Quan K. Zhu, Wayne A. Marasco. Development of dual-targeted fine-tuned immune restoring (DFIR) CAR T cell therapy for clear cell renal cell carcinoma (ccRCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 62.