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    Despite Early Promises, Challenges Remain for CAR T-Cell Therapy in Advanced RCC

    The Surprising Future of CAR-T Therapy for Kidney Cancer: Promising Advances Await

    The landscape of treatment options for advanced renal cell carcinoma (RCC) may be on the verge of a dramatic shift, thanks to the exciting potential of chimeric antigen receptor (CAR) T-cell therapy. While definitive advancements in this field are yet to be fully realized, ongoing trials exploring the use of CAR-T therapy after disease progression have shown promising results. Renowned expert Michael Hurwitz, MD, PhD, Associate Professor of Internal Medicine (Medical Oncology) at Yale School of Medicine, discussed the current state and future prospects of CAR-T therapy for RCC during the 2023 International Kidney Cancer Symposium.

    A Plethora of Trials: Exploring New Targets

    Several clinical trials are currently investigating the efficacy of CAR-T therapy in RCC, with a particular focus on novel targets such as CD70, CAIX, AXL, ROR2, VEGFR2, MUC1, and c-MET. Hurwitz’s presentation concentrated on CAIX and CD70, as these are the only targets for which results have been reported. CAIX CAR-engineered T-cell therapy, for instance, showed great promise in targeting kidney cancer specifically, given the high expression of CAIX in RCC. However, liver toxicity emerged as a significant concern, as CAIX is also present in the biliary epithelium. Administering an anti-CAIX antibody along with CAR-T therapy in an attempt to mitigate liver toxicity, unfortunately, did not yield any objective responses.

    On the other hand, CD70 emerged as an alternative target with significant potential in multiple RCC histologies, including clear cell, papillary, sarcomatoid, chromophobe, and translocation subtypes. Phase 1 clinical trials, such as the COBALT-RCC trial (NCT04438083), evaluated the efficacy of CTX130 allogeneic CRISPR-Cas9-engineered CAR-T cells in patients with advanced clear cell RCC. By testing different dose levels, the trial demonstrated promising results, including a disease control rate of 77% and an objective response rate of 17%.

    Looking Beyond Efficacy: Safety and Challenges

    Alongside efficacy, safety is a crucial consideration for CAR-T therapy. The COBALT-RCC trial demonstrated the safety of CTX130 CAR-T cells, with only mild cases of cytokine release syndrome (CRS) and infections reported. Importantly, no dose-limiting toxicities or instances of tumor lysis syndrome, infusion reactions, hemophagocytic lymphohistiocytosis, immune effector cell-associated neurotoxicity syndrome, graft-versus-host disease, or second malignancies were observed.

    In another exciting development, the ALLO-316 CAR-T cell therapy, targeting CD70, showed preliminary antitumor activity in patients with advanced or metastatic clear cell RCC in the TRAVERSE trial (NCT04696731). Although the trial reported higher rates of CRS and neurotoxicity compared to other studies, the therapy exhibited an objective response rate of 17% and a disease control rate of 89% among evaluable patients. Notably, patients with CD70-positive disease achieved an objective response rate of 30%, and the median progression-free survival reached 5.0 months in this subgroup.

    Overcoming Challenges: Durability and Tumor Microenvironment

    While CAR-T therapy holds tremendous promise, several challenges need to be addressed for it to become a significant component of the kidney cancer treatment arsenal. One such challenge is the persistence of CAR-T cells within the body, as long-lasting responses are typically associated with sustained presence. Additionally, the potential loss of target antigens post-therapy, toxicity within the tumor microenvironment, and difficulties in infiltrating the tumor pose obstacles that require further exploration and enhancement of CAR-T therapy design.

    The Future Beckons: A Beginning, Not an End

    Exciting as the current progress may be, it is important to acknowledge that CAR-T therapy for RCC is still in its early stages. The ongoing clinical trials provide a foundation for further research and development in this field. As Hurwitz mentioned, various technologies can potentially enhance the effectiveness of CAR-T cells, paving the way for more significant advancements in the future.

    In conclusion, the future outlook for CAR-T therapy in treating advanced RCC is filled with promise. Although definitive advancements are yet to be made, the ongoing trials exploring innovative targets, such as CAIX and CD70, indicate that CAR-T therapy could revolutionize the treatment paradigm for kidney cancer. By addressing challenges related to durability, tumor microenvironment toxicity, and enhanced tumor infiltration, CAR-T therapy has the potential to become a formidable weapon against RCC. The journey has just begun, and with further advancements and refinements, CAR-T therapy could become a game-changer in the fight against renal cell carcinoma.

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