CD70-Targeted Allogeneic CAR T-Cell Therapy for Advanced Clear Cell Renal Cell Carcinoma

Author:

Pal Sumanta K.1ORCID,Tran Ben2ORCID,Haanen John B.A.G.345,Hurwitz Michael E.6ORCID,Sacher Adrian78ORCID,Tannir Nizar M.9ORCID,Budde Lihua E.1ORCID,Harrison Simon J.2ORCID,Klobuch Sebastian3ORCID,Patel Sagar S.10ORCID,Meza Luis1ORCID,Dequeant Mary-Lee11ORCID,Ma Anna11ORCID,He Qiuling Ally11ORCID,Williams Leah M.11ORCID,Keegan Alissa11ORCID,Gurary Ellen B.12ORCID,Dar Henia11ORCID,Karnik Sushant11ORCID,Guo Changan12ORCID,Heath Heidi11ORCID,Yuen Rachel R.11ORCID,Morrow Phuong K.12ORCID,Agarwal Neeraj13ORCID,Srour Samer A.9ORCID

Affiliation:

1. Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, California. 1

2. Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia. 2

3. Netherlands Cancer Institute, Amsterdam, the Netherlands. 3

4. Leiden University Medical Center, Leiden, the Netherlands. 4

5. Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. 5

6. Yale School of Medicine, New Haven, Connecticut. 6

7. Princess Margaret Cancer Centre, University Health Network, Toronto, Canada. 7

8. Departments of Medicine and Immunology, University of Toronto, Toronto, Canada. 8

9. University of Texas MD Anderson Cancer Center, Houston, Texas. 9

10. Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah. 10

11. CRISPR Therapeutics, Boston, Massachusetts. 11

12. Formerly employed by CRISPR Therapeutics, Boston, Massachusetts. 12

13. Division of Medical Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah. 13

Abstract

Abstract Therapeutic approaches for clear cell renal cell carcinoma (ccRCC) remain limited; however, chimeric antigen receptor (CAR) T-cell therapies may offer novel treatment options. CTX130, an allogeneic CD70-targeting CAR T-cell product, was developed for the treatment of advanced or refractory ccRCC. We report that CTX130 showed favorable preclinical proliferation and cytotoxicity profiles and completely regressed RCC xenograft tumors. We also report results from 16 patients with relapsed/refractory ccRCC who received CTX130 in a phase I, multicenter, first-in-human clinical trial. No patients encountered dose-limiting toxicity, and disease control was achieved in 81.3% of patients. One patient remains in a durable complete response at 3 years. Finally, we report on a next-generation CAR T construct, CTX131, in which synergistic potency edits to CTX130 confer improved expansion and efficacy in preclinical studies. These data represent a proof of concept for the treatment of ccRCC and other CD70+ malignancies with CD70− targeted allogeneic CAR T cells. Significance: Although the role of CAR T cells is well established in hematologic malignancies, the clinical experience in solid tumors has been disappointing. This clinical trial demonstrates the first complete response in a patient with RCC, reinforcing the potential benefit of CAR T cells in the treatment of solid tumors. See corresponding author Sumanta K. Pal discuss this research article, published simultaneously at the AACR Annual Meeting 2024: https://vimeo.com/932606570/887520f9cb

Publisher

American Association for Cancer Research (AACR)

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