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Clinical Trial
. 2024 Jul 1;14(7):1176-1189.
doi: 10.1158/2159-8290.CD-24-0102.

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

Sumanta K Pal  1 , Ben Tran  2 , John B A G Haanen  3   4   5 , Michael E Hurwitz  6 , Adrian Sacher  7   8 , Nizar M Tannir  9 , Lihua E Budde  1 , Simon J Harrison  2 , Sebastian Klobuch  3 , Sagar S Patel  10 , Luis Meza  1 , Mary-Lee Dequeant  11 , Anna Ma  11 , Qiuling Ally He  11 , Leah M Williams  11 , Alissa Keegan  11 , Ellen B Gurary  12 , Henia Dar  11 , Sushant Karnik  11 , Changan Guo  12 , Heidi Heath  11 , Rachel R Yuen  11 , Phuong K Morrow  12 , Neeraj Agarwal  13 , Samer A Srour  9
Affiliations
Clinical Trial

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

Sumanta K Pal et al. Cancer Discov. .

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.

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Conflict of interest statement

S.K. Pal reports other support from CRISPR, Ipsen, and Exelixis during the conduct of the study. B. Tran reports other support from CRISPR during the conduct of the study; grants and personal fees from Amgen, Astra Zeneca, Astellas, BMS, MSD, Merck, Pfizer, Janssen, Bayer, Ipsen, and Sanofi and grants from Roche outside the submitted work. J.B. Haanen reports grants from Amgen, Asher Bio, BMS, BioNTech, and Sastra Cell Therapy outside the submitted work; and provided advice to Agenus, AZ, BMS, CureVac, GSK, Imcyse, Iovance Bio, Immunocore, Ipsen, Merck Serono, MSD, Molecular Partners, Obsedian Tx, Novartis, Orgenesis, Pfizer, Roche/ Genentech, Sanofi, and Third Rock Ventures and participated in the SAB of Achilles Tx, BioNTech, Instil Bio, Neogene Therapeutics (AZ), PokeAcell, Sastra Cell Therapy, Scenic, and T-Knife. M.E. Hurwitz reports other support from CRISPR Therapeutics during the conduct of the study; other support from Affini-T therapeutics, Exelixis, Pliant Therapeutics, Janssen, Regeneron, TScan, and grants from Astra Zeneca and Iovance outside the submitted work. A. Sacher reports other support from CRISPR Therapeutics during the conduct of the study; other support from Amgen, AstraZeneca, BMS, CRISPR Therapeutics, Lilly/LOXO, Genentech, GSK, Iovance, Merck, Pfizer, Spectrum, and Merck outside the submitted work. L.E. Budde reports other support from City of Hope during the conduct of the study; personal fees from BMS, Kite Pharma, and Janssen outside the submitted work; in addition, L.E. Budde has a patent for CD33CAR issued. S.J. Harrison reports other support from AbbVie, Amgen, Celgene/ BMB, CSL Bering, GSK, grants, nonfinancial and other support from Janssen Cilag, Novartis, Kite/Gilead, other support from Roche/ Genetec, Haemalogix, and Eusa outside the submitted work. S. Klobuch reports Advisory Board for Regeneron Pharmaceuticals. S.S. Patel reports personal fees from Sanofi outside the submitted work. L. Meza reports personal fees from Ipsen outside the submitted work. M. Dequeant reports a patent for genetically engineered T cells with Regnase-1 and TGFBRII disruption have improved functionality and persistence issued, a patent for Anti-idiotype antibodies targeting anti-CD70 chimeric antigen receptor issued, a patent for Methods and compositions for treating cancer issued, a patent for CD70+ solid tumor therapy using genetically engineered T cells targeting CD70 pending, a patent for methods for manufacturing genetically engineered CAR T cells pending, and a patent for Renal Cell Carcinoma Therapy using genetically engineered T cells targeting CD70 pending. A. Ma reports other support from CRISPR Therapeutics outside the submitted work. Q.A. He reports being an employee of CRISPR Therapeutics. H. Dar reports other support from CRISPR Therapeutics during the conduct of the study. P.K. Morrow reports other support from CRISPR Therapeutics during the conduct of the study. N. Agarwal reports grants from CRISPR during the conduct of the study; personal fees from Lilly, Gilead and Foundation Medicine outside the submitted work; and Neeraj N. Agarwal has received honorarium before May 2021 and during his lifetime for consulting to Astellas, AstraZeneca, Aveo, Bayer, Bristol Myers Squibb, Calithera, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Gilead, Janssen, Merck, MEI Pharma, Nektar, Novartis, Pfizer, Pharmacyclics, and Seattle Genetics; and has received research funding during his lifetime from Arnivas, Astellas, AstraZeneca, Bavarian Nordic, Bayer, Bristol Meyers Squibb, Calithera, Celldex, Clovis, CRISPR Therapeutics, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Gilead, Glaxo Smith Kline, Immunomedics, Janssen, Lava, Medivation, Merck, Nektar, Neoleukin, New Link Genetics, Novartis, Oric, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, and Tracon. No disclosures were reported by the other authors.

Figures

Figure 1.
Figure 1.
Preclinical efficacy and antitumor activity of CTX130. A, Proliferation of CTX130 versus CD70+ CAR T cells. B, CTX130 and CD70+ anti-CD70 CAR T-cell cytotoxicity as a percentage of cell lysis after repeated challenges with CD70+ A498 cells. Data points represent a single measurement. C, CTX130 cytotoxicity toward CD70high (A498), CD70low (ACHN), and CD70− (MCF7) cell lines. Results from cells treated with CTX130 are shown with solid circles, and results from cells treated with unedited T cells are shown with open squares. The graph shows the mean ± SD from 3 technical replicates with increasing ratios of CTX130 or unedited T cells to tumor cells (0.125:1 to 4:1). D, Antitumor activity of CAR T cells in an RCC xenograft model. Mice were either left untreated (n = 5) or injected with CTX130 (n = 5) or CD70+ anti-CD70 CAR T cells (n = 4). Each point represents the mean tumor volume ± SEM. E, Disruption of the PD-1 checkpoint gene is detrimental to CTX130 CAR T-cell function in a xenograft rechallenge model. Following the first injection of tumor cells, mice (n = 5 per group) were left untreated (open circles) or treated with CTX130 (open squares) or PD1− CTX130 CAR T cells (open triangles). At the day 25 rechallenge, fresh tumor cells were injected into the left flank of treated mice (CTX130-treated and PD1− CTX130-treated animals represented by solid circles and solid triangles, respectively) and a new control group (open lozenges). Each point represents the mean tumor volume ± SEM. F, Mortality due to GvHD in mice (n = 30 per group) treated with unedited T cells or low (20 million cells/mouse) or high (40 million cells/mouse) doses of CTX130. CAR, chimeric antigen receptor; CD, cluster of differentiation; EP, electroporation; GvHD, graft versus host disease; KO, knockout; PD-1, programmed cell death 1; RCC, renal cell carcinoma.
Figure 2.
Figure 2.
Clinical efficacy and pharmacokinetics of CTX130 and CD70 expression in a phase I clinical trial. A, Responses in COBALT-RCC participants stratified by DL received. B, Mean ± SEM peripheral blood concentrations of CTX130 over 28 days after first infusion at DL4 (n = 4). Values below the LOD were imputed as half the LOD value. C, Peak expansion of CTX130 in peripheral blood following the first infusion at each DL tested in the COBALT-RCC trial. Each bar represents the geometric mean ± geometric SD with each point representing the peak expansion of 1 patient (n = 16). D, Representative 20× image of CD70 IHC staining in the tumor. Scale bar, 200 μm. E, CD70 positivity in tumor cells before treatment (n = 13), day 7 after infusion (n = 9), and day 42 after infusion (n = 10). Each point represents a tumor biopsy sample from 1 patient, and bars represent median values. CAR, chimeric antigen receptor; Cmax, peak expansion concentration; DL, dose level; IHC, immunohistochemistry; LOD, limit of detection.
Figure 3.
Figure 3.
CTX131 efficacy studies. A, Tumor growth in a xenograft rechallenge model. Following the injection of tumor cells, mice (n = 4 per group) were left untreated (black circles) or treated with CTX130 (black squares), CTX130 + Regnase-1 KO (black triangles), CTX130 + TGFβR2 KO (black inverted triangles), or CTX131 (red squares). Note that only mice receiving CAR T cells showing efficacy in the previous challenge were subjected to rechallenge. Each point represents the mean tumor volume ± SEM. B, CAR T cell counts in mouse whole blood were measured by flow cytometry at day 44 after CAR T injection. CAR T cells were identified as human CD45+/CD70 CAR+/CD3− cells. Error bars, SEM. n = 2 biological replicates. LLOD = 3 counts/100 μL blood. CAR, chimeric antigen receptor; KO, knockout; LLOD, lower limit of detection; TGFβR2, transforming growth factor β receptor 2; RCC, renal cell carcinoma.
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