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

An abundance of trials exploring the use of chimeric antigen receptor (CAR) T-cell therapy in advanced renal cell carcinoma (RCC) after progression of disease suggest a promising future but definitive advancements remain to be seen, according to Michael Hurwitz, MD, PhD.

Several clinical trials are ongoing in RCC, most of which involve therapies targeting CD70, as well as CAIX, AXL, ROR2, VEGFR2, MUC1, and c-MET. “The ones I’m going to concentrate on today are the CAIX and CD70 [because] those are the only ones for which we have results,” Hurwitz, associate professor of internal medicine (medical oncology) at Yale School of Medicine in New Haven, Connecticut, in a presentation delivered during the 2023 International Kidney Cancer Symposium.¹

The first trial Hurwitz covered was that of a CAIX CAR-engineered T cell, results from which showed the importance of the “on-tumor, off-target effect.” Although CAIX is highly expressed in kidney cancer, it is also found in biliary epithelium. In the trial, half of patients in the first two cohorts had dose-limiting liver toxicity, but when an anti-CAIX antibody was administered to patients in the third cohort to mitigate the toxicity, no objective responses occurred.²

An alternative target is CD70, Hurwitz said, with high expression across clear cell, papillary, sarcomatoid, chromophobe, and translocation histologies.³

Hurwitz first discussed the phase 1 COBALT-RCC trial (NCT04438083), which evaluated CTX130 allogeneic CRISPR-Cas9–engineered CAR T cells in patients with advanced clear cell RCC.

“The advantages [of allogeneic products] are you don’t have to wait 4 weeks to get this into patients; the cells that you get are from healthy donors [with an] intact immune system, and you can make tons of it,” Hurwitz said. The trial evaluated 4 dose levels ranging from 3 × 10⁷ to 9 × 10⁸ CAR T cells, but only 1 response was seen in the first dose level cohort. Nine patients experienced stable disease, translating to a disease control rate (DCR) of 77% (n = 10). By 4 months, only 4 patients remained in stable disease. The 1 patient with partial response reached complete response by month 3 and has sustained this response through month 18.

The product was also safe, with no dose-limiting toxicities observed across any of the dose levels. Overall (n = 14), 7 patients experienced grade 1/2 cytokine release syndrome (CRS), and 4 patients experienced infections (grade 1/2, n = 2; grade ≥3, n = 2). “There were no instances of tumor lysis syndrome, infusion reactions, HLH, ICANS, GVHD or second malignancies,” Hurwitz said.⁴

Another allogeneic cell therapy, data from which were presented at the 2023 AACR Annual Meeting, has also generated excitement for the future of cellular therapy. In results from the phase 1 TRAVERSE trial (NCT04696731), ALLO-316 demonstrated preliminary antitumor activity in patients with advanced or metastatic clear cell RCC.

The trial was similar to COBALT-RCC in that investigators evaluated an anti-CD70 allogeneic CAR T-cell therapy. However, the studies had several differences. “They knocked out the T-cell receptor, so they wouldn’t recognize the recipient, and they knocked out CD52. The reason they did that is so they could use an anti-CD52 antibody, and that’s very immunosuppressive. They do that to make sure that these T cells stay around. They also knocked out CD70 because although CD70 is highly expressed in kidney cancer cells, it also is upregulated on active immune cells and they were worried about fratricide,” Hurwitz said.

The product was shown to be “pretty safe” Hurwitz said, although the rate of all-grade CRS was 58% (grade ≥3, 5%). In addition, among all patients who received ALLO-316 (n = 19), infusion-related reactions (all grade, 5%), neurotoxicity (all grade, 68%; grade ≥3, 11%), infection (all grade, 42%; grade ≥3, 21%), and prolonged grade 3 cytopenia (16%) occurred. Higher efficacy was seen with the product, Hurwitz said, with an objective response rate (ORR) of 17% and a DCR of 89% among the 18 patients evaluable for efficacy.

Notably, in patients with CD70-positive disease (n = 10), the ORR was 30% and the DCR was 100%. Moreover, median progression-free survival was 5.0 months in this population.

“They also showed that even 70 or 80 days out if they use a very strong conditioning regimen, the [cells] stayed around a long time. And we know that durability of response has to do with persistence of the cells,” Hurwitz said. Additionally, ALLO-316 was shown to eliminate CD70-positive host T cells, preventing allorejection and supporting persistence.

Hurwitz concluded by explaining that for CAR T-cell therapy to land in the kidney cancer armamentarium, several challenges will need to be addressed including persistence, antigen loss from therapy, tumor microenvironment toxicity, and the inability to infiltrate the tumor.

“This [area of research] is exciting, there are some responses, [but] we’re not there yet. This is just the beginning because there are many different technologies that we can use to make these T cells much more effective,” he said.

References

1. Hurwitz ME. CAR-T therapy for kidney cancer. Presented at: 2023 International Kidney Cancer Symposium; November 9-11, 2023. Accessed November 10, 2023.

2. Lamers Cor HJ, Slijfer S, van Steenbergen S, et al. Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: clinical evaluation and management of on-target toxicity. Mol Ther. 2013;21(4):904-912. doi:10.1038/mt.2013.17

3. Panowski SH, Srinivasan S, Tan N, et al. Preclinical development and evaluation of allogeneic CAR T cells targeting CD70 for the treatment of renal cell carcinoma. Cancer Res. 2022;82(14):2610-2624. doi:10.1158/0008-5472.CAN-21-2931

4. Pal SK, Tran B, Haanen JB, et al. CTX130 allogeneic CRISPR-Cas9–engineered chimeric antigen receptor (CAR) T cells in patients with advanced clear cell renal cell carcinoma: results from the phase 1 COBALT-RCC study. Presented at: Society for Immunotherapy of Cancer’s 37th Annual Meeting; November 6-10, 2022; Boston, MA. Accessed December 5, 2022.

5. Srour SA, Kotecha R, Curti B, et al. A phase 1 multicenter study (TRAVERSE) evaluating the safety and efficacy of ALLO-316 following conditioning regimen in pts with advanced or metastatic clear cell renal cell carcinoma (ccRCC). Presented at: 2023 AACR Annual Meeting; April 14-19, 2023; Orlando, FL. Abstract CT011.