A Novel CAR T-Cell Therapy Could Pave the Way for Improvements in Advanced ccRCC Management

Ongoing research with CAR T-cell therapy in clear cell renal cell carcinoma (ccRCC), which builds on successes achieved with this treatment modality in patients with hematologic malignancies, has supported the development of a dual-targeting CAR T-cell therapy for the treatment of patients with advanced ccRCC who have overexpression of CAIX and CD70, according to Wayne A. Marasco, MD, PhD.¹

During a presentation at the 2025 Kidney Cancer Research Summit, Marasco highlighted the goal of evaluating a dual-targeted, fine-tuned, and immune-restoring CAR T-cell therapy for the treatment of patients with CAIX- and CD70-overexpressing ccRCC. He noted that this therapeutic strategy, pending clinical investigation, may be a path toward curing this disease subtype.

Marasco is a professor of Medicine at Brigham and Women’s Hospital and a principal investigator of Cancer Immunology and Virology at Dana-Farber Cancer Institute, both in Boston, Massachusetts.

Early CAR T-Cell Therapy Research in RCC

Following the established role of CAR T-cell therapy for the management of hematologic malignancies, recent work has investigated the CAR T-cell therapy approach in solid tumors, Marasco explained. For example, the phase 1 COBALT-RCC trial (NCT04438083) evaluated CTX130, a novel CD70-targeting CAR T-cell therapy, for the treatment of patients with advanced or refractory ccRCC.² Of note, dose-limiting toxicities were not observed, and the disease control rate was 81.3%, with 1 patient remaining in durable complete response at 3 years.The study included 16 patients at least 18 years of age who weighed at least 42 kg with unresectable or metastatic RCC that had relapsed on or was refractory to standard of care.^2,3 Patients on the trial were also required to have a Karnofsky performance status of at least 80% and adequate renal, liver, cardiac, and pulmonary organ function.³

Furthermore, the phase 1 TRAVERSE trial (NCT04696731) evaluated the CAR T-cell therapy ALLO-316 for the treatment of patients with advanced or metastatic ccRCC following lymphodepletion comprising fludarabine and cyclophosphamide with or without ALLO-647.⁴ Early data from the study demonstrated that among 44 patients, the overall response rate was 20% in patients treated with the lymphodepletion regimen (n = 6/30) who had CD70-positive tumors. Treatment-emergent adverse effects (TEAEs) occurred in 96% of patients, with grade 3 or higher TEAEs observed in 84% of patients. Patients included on the study were at least 18 years of age with advanced ccRCC, an ECOG performance status of 0 or 1, and disease progression following immune checkpoint inhibition and VEGF-targeted therapy.

“What’s different about what we’re trying to do here is our target,” Marasco said in reference to the study of CAIX/CD70-directed CAR T-cell therapy in RCC.¹ “Our CAR T cells are dual-targeted, and the affinity is fine-tuned to improve safety. We do immune-restoring capabilities at the tumor site to change the tumor microenvironment [TME].”

Specifically, the dual-targeting aspect of the CAIX/CD70-directed CAR T-cell product aims to improve efficacy, whereas the fine-tuned aspect aims to improve safety by targeting only high-density antigen expressed on the tumor cells without targeting low density antigen on healthy tissues. Moreover, the immune-restoring aspect changes the TME by locally secreting checkpoint blockade inhibitors to restore antitumor immunity.

Preclinical Efficacy and Safety of CAR T-Cell Therapy in ccRCC

Early efficacy data from a preclinical study demonstrated that CD70 is not universally expressed on RCC cells, and therefore, some targets were CD70-negative, Marasco explained.

“[However,] all tumors express CAIX, which is still the molecule that is most desirable. The killing data in the immunofluorescence [analysis] show the specificity of the dual-targeted CAR [T-cell therapy] for both targets. In humanized animal studies, the [respective] CAR T-cell therapy effectively cured the animals from the tumors, and in these animals, we don’t even see the tumors after the therapy,” he said.

Although preliminary efficacy data have shown promise, safety data have been the most significant concern, notably due to CAIX overexpression, Marasco added.

“We spent over a decade working this out to be able to develop high-avidity, low-affinity antibodies as the targeting moiety. Why would you want that? Well, we certainly don’t want to target CAIX if it’s in limited quantities, because a high-affinity targeting residue will bind to it,” he said. “Therefore, you want only targeting molecules that are recognized with high density, and that’s what we engineered.”

Most notably, the immune-restoring aspect of this therapy is “the most important part of this change in the TME,” according to Marasco.

“If we [administer] CAR T-cell therapy without delivering a payload to the tumor site, we do not ever cure the animals of tumors,” Marasco emphasized. “If we deliver monoclonal antibodies at the tumor sites, which is what we’re doing, we secrete antibodies [and] checkpoint blockade inhibitors locally at the tumor site, [and] we can get complete cures.”

Future Steps for Examining CAR T-Cell Therapy in RCC

The investigational dual-targeted CAR T-cell therapy in development by Marasco and colleagues targets CAIX and CD70 and delivers an anti–PD-1 and -CTLA4 bispecific antibody at the tumor site, Marasco reported. Currently, ongoing preclinical studies with this product are nearing finishing stages, which will guide the next step of GMP manufacturing and subsequently submitting an investigational new drug (IND) application to the FDA, he explained.

“We’re on schedule to be able to complete this [preclinical research] and file an IND sometime, hopefully in September or October [2025],” Marasco concluded.

References

1. Marasco WA. Redesigning CAR T cells for solid tumors: a new path toward cures of ccRCC. Presented at: 2025 Kidney Cancer Research Summit; July 17-18, 2025; Boston, MA.
2. Pal SK, Tran B, Haanen JBAG, et al. CD70-targeted allogeneic CAR T-cell therapy for advanced clear cell renal cell carcinoma. Cancer Discov. 2024;14(7):1176-1189. doi:10.1158/2159-8290.CD-24-0102
3. A safety and efficacy study evaluating CTX130 in subjects with relapsed or refractory renal cell carcinoma (COBALT-RCC). ClinicalTrials.gov. Updated January 8, 2025. Accessed July 17, 2025. https://www.clinicaltrials.gov/study/NCT04438083
4. Srour SA, Chahoud J, Drakaki A, et al. ALLO-316 in advanced clear cell renal cell carcinoma (ccRCC): updated results from the phase 1 TRAVERSE study. J Clin Oncol. 2025;42 (suppl 16):4508. doi:10.1200/JCO.2025.43.16_suppl.4508