Dual-Targeting CAR T Therapy Shows Potential in Advanced Kidney Cancer

Researchers are building on the success of CAR T-cell therapy in blood cancers to explore its use in clear cell renal cell carcinoma, a type of kidney cancer. According to Dr. Wayne A. Marasco, this work has led to the development of a dual-targeting CAR T-cell treatment for advanced disease in patients whose tumors overexpress CAIX and CD70.

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 clear cell renal cell carcinoma. 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 in Boston, Massachusetts.

Early CAR T-Cell Therapy Research in Renal Cell Carcinoma

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 evaluated Yescarta, a novel CD70-targeting CAR T-cell therapy, for the treatment of patients with advanced or refractory clear cell renal cell carcinoma.

Dose-limiting toxicities were not observed, and the disease control rate was 81%, 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 renal cell carcinoma that had relapsed on or was refractory to standard of care. 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.

The phase 1 TRAVERSE trial evaluated the CAR T-cell therapy Carvykti for the treatment of patients with advanced or metastatic clear cell renal cell carcinoma following lymphodepletion comprising fludarabine and cyclophosphamide with or without ALLO-647. Early data from the study demonstrated that among 44 patients, the overall response rate was 20% in patients treated with the lymphodepletion regimen (6 patients) who had CD70-positive tumors. Treatment-emergent side effects occurred in 96% of patients, with grade 3 or higher side effects observed in 84% of patients. Patients included on the study were at least 18 years of age with advanced clear cell renal cell carcinoma, 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 renal cell carcinoma. “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.”

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 tumor microenvironment by locally secreting checkpoint blockade inhibitors to restore antitumor immunity.

Preclinical Efficacy and Safety of CAR T-Cell Therapy in Clear Cell Renal Cell Carcinoma

Early efficacy data from a preclinical study demonstrated that CD70 is not universally expressed on renal cell carcinoma 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 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. “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 tumor microenvironment,” 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 Renal Cell Carcinoma

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 application to the FDA, he explained.

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

References

1. “Redesigning CAR T cells for solid tumors: a new path toward cures of ccRCC,” by Dr. Wayne A. Marasco. Presented at: 2025 Kidney Cancer Research Summit; July 17-18, 2025; Boston, MA.
2. “CD70-targeted allogeneic CAR T-cell therapy for advanced clear cell renal cell carcinoma,” by Dr. Sumanta K Pal. Cancer Discovery.
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.
4. “ALLO-316 in advanced clear cell renal cell carcinoma (ccRCC): updated results from the phase 1 TRAVERSE study,” by Dr. Samer A. Srour. Journal of Clinical Oncology.

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