CRISPR-Edited, Off-the-Shelf CAR T-Cell Therapy Shows Proof of Concept in Renal Cell Carcinoma

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Evidence from a small early trial called COBALT-RCC provides proof of concept for use of an allogeneic off-the-shelf CD70-targeted chimeric antigen receptor (CAR) T-cell therapy called CTX130 in patients with advanced clear cell renal cell carcinoma (RCC). CTX130 is engineered using gene-editing technology based on clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (Cas9). Presented at the American Association for Cancer Research (AACR) Annual Meeting 2024, this is among the first evidence supporting the use of allogeneic CAR T-cell therapy in solid tumors.1 Results of the study were published simultaneously in Cancer Discovery.2

At a median follow-up of 3 years, the overall objective response rate in the trial was 63% among 16 patients with advanced clear cell RCC. One patient treated at the first dose level achieved a complete response at month 3 that was maintained at 36 months. The rate of disease control was 81.3%, median progression-free survival was 2.9 months, and median overall survival was 20.5 months.

Samer A. Srour, MB ChB, MS

Samer A. Srour, MB ChB, MS

“We can clearly say that this is the first complete response [achieved with an] allogeneic product that exceeds 3 years in kidney cancer or any other solid tumor,” explained lead study author Samer A. Srour, MB ChB, MS, Assistant Professor at The University of Texas MD Anderson Cancer Center, Houston, in a presentation during the AACR meeting. “This study is proof of concept that we can do something [with CD70-directed CAR T-cell therapy] in the solid tumor space, and hopefully we can [go on to] induce durable remissions and cure [patients] based on these results.”

Study Background and Design

RCC accounts for about 3% of all cancers, and clear cell RCC is the most common histologic subtype. Approximately 30% of patients with clear cell RCC will develop metastatic disease, and those who have disease progression on standard systemic treatments in the first line (ie, dual checkpoint inhibitor and checkpoint inhibitor/VEGF tyrosine kinase inhibitor–based combinations), have limited options if these treatments fail.

CD70 is a ligand that interacts with CD27 to control T-cell activation. It is expressed transiently on activated lymphocytes, natural killer cells, and mature dendritic cells.

“In kidney cancer, aberrant CD70 is expressed in over 80% of patients. That makes it an ideal target to explore [in this disease],” Dr. Srour explained. “Second, CD70 expression has a potential immunosuppressive role in the tumor microenvironment, which leads to aggressiveness and tumorigenesis. We hypothesized that targeting this molecule might help us improve these outcomes.”

CTX130 is derived from T cells obtained from healthy donors, which are selected, edited, and expanded before being cryopreserved for subsequent use. Preclinical data from an RCC xenograft model suggested this novel CAR T-cell therapy could be effective in clear cell RCC, he explained.

The open-label, multicenter, international, single-arm COBALT-RCC trial investigated the safety and efficacy of CTX130 in patients with advanced clear cell RCC. The study included a dose-­escalation portion (part A) and a cohort-expansion portion (part B).

Patients with unresectable or metastatic RCC with clear cell differentiation who were 18 years of age or older and weighed at least 42 kg were eligible for enrollment. Other enrollment criteria were previous exposure to a checkpoint inhibitor and VEGF inhibitor; a Karnofsky performance status of at least 80%; and adequate renal, liver, cardiac, and pulmonary organ function.

“These patients were heavily pretreated with a poor prognosis. None had favorable risk,” Dr. Srour noted. Of the 16 patients, 13 had archived tissue, and the median CD70 expression among these patients was 100%.

Treatment Schema and Key Findings

As a first step, patients underwent lymphodepletion with fludarabine plus cyclophosphamide for 3 days. Then one infusion of CTX130 began on day +1 at one of four dose levels.

“The treatment schema is very much what you see with most CAR T-cell products, with one exception. Because this is an allogeneic product, you don’t need apheresis and collection. Your patients [can therefore give informed] consent..., and within 3 to 5 days, you can start treatment,” Dr. Srour explained. First-generation CAR T-cell products derived from patients’ own T cells can take weeks to manufacture. Six patients received a second infusion, and all other patients receivied one infusion, including the patient who achieved a complete response.

No dose-limiting toxicities were observed across all dose levels. Moreover, there was no incidence of tumor-lysis syndrome, immune effector cell–associated neurotoxicity syndrome, graft-vs-host disease, or secondary malignancies.

In the overall population, half of the patients experienced grade 1 or 2 cytokine-release syndrome; however, no grade 3 or higher cytokine-release syndrome was reported. Grade 1 or 2 and grade 3 or higher infections each occurred in 18.8% of patients. Serious treatment-related adverse events occurred in four patients (all cytokine-release syndrome).

“They are living cells. They must expand to do their job,” Dr. Srour said. Pharmacokinetic analysis showed that most patients had detectable CTX130 levels after infusion, which reached a nadir after 2 to 3 days. A subsequent rapid expansion in CTX130 cells was observed, with a peak concentration achieved on days 7 to 15. CTX130 cells were no longer detected by day 28.

“We were encouraged by these results, but we thought maybe we could do better,” Dr. Srour explained. “At the same time we were treating our patients with CTX130, there was a parallel study in [patients with] T-cell lymphoma. We saw better responses [in that population, including higher] complete response and objective response rates. The CRISPR team went back and performed screening for other edits that we can make to CTX130 to improve outcomes [in patients with clear cell RCC].”

The resulting CTX131 construct they designed includes two modifications, and preclinical data suggest that CTX131 will have superior potency and efficacy vs CTX130. Based on these data, investigators have launched a phase I/II study to assess the safety and efficacy of CTX131 in adults with relapsed or refractory solid tumors ( identifier NCT05795595). 

Expert Point of View

Nicholas P. Tschernia, MD

Nicholas P. Tschernia, MD

Formal discussant of the COBALT-RCC trial, Nicholas P. Tschernia, MD, said: “The process is the product. This study highlights the potential of allogeneic [chimeric antigen receptor] T-cell therapy in solid tumors, particularly in clear cell renal cell carcinoma. CTX130 had a relatively safe profile, but there are still unknowns.” Dr. Tschernia is a physician-scientist at the Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. His focus is on developing new cellular immunotherapies for patients with cancer.

“The CTX131 construct is a newer product with two modifications. We need to be mindful of adverse events, and CRISPR can induce unwanted reactions,” he told listeners.

DISCLOSURE: The COBALT-RCC study was funded by CRISPR Therapeutics. Dr. Srour has served as a consultant for Hansa Biopharma and Novartis. Dr. Tschernia reported no conflicts of interest.


1. Srour SA, 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: Long-term follow-up and translational data from the phase 1 COBALT-RCC. AACR Annual Meeting 2024. Abstract CT002. Presented April 9, 2024.

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. April 5, 2024 (early release online).