Feasibility of allogeneic CAR-T in solid tumors shown in advanced kidney cancer
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Key takeaways:
- Allogeneic, CD70-targeted CAR-T produced stable disease in the majority of patients .
- A new trial is underway attempting to improve durability of the agent.
Sumanta K. Pal, MD, FASCO, expressed a mix of emotions.
CTX130 (CRISPR Therapeutics), an investigational CD70-targeted allogeneic chimeric antigen receptor T-cell therapy, produced promising results in a phase 1 trial for patients with advanced clear-cell renal cell carcinoma (RCC)
The findings, presented at American Association for Cancer Research Annual Meeting and simultaneously published in Cancer Discovery, showed that 80% of those treated had disease control and one patient has had an ongoing complete response for 3 years.
However, Pal also hoped to see more tumor shrinkage among the study participants.
Pal said the mix of emotions perfectly characterizes where CART-cell therapies stand in solid tumors.
“CAR T cells in solid tumors is in a very nascent stage,” Pal, co-director of City of Hope’s kidney cancer program and a Healio | HemOnc Today Editorial Board member, told Healio. “What we really demonstrate with CTX130 is that it is feasible to administer an allogeneic cell with CRISPR editing. We demonstrate that it’s safe,” he added. “We saw very limited toxicity in the scope of our study, and we saw that there’s potential for durable responses, but we need to augment the spectrum of responses that we’re seeing.”
Background
The U.S. had an estimated 82,000 new renal cell carcinoma diagnoses and 15,000 deaths in 2023, the most common being clear-cell RCC, according to background information provided by researchers.
Roughly 30% of patients develop metastases that require therapy, with standard care being immune checkpoint inhibitors alone or in combination with vascular endothelial growth factor (VEGF)-directed therapy.
Responses can range from 42% to 71%, but few patients have a complete response. Secondary treatments have limited efficacy, including salvage treatment with VEGF-directed therapy that has conferred a median PFS of 5 to 8 months and overall response rate between 28% and 43%.
“After a patient has exhausted VEGF pathway-directed therapies, we do really have to get creative,” Pal said. “That’s where I think these clinical trials come into play.”
Other studies noted CD70, which appears to limit T-cell expansion to fight tumors, had been found in 58% of lymphomas, 43% of solid tumors and 80% of clear-cell RCC samples.
“CD70 is a very pervasive antigen in kidney cancer, so it’s one that I think is always amenable to therapeutic targeting,” Pal said.
CTX130
Other studies have tried to target CD70 in various ways, including with antibody-drug conjugates, bispecific T-cell engagers and monoclonal antibodies, but with limited success — “very limited responses and no durable responses,” Pal said.
Pal and colleagues aimed for improved results with CTX130, which used CRISPR-Cas9 gene editing to insert an anti-CD70 CAR expression cassette.
The COBALT-RCC study included 16 patients with clear-cell RCC who had received at least one checkpoint or tyrosine kinase inhibitor (median age, 63 years; 87.5% men; 100% stage IV at enrollment).
They received lymphodepletion prior to CAR T-cell infusion, and patients received various dose levels and numbers of infusions of CTX130.
In all, 81% of patients achieved disease control, including 75% with stable disease and one patient with a complete response.
“What we saw, which was quite unique, is that most patients had stabilization of their cancer,” Pal said. “That was the majority of the study, and that in and of itself is a laudable goal, but we were hoping to see tumor shrinkage in a greater portion of the population. But what I think is interesting in our study is that we had one patient who developed a complete response to therapy, and his complete response has lasted for 3 years. This patient had progressed beyond targeted therapy, checkpoint inhibitors and now has complete remission of this cancer.”
Pal described the safety profile for CTX130 as “promising” and “unique,” given that no cases of immune effector cell-associated neurotoxicity syndrome (ICANS) had been observed and no reports of cytokine release syndrome higher than grade 2. Fifty percent of study participants experienced grade 1 or grade 2 CRS, 25% had serious treatment-related adverse events (all CRS), and no patient developed graft-versus-host disease.
Next steps, clinical implications
Pal and colleagues hope for more, however, which is why an open-label investigation is already underway for a next-generation cellular therapy — CTX131, which has been edited to improve the durability of the T cell.
CTX130 could be detected in the bloodstream 20 minutes after infusion, declined around day 2 or 3, had an expansion and peak around day 7 to 15, and then decreased to undetectability at day 28.
“There’s two edits [in CTX 131] that are actually specifically intended to increase the durability of the T cell in the bloodstream,” Pal said. “By making these two edits and other portions of the cell, I think that we can increase the T-cell persistence.”
No findings from the multicenter phase 1/phase 2 trial of CTX131 are currently available; however, Pal believes the approach could be applicable to other solid tumor types down the road.
“I think the future is exploiting multiple tumor antigens across the spectrum of tumor types,” he said. “It’s going to take a while for this field to evolve, and right now we’re at a very, very preliminary stage. I think that seeing signals like we do in CTX130 is encouraging, but we do have to broaden the scope of response and, hopefully, we’ll see that this paradigm exists across other types as well.”
References:
- Pal SK, et al. Cancer Discov. 2024;doi:10.1158/2159-8290.CD-24-0102.
- Srour SA, et al. Abstract CT002. Presented at: American Association for Cancer Research Annual Meeting; April 5-10, 2024; San Diego.
For more information:
Sumanta K. Pal, MD, FASCO, can be reached at spal@coh.org.
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Srour SA, et al. Abstract CT002. Presented at: American Association for Cancer Research Annual Meeting; April 5-10, 2024; San Diego.
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