CRISPR-CAR T Therapy Yields First Allogeneic Complete Response in R/R Solid Tumors
Data from the COBALT-RCC study in renal cell carcinoma were presented at SITC 2022.
CTX130 was well-tolerated and yielded a complete response (CR) in relapsed or refractory renal cell carcinoma (RCC).1
These data, from the first-in-human phase 1 COBALT-RCC clinical trial (NCT04438083), were presented at the Society for Immunotherapy of Cancer’s (SITC) 37th Annual Meeting, November 8-12, 2022, in Boston, Massachusetts, by Sumanta Pal, MD, professor, department of medical oncology and therapeutics research and codirector, Kidney Cancer Program, and medical oncologist, City of Hope.
“We are very pleased by the encouraging data from our first-in-human clinical trial exploring CD70-targeting CAR-T cell therapy in clear cell RCC. In this trial, treatment with CTX130 resulted in a durable complete response, and the trial demonstrated a favorable disease control rate overall. We remain excited by the results presented today for the CTX130 trial for the treatment of relapsed or refractory RCC,” Phuong Khanh Morrow, MD, FACP, chief medical officer, CRISPR Therapeutics, said in a statement.2 “Additionally, we presented a poster highlighting preclinical data that demonstrates that CRISPR-edited allogenic anti-CD83 CAR-T cells show potent activity in models of AML and can be a promising CAR-T target for the treatment of AML.”
CTX130 is an allogeneic, CRISPR/Cas9 gene-edited, CD70-targeted, chimeric antigen receptor (CAR) T-cell therapy developed by CRISPR Therapeutics and being investigated at City of Hope, among other clinical trial sites. The therapy is made using an adeno-associated virus vector to insert an anti-CD70 CAR cassette into the TRAC locus. It is designed to disrupt TRAC, β2M, and CD70.
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COBALT-RCC enrolled 14 patients with RCC with clear cell differentiation,prior exposure to checkpoint and vascular endothelial growth factor inhibitors, and adequate Karnofsky performance status and organ functions. Part a (dose escalation) primarily evaluated incidence of adverse events (AEs) and dose-limiting toxicities and part b (cohort expansion) primarily evaluated the objective response rate (ORR). Secondary endpoints evaluated best overall response, progression-free survival, and overall survival. Participants were treated with either 3x107, 1x108, 3x108, or 9x104 cells. Patients’ tumors had a median CD70 expression of 100% (range, 1-100) and a mean of over 75%.
“At present, a treatment that offers patients with advanced kidney cancer the possibility of a durable remission with limited toxicity remains elusive. Our data shared today show encouraging activity for an allogeneic CAR-T therapy in this setting and highlights the potential of this modality for these patients,” Pal added to the statement.2
Investigators found that half of patients had grade 1 or 2 cytokine release syndrome (CRS) but no patients had more severe CRS. Three patients had CRS counted as a serious AE related to CTX130. The median time to CRS onset was 1 day and median duration was 2 days. There were no cases of immune effector cell-associated neurotoxicity syndrome or graft-versus-host disease. Three patients had serious AEs of infections unrelated to treatment (grade 5 pneumonia and grade 4 dyspnea resulting in death). There were no incidences of tumor lysis syndrome, secondary malignancies, infusion reactions, or hemophagocytic lymphohistiocystosis, and altogether, the therapy had an acceptable safety profile.
Investigators assessed efficacy and found that 1 participant in dose level 1 (DL1) had a partial response that deepened to a CR in 3 months, which has been maintained as of 18 months post-infusion. Nine patients (2 in DL1, 2 in DL2, 2 in DL3, and 3 in DL4) had stable disease (SD); 4 patients still had SD at 4 months. There was an overall disease control rate of 77%.
“These encouraging results really underscore the potential of further increasing potency...To our knowledge, the durable complete response is the first to be achieved with allogeneic CAR T-cell therapy in patients with relapsed/refractory solid tumors,” Pal said during his presentation.1
CTX131, a version of the therapy with second-generation edits, is currently being developed and will disrupt regnase-1 and TGFβR2. The disruption of this combination of targets was shown to increase potency by at least 10 times in preclinical studies. CRIPSR is planning clinical studies for 2023.
Click here to read more coverage of SITC 2022.
REFERENCES
1. Pal S. 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: SITC 37th Annual Meeting, November 8-12, 2022, in Boston, Massachusetts.
2. CRISPR Therapeutics presents data at the Society for Immunotherapy of Cancer (SITC) 37th Annual Meeting. News release. CRISPR Therapeutics. November 10, 2022. http://ir.crisprtx.com/news-releases/news-release-details/crispr-therapeutics-presents-data-society-immunotherapy-cancer
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