CTX112 Yields Clinically Meaningful Results in Relapsed or Refractory B-Cell Malignancies

CTX112, a next-generation allogeneic CRISPR-Cas9–engineered CD19 chimeric antigen receptor (CAR) T-cell therapy, has shown better efficacy than first-generation allogeneic CAR T-cell therapies at low doses, including higher response rates and pharmacokinetic improvements in patients with relapsed or refractory B-cell malignancies.

Data from a phase 1/2 study of CTX112 presented at the 66th American Society of Hematology Annual Meeting & Exposition were obtained from patients with various disease subtypes including include large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, mantle cell lymphoma, and chronic lymphocytic leukemia or small lymphocytic lymphoma. The patients underwent lymphodepleting chemotherapy consisting of fludarabine 30 mg/m² and cyclophosphamide 500 mg/m² for 3 days. Patients then received CTX112 infusions at doses ranging from 30 × 10⁶ CAR+ T cells during dose level (DL) 1 to 300 × 10⁶.

During more than 3 months of follow-up, the objective response rate observed was 67%, and the confirmed complete response rate was 44%. Notably, response lasted beyond 6 months in four patients. One patient treated with CTX112 during DL1 remains in CR more than a year after CAR T-cell infusion. The responses were deemed clinically meaningful.

No dose-limiting toxicities of graft-versus-host disease (GVHD) or adverse events of GVHD, hemophagocytic lymphohistiocytosis, or grade 3 or higher infections occurred during the study. Within 30 days, every occurrence of grade 3 or higher cytopenia after CTX112 infusion was resolved.

Incidences of grade 1/2 cytokine release syndrome (CRS) were seen in 44% of patients, but no grade or higher 3 CRS occurred. Twenty-two percent of patients experienced grade 1 immune effector cell–associated neurotoxicity syndrome, and no grade 2 or higher events occurred.

In comparison with the first-generation agent, CTX110 at DL3, CTX112 had a mean maximum concentration (C_max) that was seven times higher (26,235 vs 3,773 copies/μg). The C_max for CTX112 was significantly higher than first-generation CAR T-cell therapy at DL14, where the difference in C_max was 133,701 versus 13,830 copies/μg*days.

According to investigators led by Armin Ghobadi, MD, of the Siteman Cancer Center, St. Louis, Missouri, this research is the first clinical evidence that increased expansion and functional persistence of CAR T cells can occur when there are disruptions in the genes encoding regnase-1 and transforming growth factor beta receptor 2.

REFERENCE

Ghobadi A, McGuirk J, Shaughnessy P, et al. CTX112, a next-generation allogeneic CRISPR-Cas9 Engineered CD19 CAR T Cell with novel potency edits: data from phase 1 dose escalation study in patients with relapsed or refractory b-cell malignancies. Presented at: 66th American Society of Hematology Annual Meeting & Exposition; December7-10, 2024; San Diego, CA