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TOPLINE:

Allogeneic CTX110, a CD19-targeted CAR T-cell immunotherapy, produced dose-dependent responses in patients with relapsed/refractory B-cell non-Hodgkin lymphoma in a multicenter phase 1/2 trial. Among patients who received a first infusion at dose level 3 or greater, the objective response rate was 65% and the complete response rate was 39%. Grade 3 or greater treatment-emergent adverse events were common, most frequently neutropenia (59%), anemia (35%), and thrombocytopenia (35%); serious adverse events occurred in 32% of patients. 

METHODOLOGY:

• Although autologous CD19 CAR T-cell therapy is effective in patients with non-Hodgkin lymphoma, its use is limited by manufacturing delays, cost, and variable product quality. Investigational allogeneic products may offer off-the-shelf availability, engineered approaches to reduce graft-vs-host disease risk, and the potential for repeat dosing, but their long-term efficacy and safety still need to be established.
• To evaluate the safety and efficacy of CTX110, researchers conducted a multicenter, single-arm, phase 1/2 study involving 63 patients (median age, 65 years) with relapsed/refractory B-cell non-Hodgkin lymphoma between 2019 and 2024. In phase 1, dose escalation was followed by cohort expansion; in phase 2, efficacy was evaluated in cohorts identified in phase 1.
• Patients received standard lymphodepletion chemotherapy followed by one CTX110 infusion at escalating dose levels — levels 1-4 (3×10⁷ CAR T cells to 6×10⁸ CAR T cells), in the dose-escalation phase (n = 32), or two infusions at level 4 on days 1 and 35 in the cohort expansion phase (n = 31).
• Primary endpoints were incidence of dose-limiting toxicities and objective response rate. The median follow-up duration was 8.5 months, with follow-up extending to a median of 34 months among ongoing responders.
• Overall, 59% had primary refractory disease, 43% had received three or more prior treatment lines, and 81% had stage III or IV disease at baseline.

TAKEAWAY:

• Response rates increased with the dose and were observed beginning at dose level 2 (1×10⁸ CAR T cells). Among 57 patients who received the first CTX110 infusion at level 3 or higher (3×10⁸ to 6×10⁸ CAR T cells), the objective response rate was 65% (37/57) and the complete response rate was 39% (22/57); 5 of 22 patients (23%) who achieved a complete response maintained it at a median follow-up period of 34 months.
• The two-infusion regimen at dose level 4 (days 1 and 35) appeared to prolong response duration compared with a single infusion at dose level 3 or higher (median duration of response, 4.2 vs 1.7 months; hazard ratio, 0.65), suggesting repeat dosing may improve response durability.
• Among nine patients who received a second course of treatment after progression, six responded again to therapy (four complete responses and two partial responses), and the median duration of response after retreatment was 4.8 months.
• Regarding adverse events, cytokine release syndrome occurred in 54% of patients and was predominantly grade 1-2, whereas immune neurotoxicity occurred in 13%, including two grade ≥ 3 events. Grade 3 or greater treatment-emergent adverse events included neutropenia (59% of patients), anemia (35% of patients), and thrombocytopenia (35% of patients). Serious adverse events occurred in 32% of patients.

IN PRACTICE:

In this early-stage trial, the findings indicate the “potential for deep and durable responses following a single infusion of CTX110 preceded by standard [lymphodepletion] chemotherapy, as well as the potential to achieve a second response after additional infusions in patients who experience [disease progression],” the study authors wrote. 

This study of first-generation allogeneic CAR T-cell therapy provides the “foundation for next-generation allogeneic CAR T-cell therapy, zugocabtagene geleucel (zugo-cel; formerly CTX112), which has additional edits to enhance CAR T-cell proliferation and potency.”

SOURCE:

The study, led by Joseph P. McGuirk, The University of Kansas Medical Center, Kansas City, Kansas, and Armin Ghobadi, Washington University School of Medicine, St. Louis, was published online in Blood Advances.

LIMITATIONS:

Limitations included that the study was a single-arm phase 1/2 study with no randomized comparison. Other limitations include the small sample size, exploratory design, and enrollment of a heterogeneous, heavily pretreated population. Although response rates at higher dose levels resembled those reported for approved autologous CD19 CAR T products, the authors noted that further modifications to CTX110 may be needed to improve potency. 

DISCLOSURES:

This study was funded by CRISPR Therapeutics. McGuirk disclosed serving as a consultant for multiple companies, including Kite Pharma, AlloVir, Novartis Pharmaceuticals, Fosun Kite Biotechnology, and CRISPR Therapeutics; receiving honoraria for lectures and educational events from CRISPR and others. Ghobadi disclosed receiving research support from Secura Bio, Genentech, and Kite; royalties from book publications and consulting/advisory board fees from Amgen, Atara, Bristol Myers Squibb, CRISPR, Kite, and Wugen. Full disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.