A first-in-human clinical trial has demonstrated promising results for a trispecific CAR T-cell therapy targeting three B-cell antigens, with researchers reporting encouraging remission rates and a favorable safety profile in patients with relapsed or refractory B-cell malignancies.
The phase I study, published in Blood Cancer Discovery, was led by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James). It investigated a novel CAR T-cell product targeting CD19, CD20, and CD22, designed to address one of the major limitations of conventional CAR T therapies: disease relapse caused by the loss or downregulation of target antigens.
Although CD19-directed CAR T-cell therapies have transformed the treatment of certain blood cancers, antigen escape remains a significant obstacle. By simultaneously targeting three antigens, the investigational therapy aims to maintain antitumor activity even when cancer cells lose expression of individual targets. The construct also incorporates an OX40 costimulatory domain, which has previously been associated with improved T-cell survival, persistence, and antitumor activity.
Accelerating CAR T manufacturing
A distinguishing feature of the study was its use of point-of-care manufacturing, potentially reducing the time and complexity associated with conventional CAR T-cell production.
The researchers used the CliniMACS Prodigy automated manufacturing platform from Miltenyi Biotec to produce the cells at Ohio State's cell processing laboratory, incorporating a lentiviral vector developed by Lentigen Technology.
The process achieved a median manufacturing time of seven days, with a range of six to 10 days. Successful manufacturing was achieved for 16 of 17 patients, with one failure occurring in a heavily pretreated patient.
The trial enrolled 18 patients, of whom 16 received treatment. Participants had various relapsed or refractory B-cell malignancies and had undergone a median of three previous treatment regimens.
Encouraging responses in lymphoma
Across the treated population, the overall response rate was 50 percent, with complete responses observed in 38 percent of patients. Outcomes were particularly encouraging among patients with B-cell non-Hodgkin lymphoma, where five of six patients (83 percent) achieved complete remission. Four of these five patients remained in remission beyond one year.
However, responses varied considerably across disease types. The complete response rate was 25% among patients with B-cell acute lymphoblastic leukemia, while patients with chronic lymphocytic leukemia or prolymphocytic leukemia experienced stable disease. Neither patient with Richter transformation responded.
The one-year overall survival rate across the study population was approximately 61%.
The therapy also demonstrated a favorable safety profile. Grade 1 or 2 cytokine release syndrome occurred in 25 percent of patients, with no severe cases, dose-limiting toxicities, or instances of immune effector cell-associated neurotoxicity syndrome reported.
Understanding treatment resistance
Further analysis revealed that T-cell exhaustion, rather than insufficient CAR T-cell expansion, may influence treatment outcomes.
Using high-dimensional spectral flow cytometry, the researchers identified increased expression of exhaustion-associated markers, including PD-1, TIM-3, and TOX, in pretreatment T cells from patients whose disease subsequently progressed.
CAR T-cell expansion did not correlate significantly with treatment dose or clinical response, suggesting that cellular characteristics may be more important than expansion alone.
Although the small, heterogeneous patient population limits definitive conclusions, the findings provide early evidence supporting trispecific antigen targeting and rapid, decentralized manufacturing.
The researchers suggest that larger studies are needed to validate the clinical benefits, while further investigation into T-cell exhaustion as a key biomarker could help identify patients most likely to respond to treatment and guide future CAR T-cell optimization.
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