Next-Generation CAR T-Cell Therapies Explored in R/R B-Cell Malignancies

The challenge of managing relapsed or refractory B-cell malignancies continues to thwart the efforts of oncologists and hematologists, but emerging data about next-generation chimeric antigen receptor (CAR) T-cell therapy may lead to success. In a presentation during the 2025 Immune Cell Effector Therapy Conference,¹ Sunil Abhyankar, MD, highlighted findings from early-stage research involving DuoCAR20.19.22-D95 in a phase 1 trial (NCT06879340) evaluating its safety, dosage, efficacy, and long-term risks.

“There are a number of challenges associated with CAR T-cell therapy, including access and lack of response or relapse,” Abhyankar, a professor of medicine in the Division of Hematologic Malignancies and Cellular Therapeutics at the University of Kansas Medical Center in Kansas City, said during the presentation. Traditional CAR therapies target CD19, but the triple-threat construct of DuoCAR20.19.22-D95 engages CD19, CD20, and CD22, which are 3 common proteins found on the surface of B-cell malignancies such as acute lymphoblastic leukemia (B-ALL) and non-Hodgkin lymphoma (B-NHL).²

Enrolled patients will be stratified based on the diagnosis of B-ALL (pretreated with CAR or CAR-naive), B-NHL (pretreated with CAR), or B-NHL (CAR-naive). In the dose escalation phase, phase 1 will determine the maximum tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D) for the subsequent phase 2 dose-expansion study.

The trial duration for individual participants is 15 years from DUOCAR20.19.22D95-CAR T cell infusion. Following infusion, dosage-limiting toxicity assessments will continue through the end of the day 30 visit during dose escalation phase 1. Efficacy and routine safety monitoring for the phase 1 cohort will occur at established protocol-defined intervals through year 2 or until the start of a new treatment regimen, whichever occurs first.

“Early manufacturing and logistical practices have been established,” Abhyankar said. “Pre–good manufacturing processing runs were conducted to determine the run times, with IL-7 and IL-15 used during manufacturing.”

Investigators have enrolled 4 patients, with 1 patient undergoing CAR T-cell infusion. Abhyankar said there were no safety concerns associated with patient 1, who is undergoing further safety data analysis. Further, efficacy data are pending, and biomarker and CAR T-cell expansion data are undergoing analysis by KCAS Bio, a contract research organization.

The urgency in developing these next-generation therapies is underscored by the challenges plaguing current CAR T-cell treatments. Despite their revolutionary success, access remains a significant barrier due to complex, lengthy manufacturing times and the need for bridging therapy. Furthermore, long-term durability is an issue, with approximately 40% to 50% of adult patients with B-ALL relapsing within 1 year. Relapse is often driven by T-cell exhaustion or the cancer cells’ ability to stop expressing the CD19 antigen, rendering the CAR T cells invisible.

The DuoCAR20.19.22-D95 approach directly confronts this antigen escape problem. The in-house manufacturing capability at The University of Kansas aims to streamline production and improve accessibility for patients.

Abhyankar highlighted another enhanced approach, with results recently published in the New England Journal of Medicine, involving CAR T cells armored to secrete the cytokine IL-18 in a small phase 1 study evaluating huCART19-IL18 (NCT04684563).³ Investigators assessed the safety, feasibility, and preliminary efficacy of huCART19-IL18 in patients with relapsed or refractory lymphoma after previous anti-CD19 CAR T-cell therapy.

A total of 21 patients received the armored CAR T-cell therapy. Cytokine release syndrome occurred in 62% of the patients (47% with grade 1 or 2), and immune effector cell–associated neurotoxicity syndrome occurred in 14% (all grade 1 or 2). No unexpected adverse events were observed. Robust CAR T-cell expansion was detected across all dose levels.

At 3 months after infusion, a complete or partial response was reported in 81% of the patients (90% CI, 62%-93%), and a complete response in 52% (90% CI, 33%-71%).

With a median follow-up of 17.5 months (range, 3-34), the median duration of response was 9.6 months (90% CI, 5.5-not reached).

“This demonstrates that engineering CAR T cells to modify the tumor microenvironment can resensitize even the most treatment-resistant cancers to immunotherapy,” Abhyankar said. “For patients who have exhausted all conventional treatments, these CAR T-cell therapies symbolize a shift toward more intelligent, resilient, and accessible cellular immunotherapies.”

REFERENCES:

1. Abhyankar S. Pioneering cellular therapies transforming treatment for ALL. Presented at: 2025 National Immune Cell Effector Therapy (ICE-T) Conference; July 26, 2025; Orlando, FL

2. Schneider D, Xiong Y, Wu D, et al. Trispecific CD19-CD20CD22-targeting duoCAR-T cells eliminate antigen-heterogeneous B cell tumors in preclinical models. Sci Transl Med. 2021;13(586):eabc6401. doi:10.1126/scitranslmed.abc6401

3. Svoboda J, Landsburg DJ, Gerson J, et al. Enhanced CAR T-cell therapy for lymphoma after previous failure. N Engl J Med. 2025;392(18):1824-1835. doi:10.1056/NEJMoa2408771