LV20.19 CAR T-Cell Therapy Yields 100% ORR and Manageable Toxicity in R/R MCL

Mantle Cell Lymphoma |
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On-site adaptive manufacturing of the lentiviral anti-CD20 and -CD19 CAR T-cell therapy LV20.19 resulted in a high complete response (CR) rate and favorable tolerability in patients with relapsed/refractory mantle cell lymphoma (MCL), according to preliminary findings from a phase 1/2 study (NCT04186520).

Findings published in the Journal of Clinical Oncology showed that patients treated with LV20.19 (n = 17) achieved a best overall response rate (ORR) of 100%, including a CR rate of 88% and a partial response (PR) rate of 12%. The 90-day CR rate exceeded the predefined efficacy threshold for patients treated in phase 2 (n = 14) at 86% (one-sided 95% Wilson CI, 64.7%-100%).

At a median follow-up of 15.8 months, only 2 patients had experienced relapse, and neither median progression-free survival (PFS) nor overall survival (OS) had been reached among patients still alive.

Regarding safety, cytokine release syndrome (CRS) occurred in 94% of patients, and all instances were grade 1 or 2. Immune effector cell–associated neurotoxicity syndrome (ICANS) was reported in 18% of patients, including 2 reversible cases of grade 3 ICANS.

"On-site adaptive manufactured LV2019 CAR T cells are feasible, safe, and efficacious for relapsed/refractory MCL with [a] best ORR of 100%, a favorable safety profile, and few relapses to date," lead study author, Nirav Shah, MD, MSHP, and colleagues, wrote in the publication. Shah is an associate professor at the Medical College of Wisconsin in Milwaukee.

Phase 1/2 Study Design and Eligibility Criteria

The phase 1/2 study of LV20.19 CAR T cells was a single-arm, interventional trial evaluating safety, efficacy, and manufacturing feasibility of the product in patients with relapsed or refractory MCL and other hematologic malignancies.

Eligible patients for the phase 1/2 study were required to be between 18 and 80 years of age with a confirmed diagnosis of relapsed or refractory B-cell non-Hodgkin lymphoma. All patients needed to have a Karnofsky performance score of at least 70 and an expected survival of more than 12 weeks.

Measurable disease, defined by nodal lesions greater than 15 mm in long axis, extranodal lesions greater than 10 mm in both axes, or biopsy-proven bone marrow involvement, was required within 4 weeks of informed consent

In phase 1, 3 patients received a single infusion of LV20.19 CAR T cells at a fixed dose of 2.5 × 10⁶ cells/kg. Phase 2 expanded the cohort to include 14 additional patients, all of whom were treated with LV20.19 CAR T cells manufactured on-site using the CliniMACS Prodigy system. This adaptive manufacturing process ranged from 8 to 12 days and was designed to optimize T-cell phenotypes, specifically enriching for naive and stem cell memory (SCM)–like subsets.

The broader phase 1/1b portion included 5 study arms evaluating fixed vs flexible manufacturing timelines, the impact of mandated cryopreservation, and expansion into chronic lymphocytic leukemia and central nervous system lymphoma populations. In phase 2, the study assessed the feasibility of this manufacturing schema and used 3-month CR rate as the key efficacy outcome.

The primary end point of the study was the incidence of adverse effects (AEs) within 28 days of CAR T-cell therapy infusion. Secondary end points included ORR, PFS, OS, and feasibility of adaptive CAR T-cell manufacturing.

Baseline Patient Characteristics

The median age was 63 years (range, 50-74), and the majority of patients were male (n = 15; 88%). Prior autologous stem cell transplant had been received by 8 patients (47%), and 2 patients (12%) had undergone prior allogeneic transplant. Elevated lactate dehydrogenase (LDH) levels on the day of CAR T-cell infusion were reported in 6 patients (35%). Marrow involvement prior to CAR T-cell infusion was present in 14 patients (82%).

Exposure to a BTK inhibitor was reported in 16 patients (94%), and 13 patients (76%) had disease progression on a BTK inhibitor. Of these, 6 patients (35%) had progression following treatment with the noncovalent BTK inhibitor pirtobrutinib (Jayprica).

The median number of prior treatment lines, including transplant, was 4 (range, 2-8). Prior bendamustine exposure was reported in 13 patients (76%), with 2 patients (12%) having received bendamustine within 1 year of study enrollment.

MCL International Prognostic Index (MIPI) scores were available for 14 patients: 6 patients (35%) were classified as low risk, 4 (31%) as intermediate risk, and 4 (31%) as high risk; MIPI data were missing for 3 patients (18%).

Complex cytogenetics were identified in 3 patients (18%) with p53 aberrations present in 8 patients (47%), including 6 with p53 mutations (35%) and 3 with 17p deletions confirmed by fluorescence in situ hybridization or cytogenetic analysis (18%).

Safety Analysis Continued

According to Shah and colleagues, “the toxicity profile of LV20.19 CAR T cells was favorable compared with available FDA-approved CAR T products with no patient requiring ICU-level care in the first 28 days.”

Two patients (12%) developed late-onset neurologic symptoms not characteristic of classic ICANS, presenting with intermittent confusion and numbness at days 141 and 158 post-infusion. Both patients had significantly elevated nucleated cell counts in the CSF and detectable LV20.19 CAR T cells. Symptoms resolved following a single dose of intrathecal hydrocortisone without systemic steroid administration.

Hematologic toxicities were among the most commonly observed grade 3 or higher adverse effects in patients treated with LV20.19 CAR T-cell therapy. The most frequent grade 3 or higher AEs included neutropenia (47%), anemia (29%), and thrombocytopenia (18%). Authors noted that these AEs were consistent with the expected hematologic profile of CAR T-cell therapy.

Hypogammaglobulinemia was also observed in this population. At day 90, the median immunoglobulin G level was 398 mg/dL (range, 135-917). To mitigate infectious risk, 65% of patients (n = 11) received prophylactic intravenous immunoglobulin supplementation post-CAR T-cell infusion

No treatment-related deaths were reported during the 28-day post-infusion period.

Reference

Shah N, Colina AS, Johnson BD, et al. Phase I/II study of adaptive manufactured lentiviral anti-CD20/anti-CD19 chimeric antigen receptor T cells for relapsed, refractory mantle cell lymphoma. J Clin Oncol. Published online March 31, 2025. doi:10.1200/jco-24-02158