CAR T-Cell Therapy Advances: Long-Term Remissions, Pregnancy Outcomes, and New Trial Data

Recent findings across multiple studies and presentations highlight both the therapeutic promise and the ongoing challenges of chimeric antigen receptor (CAR) T-cell therapy. Ten-year follow-up data from a landmark lymphoma trial show that a single infusion can produce durable remissions, while a separate international study reports healthy pregnancies in women with autoimmune diseases after CAR T-cell treatment. New trial results in hepatocellular carcinoma and mechanistic research into T-cell dysfunction also expand the field's understanding.

In the lymphoma trial, 12 of 38 patients treated with a single dose of CD19-targeted CAR T-cell therapy remained lymphoma-free at 10 years. The 10-year lymphoma-free survival was 38% overall, including 32% among patients with large B-cell lymphoma (LBCL) and 47% among those with follicular lymphoma. No relapses occurred after 5.4 years of follow-up, and no patient with follicular lymphoma relapsed after 2.7 years. Ten-year overall survival was 17% in the LBCL group and 50% in the follicular lymphoma group. The results, published in the New England Journal of Medicine, indicate that CD19-directed CAR T-cell therapy can achieve long-term remissions and may cure some patients. Regarding safety, two patients had persistent grade 2 or 3 neutropenia, and nine patients developed second primary cancers, for a 10-year cumulative incidence of 21% compared with 11% in a matched population.

An international study published in the New England Journal of Medicine examined pregnancies after CAR T-cell therapy in women with severe autoimmune diseases. Among 14 pregnancies and 8 births documented, no complications were reported, and all babies were born healthy with an age-appropriate immune system. The autoimmune disease did not return during pregnancy even though patients had stopped immunosuppressive medication, supporting treatment discontinuation and family planning for these patients.

A pilot cohort of a phase 1/2 trial tested a dose-dense strategy for CD19-directed CAR T-cell therapy in relapsed/refractory B-cell non-Hodgkin lymphoma, with a second infusion at day 14 at the same dose and without repeat lymphodepletion. Seventeen of 20 treated patients received both infusions. Any-grade cytokine release syndrome occurred in 59% and neurotoxicity in 18%. CAR T-cell re-expansion after the second infusion occurred in 94% of patients. Overall and complete response rates were 47% and 41%, respectively. Among responders, the 8-year duration-of-response rate was 63%, compared with 26% in patients treated with a single infusion, indicating durable responses with early redosing.

A first-in-human trial evaluated C-CAR031, a GPC3-specific CAR T-cell product with a dominant-negative TGFβ receptor II, in 36 patients with advanced, treatment-refractory hepatocellular carcinoma. Cytokine release syndrome occurred in 34 patients, with two grade 3 cases, and nine patients had non-haematological adverse events of grade 3 or higher. Tumour regression was observed in 32 patients, with a median best reduction of 41.6% in target lesions. The objective response rate was 44.4%, and the median duration of response was 4.4 months. Median progression-free survival was 4.2 months and median overall survival was 14.2 months. Analyses suggested that GPC3 antigen loss and increased TGFβ levels may contribute to resistance.

Research published in Nature Cancer identified iron-driven ferroptosis as a determinant of CAR-T cell dysfunction. Integrated analyses of clinical samples from patients with multiple myeloma and acute lymphoblastic leukemia showed that rapid CAR-T expansion after infusion is followed by a diminution phase with ferroptosis-associated features and elevated serum iron. Excess intracellular iron impaired CAR-T cell function by promoting ferroptosis through mitochondrial reactive oxygen species and lipid peroxidation, partly via ACSL4-associated lipid remodeling. Genetic ablation of ACSL4 in CAR-T cells substantially enhanced antitumor efficacy, pointing to a targetable barrier to durable CAR-T responses.

Infection remains a common and clinically significant complication after CAR T-cell therapy, with reported infection rates ranging from approximately 45% to 72% across data. The highest risk period is within the first 30 days after infusion, but vulnerability can extend beyond the acute window, particularly with persistent cytopenias and hypogammaglobulinemia. Early infections are most frequently bacterial, while opportunistic infections become more prominent between 30 and 100 days, and long-term immune dysregulation can sustain risk beyond 100 days. Overall infection rates commonly exceed 30% to 50%, underscoring the need for structured prophylaxis and monitoring.

At the American Society of Gene and Cell Therapy Annual Meeting, Fate Therapeutics presented data on its off-the-shelf CAR T-cell programs. In a Phase 1 study of FT819 in systemic lupus erythematosus, three patients receiving a single dose without conditioning chemotherapy achieved SRI-4 response, and two of three achieved lupus low disease activity state, with depletion of major B-cell clones lasting up to 12 months. Preclinical data for FT839, a dual CAR T-cell therapy targeting CD19 and CD38, showed depletion of over 99% of B cells, plasmablasts, and plasma cells and more than 90% of activated T cells in rheumatoid arthritis and SLE samples while sparing non-activated T cells. Preclinical data for FT836, targeting MICA/B antigens, demonstrated tumor control in multiple xenograft models, and the therapy is being evaluated in clinical trials for advanced solid tumors and relapsed/refractory multiple myeloma. The FDA has selected FT819 for its Chemistry, Manufacturing, and Controls Development and Readiness Pilot Program.