Anito-Cel Delivers Durable Responses With Low Neurotoxicity in RRMM

Anitocabtagene autoleucel (anito-cel), an investigational B-cell maturation antigen (BCMA)-directed autologous chimeric antigen receptor (CAR) T-cell therapy, led to a high response rate with durable benefit in patients with heavily pretreated relapsed or refractory multiple myeloma, according to results from a phase 1 trial (NCT04155749) published in The New England Journal of Medicine (NEJM).¹

Among 38 treated patients, all (100%) had a response, including a complete response in 79%, at a median follow-up of 38.1 months. The 24-month progression-free survival (PFS) rate was 57%, with a median PFS of 30.2 months; the 36-month overall survival (OS) rate was 65%. The trial also showed no high-grade cytokine release syndrome (CRS) and no delayed neurotoxicity, which investigators attributed to the different binding domain used for anito-cel compared with approved CAR T-cell therapies.

“I'm optimistic that the safety profile is going to be a driver of the decision-making, expanding patient access, expanding the eligible patient pool, and decreasing the need for substantial follow-up in our BCMA CAR T patients,” said Matthew Frigault, MD, lead author of the publication and deputy program director for the Cellular Methodist Program at Mass General Brigham Cancer Institute, in an interview with Targeted Oncology^TM.

Phase 1 Trial Background

The phase 1 trial evaluated anito-cel, which uses a synthetic d-domain BCMA binder (ddBCMA), at 2 dose levels, 100 × 10⁶ CAR-positive T cells and 300 × 10⁶ CAR-positive T cells, in patients with relapsed or refractory multiple myeloma who had received 3 or more prior lines of therapy or had triple-class refractory disease; almost 70% were penta-drug refractory.

The primary end points were adverse events during the treatment period and establishment of the recommended phase 2 dose. Of 40 patients enrolled, 38 received anito-cel. The study was led by investigators at the Mass General Brigham Cancer Institute and the UChicago Medicine Comprehensive Cancer Center.^1,2

Key Efficacy and Safety Findings

Despite three-quarters of the heavily pretreated cohort who received bridging therapy not responding to it, the majority had a complete response after receiving anito-cel with a median duration of response of 29.1 months, with a median progression-free survival of 30.2 months.¹ According to Frigault, the first patient treated with anito-cel still has a response beyond 5 years without additional treatment.

All 38 treated patients had an adverse event during the treatment period, and 37 (97%) had a grade 3 or higher adverse event. Among patients who received the recommended phase 2 dose of 100 × 10⁶ CAR-positive T cells, 94% had CRS of grade 1 or 2, with no grade 3 or higher events reported. Immune effector cell-associated neurotoxicity syndrome (ICANS) of grade 1 or 2 occurred in 16% of patients, and 1 patient (3%) had a grade 3 event; no non-ICANS or delayed neurotoxic effects occurred. Frigault viewed the lack of these rare but serious neurotoxicities at this longer follow-up as promising and also stressed the lack of immune effector cell–associated enterocolitis, another notable delayed complication of commercially available CAR T-cell therapy.

“These were great results for a phase 1 trial,” senior author Michael R. Bishop, MD, Professor of Medicine and Director of the David and Etta Jonas Center for Cellular Therapy at UChicago Medicine, stated in a news release.² “Even at a low dose of anito-cel, we were seeing complete responses in the majority of patients right off the bat, and not a single patient developed severe toxicities, so we wanted to investigate further why that might be.”

Comparing ddBCMA to Existing BCMA CAR T

In complementary in vitro studies published with the phase 1 data, the investigators compared the anito-cel ddBCMA binder with a dual variable heavy-chain domain (dual-VHH) binder corresponding to the published sequence for ciltacabtagene autoleucel (cilta-cel; Carvykti). The ddBCMA binder demonstrated a faster off-rate than the dual-VHH binder; although cytotoxicity was similar between the 2 binders, ddBCMA CAR T cells produced fewer inflammatory cytokines and did not result in activation without antigen or off-target cytotoxic effects.

“In the absence of seeing toxicities in anito-cel both here and in the pivotal study thus far, and the primary difference being the binder itself, we were able to better characterize what the binder was doing, how they compared, and it seemed that anito-cel didn't have as much of a strong immune synapse and didn't have as much of an inflammatory response upon activation,” said Frigault.

Clinical Implications

Based on the phase iMMagine-1 trial (NCT05396885), anito-cel is being considered for accelerated FDA approval with a target date of December 23, 2026. Among 75 of 117 treated patients who received at least 3 prior lines of therapy and were evaluated for minimal residual disease (MRD), anito-cel yielded a 93% rate of MRD negativity.³

At the International Myeloma Society Annual Meeting, matching-adjusted indirect comparisons comparing iMMagine-1 patients to those in pivotal trials of bispecific antibodies found higher odds of deep responses with anito-cel vs teclistamab (Tecvayli) and talquetamab (Talvey) as fourth-line treatment.⁴

“Whenever you have a highly efficacious product like cilta-cel or anito-cel…you don’t want to trade one negative event, meaning myeloma…for something else. You may cure the disease, but if you leave the patient with a functional deficit, or parkinsonism, or intractable enterocolitis and diarrhea…how are we helping and how are we improving the human condition?” said Frigault. He said that currently, CAR T–treated patients are monitored for months for neurotoxicities and enterocolitis; a therapy that avoids these toxicities can give patients more freedom and less anxiety about delayed adverse events.

REFERENCES

1. Frigault MJ, Dhakal B, Jakubowiak AJ, et al. Phase 1 study of anito-cel, a d-domain BCMA CAR T cell for refractory or recurrent myeloma. N Engl J Med. 2026;395(12):1180-1192. doi:10.1056/NEJMoa2603527

2. Novel CAR-T therapy shows promising safety and durable responses in hard-to-treat multiple myeloma. News release. Mass General Brigham. Accessed September 28, 2026. https://tinyurl.com/2mhx3j3x

3. Kaur G, Freeman CL, Dhakal B, et al. Phase 2 registrational study of anitocabtagene autoleucel for relapsed and/or refractory multiple myeloma (RRMM): updated results from iMMagine-1. Presented at: 2025 EHA Congress; June 12-15, 2025; Milan, Italy. Abstract S201.

4. Patel K, Hungria V, Hasegawa K, et al. Matching-adjusted indirect comparisons (MAICs) of anitocabtagene autoleucel (anito-cel) versus teclistamab and talquetamab for the treatment of 4L+ relapsed and/or refractory multiple myeloma (RRMM). Presented at: 23rd International Myeloma Society Annual Meeting; September 23-26, 2026; Glasgow, Scotland.