Freeman on Anito-cel's Differentiation in Myeloma CAR T

In an interview with Targeted Oncology^TM, Ciara Freeman, MD, medical oncologist at Moffitt Cancer Center, discusses anitocabtagene autoleucel (anito-cel), an autologous BCMA-directed CAR T-cell therapy for the treatment of multiple myeloma. Data from the phase 2 registrational iMMagine-1 study (NCT05396885) were presented at the 2024 American Society of Hematology (ASH) Meeting. Here, Freeman discusses how anito-cel differs from existing CAR T-cell therapies for the treatment of myeloma.

Anito-cel utilizes a novel and compact D-Domain binder for targeting BCMA, instead of the traditional single-chain variable fragment derived from antibodies used in other CAR T therapies. This D-Domain is a small, stable, fully synthetic protein with a hydrophobic core and no disulfide bonds. Its smaller size is believed to facilitate higher transduction efficiency, leading to a higher proportion of CAR-positive T-cells and increased CAR density on the T-cell surface. This could potentially enhance antigen binding and more efficient killing of myeloma cells. The D-Domain is also thought to have a fast off-rate from the BCMA target, which may allow for effective killing of cancer cells without prolonged inflammation, potentially contributing to a more manageable safety profile. 

"...The fact that it has this faster off-rate, so it comes away from the target faster, so it doesn't remain as tightly bound, may confer additional benefits in terms of how it works," Freeman explains in the interview.

On safety, early clinical trial data suggests that anito-cel may have a differentiated safety profile, particularly regarding neurotoxicity. Notably, in the iMMagine-1 trial, no delayed neurotoxicities, including cranial nerve palsies, Guillain-Barré syndrome, or Parkinsonian-like symptoms, have been observed to date with anito-cel. This is a significant point as some other BCMA-directed CAR T therapies have been associated with these types of neurotoxicities. The incidence of severe cytokine release syndrome (CRS), another common adverse effect of CAR T therapy, appears to be relatively low with anito-cel in early studies, with most cases being mild or moderate and resolving quickly. 

Early results from phase 1 and the ongoing phase 2 iMMagine-1 trial have shown high overall response rates (up to 95-100%) and deep responses, including high rates of complete remission and minimal residual disease (MRD) negativity, in heavily pretreated patients. Progression-free survival and overall survival data are maturing, but early indications suggest durable responses. 

REFERENCE:

Freeman CL, Dhakal B, Kaur G, et al. Phase 2 registrational study of anitocabtagene autoleucel for the treatment of patients with relapsed and/or refractory multiple myeloma: preliminary results from the IMMagine-1 trial. Blood 2024; 144 (Supplement 1): 1031. doi: 10.1182/blood-2024-198499