Preliminary results from the phase 2 registrational iMMagine-1 trial show that anitocabtagene autoleucel (anito-cel), a novel BCMA-directed CAR T-cell therapy, is demonstrating impressive efficacy and a potentially differentiated safety profile in patients with relapsed/refractory multiple myeloma.
The data, presented at the 2024 American Society of Hematology (ASH) Meeting, revealed overall response rates of up to 95-100% in heavily pretreated patients, including high rates of complete remission and minimal residual disease (MRD) negativity.
"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," explained Ciara Freeman, MD, medical oncologist at Moffitt Cancer Center, in an interview with Targeted Oncology.
Novel D-Domain Technology Sets Anito-cel Apart
Unlike other CAR T therapies that use traditional single-chain variable fragments derived from antibodies, anito-cel employs a compact D-Domain binder to target B-cell maturation antigen (BCMA). This fully synthetic protein features a hydrophobic core without disulfide bonds, and its smaller size is believed to offer several advantages.
The D-Domain's design potentially enables:
- Higher transduction efficiency
- Increased proportion of CAR-positive T-cells
- Greater CAR density on T-cell surfaces
- Enhanced antigen binding for more efficient myeloma cell killing
Perhaps most notably, the D-Domain's faster off-rate from the BCMA target may allow for effective cancer cell elimination without prolonged inflammation, potentially contributing to anito-cel's favorable safety profile.
Differentiated Safety Profile
Early clinical trial data suggests anito-cel may offer safety advantages compared to other BCMA-directed CAR T therapies. In the iMMagine-1 trial, researchers have not observed delayed neurotoxicities, including cranial nerve palsies, Guillain-Barré syndrome, or Parkinsonian-like symptoms—complications that have been associated with some other BCMA-targeted CAR T therapies.
Additionally, the incidence of severe cytokine release syndrome (CRS) appears relatively low with anito-cel, with most cases being mild or moderate and resolving quickly. This safety profile could be particularly important for multiple myeloma patients, who are often older and may have comorbidities.
Positioning in the Treatment Landscape
While the clinical efficacy of anito-cel appears promising, questions remain about where it will fit in the evolving multiple myeloma treatment paradigm. Currently, the iMMagine-1 study is investigating anito-cel in patients with more advanced disease who have undergone multiple prior lines of therapy.
"Given this focus on a later-line setting, it is less likely that the results of iMMagine-1 will lead to an expanded indication for anito-cel in the second-line setting," noted Dr. Freeman. Instead, anito-cel's initial indication will likely be for patients with more refractory disease who have exhausted other treatment options, particularly those who are triple-class exposed (refractory to an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody).
This contrasts with ciltacabtagene autoleucel (cilta-cel; Carvykti), which has already secured approval for patients with relapsed or refractory multiple myeloma who have demonstrated resistance to lenalidomide after at least one prior line of therapy, positioning it as a second-line treatment option.
Future Directions
The ongoing iMMagine-3 study (NCT06413498) may provide insights into whether BCMA-targeting CAR T-cell therapies could be moved to earlier treatment lines. This randomized trial compares idecabtagene vicleucel (ide-cel; Abecma) against standard of care regimens in patients who have received one to three prior lines of therapy.
Positive results from iMMagine-3 could potentially pave the way for the approval of ide-cel and other BCMA-targeting CAR T-cell therapies, including anito-cel, for use in earlier lines of therapy. This would represent a significant advancement in the treatment algorithm for multiple myeloma, offering the potential for long-term disease control earlier in the course of the illness.
As research continues, the optimal sequencing and positioning of these innovative CAR T-cell therapies will be determined through thorough analysis of response rates, progression-free survival, overall survival, and the incidence and severity of treatment-related toxicities.
Practical Implementation Challenges
Despite the excitement surrounding CAR T-cell therapies like anito-cel, practical implementation in clinical practice presents several hurdles. These challenges range from patient selection and management of potential toxicities to logistical considerations within treatment centers.
As the field advances, addressing these practical challenges will be crucial to ensuring that eligible patients can access these potentially transformative therapies in a timely and safe manner.
