Dr Dhakal on the Investigation of Novel CAR T-Cell Therapy Approaches in Myeloma

[In vivo CAR T-cell therapy] avoids all the logistics of the autologous and also allogeneic CAR T[-cell therapies] in terms of lymphodepletion [and] apheresis.

Binod Dhakal, MD, MS, a professor of medicine in the Division of Hematology and Oncology at the Medical College of Wisconsin and assistant director of experimental therapeutics at the Clinical Cancer Center at Froedtert Hospital, discussed the ongoing evaluation of novel CAR T-cell therapy constructs, including allogeneic and in vivo agents, in relapsed/refractory multiple myeloma.

Although the autologous CAR T-cell therapies ciltacabtagene autoleucel (Carvykti; cilta-cel) and idecabtagene vicleucel (Abecma; ide-cel) are both FDA-approved for select patients with relapsed/refractor multiple myeloma, these autologous therapies still present challenges with access, wait times, lymphodepletion, and relapse, Dhakal explained.

The development of allogeneic agents could represent one avenue to address these challenges, he continued, pointing to CB-011, an off-the-shelf BCMA-directed CAR T-cell therapy designed with immune cloaking, as an agent currently under clinical investigation. Data from the phase 1 CaMMouflage trial (NCT05722418) presented at the 2026 EHA Congress showed that among BCMA therapy–naive patients given the selected dose of 4.5 × 10⁸ cells following lymphodepletion with cyclophosphamide and fludarabine (n = 12), the overall response rate (ORR) was 92%, including a complete response (CR) or better rate of 83%; 91% of evaluable patients (n = 11) were minimal residual disease (MRD) negative. The trial is also enrolling anti-BCMA therapy–exposed patients, a growing population as CAR T-cell therapy and bispecific antibodies move into earlier lines, Dhakal said. If validated in larger cohorts with longer follow-up, such a product could improve access, shorten vein-to-vein time, and lower cost, he added.

With in vivo CAR T-cell therapy, the CAR vector is given directly to the patient, who then generates CAR T cells in the body, Dhakal explained. Proof of concept for this approach came from an investigator-initiated phase 1 study (NCT06791681) of ESO-T01 in China, in which 4 of 5 heavily pretreated patients responded, including 3 with a stringent CR, after a single infusion without leukapheresis or lymphodepletion, he said.

In the first-in-human phase 1 inMMyCAR study (NCT07075185) of the lentiviral vector KLN-1010, updated data presented at the 2026 ASCO Annual Meeting showed an ORR of 100% across 3 dose levels (n = 18), with all evaluable patients (n = 14) MRD negative at a median follow-up of 2.8 months.

Durability, comparisons with autologous products, and longer-term safety remain key questions, Dhakal concluded, noting that many companies are pursuing in vivo constructs in multiple myeloma and autoimmune disease.