inMMyCAR: in vivo CAR-T therapy for multiple myeloma

At ASH 2025, Prof Dr Phoebe Joy Ho, professor of hematology at the University of Sydney and Royal Prince Alfred Hospital in Sydney, Australia, presented a late-breaking abstract at ASH 2025 describing a first-in-human clinical trial of in vivo CAR T-cell therapy for multiple myeloma. 

This novel approach is based on systemic delivery of a lentiviral vector engineered to selectively transduce T cells in vivo. The vector incorporates an anti-CD3 single-chain variable fragment to confer T-cell targeting and a modified vesicular stomatitis virus glycoprotein with disrupted LDL receptor binding while preserving fusogenic activity, thereby maintaining transduction efficiency. As with conventional ex vivo CAR T products, the vector is self-inactivating and replication-incompetent. Importantly, with this strategy, there is no requirement for lymphodepleting chemotherapy.

Preclinical studies in xenograft and other animal models demonstrated superior anti-myeloma activity compared with ex vivo–manufactured CAR T cells, along with the generation of less differentiated, memory-like T-cell phenotypes associated with improved persistence and tumor eradication. On this basis, a phase I, first-in-human trial using a standard 3+3 dose-escalation design was initiated in patients with relapsed or refractory multiple myeloma previously exposed to an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody.

Preliminary clinical data were reported for four patients treated at dose level 1 (n=3) or dose level −1 (n=1) (de-escalation was prompted by the high efficacy and a favorable safety profile of the treatment). All patients achieved minimal residual disease–negative responses within one month of treatment. In the first two patients, MRD negativity was sustained at three months, and the patient with the longest follow-up (~five months), achieved a complete response. The remaining patients were in partial response, attributed to delayed clearance of paraprotein, with additional evidence of activity demonstrated by marked reductions in involved free light chains and soluble BCMA levels.

Treatment was well tolerated, with minimal cytopenias. One transient episode of grade 4 neutropenia resolved rapidly and was attributed to neutrophil margination. Infusion reactions occurred in three patients, with only one grade 3 event, all resolving promptly with standard management. 

These early results support the feasibility, safety, and potent anti-myeloma activity of in vivo CAR T-cell therapy and highlight its potential as an off-the-shelf, rapidly deployable immunotherapy platform.