Multiple myeloma is a malignancy characterized by the uncontrolled proliferation of plasma cells in the bone marrow and accounts for approximately 10% of all hematological cancers. Despite advances in treatment modalities such as proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies, relapse remains inevitable in the majority of patients, continuing to impose a substantial global health burden. In recent years, chimeric antigen receptor T-cell (CAR-T) therapy has fundamentally transformed the treatment landscape of hematological malignancies, particularly B-cell-derived cancers. B-cell maturation antigen (BCMA)-targeted CAR-T products have demonstrated deep and durable responses in patients with advanced relapsed/refractory multiple myeloma. However, these therapies rely on logistically complex procedures, including leukapheresis, individualized cell manufacturing, and lymphodepleting chemotherapy, which significantly limit accessibility, especially for patients with rapidly progressive disease.
The phase 1 study conducted by An and colleagues aimed to evaluate the safety and tolerability of ESO-T01, a lentiviral vector developed to overcome these logistical limitations, in patients with relapsed or refractory multiple myeloma. ESO-T01 is described as a nanobody-assisted, immune-shielded vector designed to generate CAR-T cells directly in vivo through intravenous infusion without requiring cell harvesting or ex vivo manufacturing processes. The study specifically addressed the limitations of conventional autologous CAR-T approaches by eliminating leukapheresis, prolonged manufacturing times, and lymphodepleting chemotherapy, thereby potentially improving treatment accessibility.
This single-center, single-arm, open-label phase 1 trial was conducted at Tongji Hospital in Wuhan, China, and enrolled adult patients with relapsed/refractory multiple myeloma between January and March 2025. Five male patients (median of three prior lines of therapy) received a single intravenous infusion of ESO-T01 at a dose of 0.2 × 10⁹ transduction units without leukapheresis, ex vivo cell processing, or lymphodepleting chemotherapy. The primary endpoint was safety and tolerability, while secondary endpoints included efficacy, pharmacokinetic, and pharmacodynamic parameters. CAR-T cell expansion was monitored using flow cytometry and quantitative PCR, whereas cytokine profiling was assessed through chemiluminescence-based assays. Minimal residual disease (MRD) was evaluated using multiparameter flow cytometry with a sensitivity threshold of 10⁻⁵.
No dose-limiting toxicities (DLTs) were observed during the study; however, grade 3 or higher adverse events were reported in all five patients. Cytokine release syndrome (CRS) occurred in four patients and was managed with corticosteroids, tocilizumab, or supportive care. One patient with extramedullary disease died due to spinal cord compression, underscoring the importance of anatomical risk assessment prior to in vivo CAR-T induction. In terms of efficacy, objective responses were achieved in four of the five patients; all responding patients achieved MRD negativity by day 60, while three patients attained a stringent complete response (sCR). Cytokine profiling revealed an early innate immune wave within the first 24 hours following infusion, followed by a second adaptive wave between days 6 and 14 that coincided with CAR-T expansion. This biphasic pattern was considered a biological characteristic specific to the in vivo CAR-T platform. Overall, these findings provide preliminary evidence that in vivo CAR-T generation, independent of conventional CAR-T components such as leukapheresis, ex vivo manufacturing, and lymphodepleting chemotherapy, may demonstrate a feasible and manageable safety profile. Nevertheless, validation in larger patient cohorts with longer follow-up periods remains necessary.
Translated by: Ayşenur Güneş
Editor: Elinsu Ak
Reference: An, N., Wang, D., Zhang, P. et al. In vivo generation of anti-BCMA CAR-T cells in relapsed or refractory multiple myeloma: a phase 1 study. Nat Med (2026). https://doi.org/10.1038/s41591-026-04244-6
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