BCMA-CART (Unicar-Therapy)

For patients with multiple myeloma progression after anti-BCMA chimeric antigen receptor (CAR) T-cell therapy, the optimal salvage treatment strategies remain unclear. GPRC5D-directed CAR T cell might be a potential option. The aim of this trial was to investigate the activity and safety of anti-GPRC5D CAR T cells in patients with progressive multiple myeloma after anti-BCMA CAR T-cell therapy.

In this phase 2, open-label, single-arm, phase 2 trial, at the Affiliated Hospital of Xuzhou Medical University in China, we enrolled patients (aged 18-70 years old) with relapsed or refractory multiple myeloma who had progressed disease after anti-BCMA CAR T-cell therapy and a life expectancy of more than 12 weeks without active infections, serious liver, heart, or other diseases. Patients were assigned to receive a single dose of intravenous anti-GPRC5D CAR T cell at 2 × 10⁶ cells per kg. The primary endpoint was the overall response rate, including stringent complete response, complete response, very good partial response, and partial response, according to the standard International Myeloma Working Group response assessment criteria. Activity and safety analyses were done in the patients who received a dose of anti-GPRC5D CAR T cell as defined in the protocol. This trial is registered with the Chinese Clinical Trial Registration Center, ChiCTR2100048888, and is ongoing.

Between Dec 1, 2021, and May 1, 2024, 42 patients were screened, 37 were enrolled and received anti-GPRC5D CAR T-cell therapy. Median age was 59 years (IQR 51-65), 17 (46%) of 37 patients were male and 20 (54%) female. All patients were Asian. At a median follow-up of 12·6 months (IQR 8·2-20·8), the overall response rate was 84% (95% CI 68-94, 31 of 37 patients), including 13 (35%) complete responses or better. The most common grade 3-4 adverse events were haematological toxicities, including leukopenia (34 [92%] of 37 patients), lymphopenia (36 [97%]), neutropenia (29 [78%]), anaemia (23 [62%]), and thrombocytopenia (23 [62%]). 26 (70%) of 37 patients had cytokine release syndrome, which was of grade 3 in two (5%) patients. One case of grade 1 immune effector cell-associated neurotoxicity syndrome was observed. There were no treatment-related deaths in the trial.

Anti-GPRC5D CAR T-cell salvage therapy induced a high response rate, and could be a potential treatment option in relapsed or refractory multiple myeloma patients who have progressed after anti-BCMA CAR T-cell treatment. Further investigations are warranted to establish the long-term efficacy and safety of this therapeutic approach.

National Natural Science Foundation of China and the General Project of Jiangsu Commission of Health.

In recent years, chimeric antigen receptor (CAR)-engineered cellular therapy has brought remarkable advancements in cancer immunotherapy and autoimmune disease treatment. CAR T-cell therapy has demonstrated high efficacy in multiple myeloma (MM), but its durability is limited due to immune suppression within the tumor microenvironment (TME). This study elucidates how cancer-associated fibroblasts (CAFs) impair BCMA CAR T-cell function, and describes development of dual-specific CAR T-cells targeting CAFs. The results showed that CAFs promoted CAR T-cell exhaustion via TGF-β, PD-L1, IL-10, and the FAS/FASL pathway. BCMA-FAP and BCMA-CS1 CAR T cells exhibited enhanced cytotoxicity against MM cells and CAFs, overcoming TME-mediated suppression. E-cadherin-targeting CAR MSCs (Ecad CAR-MSCs) to address graft-versus-host disease (GvHD) were also developed for this study. These CAR MSCs significantly reduced GvHD by selectively accumulating in the intestinal epithelium, suppressing T-cell activation via IL-10 and galectin-9 while promoting Treg induction. These findings suggest that CAF-targeting dual-specific CAR T cells enhance the efficacy of MM immunotherapy, while Ecad CAR-MSCs offer a novel approach to treating GvHD. These approaches hold promise for clinical translation to improve outcomes in cellular therapy.