GPRC5D-Targeted CAR-T Shows Promise in Heavily Pre-treated Multiple Myeloma

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Of the 17 patients treated, 12 patients achieved a response, including 6 who achieved a complete response.

MCARH109, a chimeric antigen receptor (CAR) T-cell therapy targeted at G protein–coupled receptor, class C, group 5, member D (GPRC5D), yielded responses and demonstrated that GPRC5D is an active immunotherapeutic target in a phase 1 clinical trial (NCT04555551) for patients with heavily pretreated multiple myeloma (MM) carried out at Memorial Sloan Kettering Cancer Center (MSKCC), according to results published in The New England Journal of Medicine.1

Of the 17 patients treated in the trial, 12 patients (71%) achieved a response, including 6 patients who achieved a complete response.1,2 More than a year after treatment, 2 patients are still showing a response. Ten of the patients who received MCARH109 had previously been treated with B-cell maturation antigen (BCMA)–directed therapies, including 8 who had previously been treated with BCMA-directed CAR-T therapies; 7 of these patients achieved a response. In terms of safety, 1 patient in the highest dose group experienced grade 4 cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS), while 2 patients in the highest dose group experienced a grade 3 cerebellar disorder, the cause of which was unclear. In the lower dose groups, all instances of CRS were below grade 3 and 0 cases of ICANS or cerebellar disorder occurred.

“CAR T-cell therapies targeting BCMA ­– a protein prevalent on immune system B cells – have shown promise in advanced myeloma, but many patients relapse,” Eric L. Smith, MD, PhD, Dana-Farber Cancer Institute, co-senior author of the study, said in a statement.2 “We developed CAR T-cells targeting an antigen that we identified – called GPRC5D – which were effective in the laboratory against myeloma cells and in animal models of the disease, including those that no longer responded to BCMA-targeting CAR T-cells. Our phase 1 study represents the first time this second-generation CAR T-cell therapy has been tested in patients.”

The ages of the patients treated in the study ranged from 38 to 76 years (median, 60), and the patients had received between 4 and 14 (median, 6) previous lines of therapy.1 Fourteen patients (82%) had disease refractory to the last line of therapy. Sixteen patients received bridging therapy prior to lymphodepletion; 15 of these patients (94%) had disease refractory to bridging therapy. The patients in the study were divided across 4 dose groups for MCARH109 administration, with 3 receiving 25×106 CAR T-cells, 3 receiving 50×106 CAR T-cells, 6 receiving 150×106 CAR T-cells (determined to be the maximum tolerated dose), and 5 receiving the highest dose at 450×106 CAR T-cells. In the lower 3 dose groups, 58% of patients achieved a response, and the median duration of response was 7.8 months.

Overall, the adverse events (AEs) observed were comparable to those typically seen in BCMA-directed CAR T-cell therapies.2 CRS was reported in 15 of the treated patients but was mild to moderate in all cases excepting the grade 4 case mentioned above. Additional toxic effects, which were expected based on the expression of GPRC5D in some normal cells in the hair follicles of the skin and hard keratinizing tissue, included transient rash, dysgeusia, and nail changes; all of these AEs were grade 2 or lower.1 There were no patient deaths from AEs associated with MCARH109.2

“The occurrence of cerebellar symptoms in [2 patients] who received 450×106 CAR T-cells will require additional studies to better understand the cause and management,” Smith and colleagues wrote.1 “The exact cause of these symptoms is unclear but could possibly be related to low-level expression of GPRC5D in the cerebellum or the inferior olivary nucleus. Reports of delayed Parkinsonism-like neurologic toxic effects have also been reported in 1 to 5% of patients treated with cilta-cel and is attributed to potential expression of BCMA in the basal ganglia.”

The investigators ultimately concluded that because there was a high likelihood of response noted across all 4 dose levels, especially among the patients with limited or no other therapeutic options, GPRC5D represents a promising target for the treatment of myeloma. They mentioned that the targeting of antigens such as GPRC5D as a potential alternative to sequential targeting of BCMA is an area of interest for future research, as is the potential for combination therapies targeting both BCMA and GPRC5D. The investigators also pointed out that an additional phase 1 clinical trial for GPRC5D-targeted CAR T-cell therapy (NCT04674813) for patients with relapsed/refractory MM has begun enrolling patients.

REFERENCES
1. Mailankody S, Devlin SM, Landa J, et al. GPRC5D -targeted CAR T-cells for myeloma. N Engl J Med. 2022;387(13):1196-1206. Doi: 10.1056/NEJMoa2209900
2. CAR T-cell therapy proves effective in first trial in patients with resistant multiple myeloma. News release. Memorial Sloan Kettering Cancer Center. September 28, 2022. https://www.mskcc.org/news-releases/car-t-cell-therapy-proves-effective-first-trial-patients-resistant-multiple-myeloma 
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