GPRC5D Antigen–Targeted CAR T-cell Therapy Induces Strong Response in Resistant Multiple Myeloma

Renier Brentjens, MD, PhD

MCARH109, a CAR T-cell therapy targeting the “enigmatic” GPRC5D antigen, generated remissions in 70.6% of patients with relapsed/refractory multiple myeloma, according to data from a first-in-human phase 1 trial (NCT04555551).¹

Twelve of 17 patients experienced a measurable decline in their cancer after receiving MCARH109 CAR T cells. Six patients (35%) achieved complete response, and 10 patients (59%) had very good partial response or better. Eight patients (47%) had minimal residual disease negativity in bone marrow.

Although the study population was small, coauthor Renier Brentjens, MD, PhD, The Katherine Anne Gioia Endowed Chair in Cancer Medicine, chair of the department of medicine, and deputy director at Roswell Park Comprehensive Cancer Center; said these findings open up a new plan of attack for treating multiple myeloma.

“What’s scientifically exciting is that we now have 2 populations of targeted cells which we think we can now feasibly treat patients with concomitantly, potentially, and that is very exciting,” he explained in an interview with OncLive^®. “That will certainly help set a proof of principle for other malignancies that we will target with CAR T cells, including solid tumor malignancies. It really is a significant step forward in the field. It’s still to be seen how meaningful this is—whether it’s an opportunity to prolong responses…or to potentially enhance responses. We’re very excited about that part of it.”

Physicians have achieved deep, durable responses using B-cell maturation antigen (BCMA)–targeting CAR T-cell therapies in patients with multiple myeloma. However, data from some studies show that progression-free survival is less than 12 months, an indicator of myeloma recurrence despite the persistence of CAR T cells.² Relapse is common, and mechanisms of resistance are not fully defined, although recent data suggests that the identification of BCMA expression, copy number variation, and point mutations appeared to be key indicators of resistance for patients receiving BCMA-targeting CAR T-cell therapy or T-cell engagers.³

Investigators at Roswell Park developed MCARH109 in partnership with Memorial Sloan Kettering Cancer Center (MSKCC) and Dana-Farber Cancer Institute. Brentjens said investigators began exploring cellular therapeutic targets for multiple myeloma about 10 years ago. They identified 3 targets including BCMA, which is now FDA approved in the form of drugs, such as ciltacabtagene autoleucel (Carvykti), and the antigen GPRC5D.

“GPRC5D is an intriguing target because it’s really nicely upregulated on multiple myeloma cells, but not expressed in most normal tissues, with some exceptions in the skin, for example,” he explained. “We knew even back then that we were likely going to have to go after more than 1 target.”

Duration is limited for BCMA-directed therapy and there are few treatment options for patients who relapse. In preclinical models, investigators found in vitro and in vivo antitumor efficacy with GPRC5D CAR T cells in multiple myeloma, including in a BCMA antigen escape model. GPRC5D is highly expressed in myeloma cell lines and in bone marrow plasma cells of patients with multiple myeloma. The antigen is found less often in plasma cells in normal tissue and has low expression in a subset of cells in the hair follicles and hard keratinizing tissue.

The 17 patients in the phase 1 trial, conducted at MSKCC, had undergone a median of 6 prior treatments for myeloma, including CAR T-cell therapy targeting BCMA, proteasome inhibitors, immunomodulatory agents (IMiDs), and anti-CD38 antibody–based therapies. Eligible patients had an ECOG score of 0 or 1 and adequate organ function. Baseline GPRC5D expression in the bone marrow was not required for enrollment.

Patients could receive bridging therapy following apheresis but had to discontinue at least 2 weeks before initiating lymphodepleting chemotherapy. Lymphodepletion consisted of daily 300 mg/m² cyclophosphamide plus 30 mg/m² fludarabine for 3 consecutive days. Two days after the completion of lymphodepletion, investigators administered MCARH109 at 4 dose levels: 25 × 10⁶, 50 × 10⁶, 150 × 10⁶, and 450 × 10⁶ CAR T cells.

Investigators followed all patients until disease progression. Long-term follow-up continued until death or withdrawal of consent.

The median patient age was 60 years (range, 38-76). All patients received previous treatment with 2 proteasome inhibitors, 2 IMiDs, and 1 anti-CD38 antibody. Sixteen patients (94%) had triple-refractory disease.

Ten patients (59%) had received previous treatment with BCMA-targeted therapies, including 8 (47%) who received previous BCMA CAR T-cell therapy. Nine responded to BCMA-targeted therapy and 2 were refractory to the treatment. The median time from last BCMA therapy to MCARH109 infusion was 16.4 months (range, 4.4-36.6).

All patients had previously received high-dose melphalan and undergone an autologous stem cell transplantation. Three patients (18%) had previously received allogeneic transplantation.

Fourteen patients (82%) were refractory to their last line of therapy. Sixteen patients (94%) received bridging therapy after leukapheresis; 15 were refractory to bridging therapy.

Three patients (18%) had nonsecretory myeloma at baseline, and 8 (47%) had extramedullary plasmacytoma. Thirteen (76%) had one or more high-risk cytogenetic features, defined by the presence of 1q gain, del(17p), t(4;14), or t(14;16).

At a median follow-up of 10.1 months (95% CI, 8.5–not reached [NR]), 6 of 12 patients (50%) with a partial response or better remained progression free. Two patients have completed more than 1 year of follow-up after MCARH109 infusion.

The median duration of response (DOR) was 7.8 months (95% CI, 5.7-NR) in the entire cohort. The median DOR was also 7.8 months (95% CI, 4.6-NR) in patients who received 25 × 10⁶ to 150 × 10⁶ CAR T cells.

At the maximum tolerated dose of 150×10⁶ cells, 58% of patients had a response.

Seven of 10 patients who received previous BCMA-targeted therapies had partial response or better. The same was true for 3 of 6 patients (50%) treated at doses of 25 × 10⁶ to 150 × 10⁶ cells.

Fourteen patients experienced grade 1/2 cytokine release syndrome (CRS). One patient at the highest dose level (450 × 10⁶ CAR T cells) had a grade 4 CRS event. Investigators said this patient had grade 4 immune effector cell–associated neurotoxicity syndrome (ICANS) and grade 4 macrophage activation syndrome, which constituted a dose-limiting toxic effect. No other patients had ICANS or macrophage activation syndrome.

Two other patients at the highest dose level experienced a grade 3 cerebellar disorder that investigators determined was possibly related to MCARH109 and constituted a dose-limiting toxic effect for this dose.

The most common grade 3 or higher adverse effects (AEs) included neutropenia (94%), thrombocytopenia (65%), and anemia (35%). Nonhematologic grade 3 or higher events were uncommon.

Three patients (18%) experienced infections. Two experienced grade 3 events (bacterial infection and parvovirus infection, respectively).

Twelve patients were treated at dose levels that did not produce unacceptable AEs (25 × 10⁶ to 150 × 10⁶ CAR T cells). Seven of those (58%; 95% CI, 28%-85%) had an objective response.

“They had relapsed or been refractory to BCMA-targeted CAR T cells, and yet we are still able to demonstrate clinical meaningfully clinical responses using the GPRC5D CAR T cells,” Brentjens said. “We now actually have 2 targets for patients with multiple myeloma rather than just 1. We can start to potentially explore [targeting 2] different antigens on the multiple myeloma tumor cell, either sequentially or concurrently, which is really exciting to potentially utilize this dual targeted approach to get more durable and long-term remissions in patients.

“To the best of my knowledge, this the first time that we really have identified 2 targets on 1 tumor cell, both of which demonstrate really promising and significant responses. That really begs the question of, if we put the 2 populations together, will there be a synergistic benefit when assessing durability of response?”

References

1. Mailankody S, Devlin SM, Landa J, et al. GPRC5D-targeted CAR T cells for myeloma. N Engl J Med. 2022;387:1196-206. doi:10.1056/NEJMoa2209900
2. Samur MK, Fulciniti M, Aktas Samur A, et al. Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma. Nat Commun. 2021;12:868 doi:10.1038/s41467-021-21177-5
3. Lee H, Maity R, Ahn S, et al. Point mutations in BCMA extracellular domain mediate resistance to BCMA targeting immune therapies. Presented at: 2022 International Myeloma Society Annual Meeting and Exposition; August 25-27, 2022; Los Angeles, CA. Abstract OAB-005.