Early Data on GPRC5D-Directed CAR T-Cell Therapy Open Doors for New Myeloma Treatment Strategies – Precision Oncology News

NEW YORK Bristol Myers Squibb is advancing a larger, multi-center trial of its investigational GPRC5D-targeting CAR T-cell therapy after a proof-of-principle trial in heavily treated multiple myeloma patients yielded encouraging response rates.

Meanwhile, based on the activity seen in this early-stage study, researchers are also exploring the potential of dual CAR T-cell therapy simultaneously targeting GPRC5D and BCMA in multiple myeloma.

The data that enticed BMS and researchers came from a single-center trial and was recently published in the New England Journal of Medicine, showing a 71 percent response rate among multiple myeloma patients who received the autologous CAR T-cell therapy, dubbed MCARH109, after five or more prior treatments. BMS gained the rights to develop the CAR T-cell therapy in 2019, when it acquired Celgene, which had previously acquired Juno Therapeutics. Juno bought the rights to develop CAR T-cell therapies using antibodies targeting GPRC5D from Memorial Sloan Kettering in 2016.

In the Phase I trial published in NEJM, patients were treated at MSK, and their autologous T cells were engineered to target the GPRC5D protein in MSK's Cell Therapy Cell Engineering Facility. The trial enrolled 17 multiple myeloma patients, all of whom had received at least three prior therapies, but most of whom received more than that. The median number of prior treatment lines was six, and eight patients had already received BCMA-directed autologous CAR T-cell therapy.

Across all four dose levels of the GPRC5D-directed CAR T-cell therapy, 71 percent of patients responded, and 35 percent experienced a complete response or stringent complete response. After a median follow-up of 10.1 months, 50 percent of the patients who experienced at least a partial response remain progression-free, and the therapy was generally safe with side effects comparable to those seen with B-cell maturation antigen (BCMA)-directed CAR T-cell therapies.

According to Renier Brentjens, the deputy director of the Roswell Park Comprehensive Cancer Center and a co-senior author on the Phase I study, one of the most encouraging findings was that of the eight patients who'd already received BCMA-targeted CAR T-cell therapy, 75 percent responded to MCARH109.

"That was key, because it means that with this type of technology, you get more than one chance at bat," said Brentjens, who worked at MSK at the start of the trial. "If you don't get long-term remission, but you get a year of disease-free survival out of one [CAR T-cell therapy], then we know that we still have another option in our back pocket."

The finding that GPRC5D-directed CAR T-cell therapy could be effective for multiple myeloma patients who have already received BCMA-directed CAR T-cell therapy comes on the heels of US market approval of two multiple myeloma CAR T-cell therapies that target BCMA. Last year, the US Food and Drug Administration approved 2seventy Bio (formerly Bluebird Bio) and BMS's Abecma (idecabtagene vicleucel) as a fifth-line treatment for relapsed or refractory multiple myeloma patients, and in March, Janssen and Legend Biotech netted approval for Carvykti (ciltacabtagene autoleucel) for the same patient population. These drugs are approved in Europe in this setting, too.

The arrival of CAR T-cell therapy in multiple myeloma has been encouraging for patients whose cancers haven't responded to prior treatment regimens. Abecma and Carvykti both led to high response rates in pivotal trials, and many patients have benefited from the autologous therapies since they've entered the US and European markets. But as Brentjens and colleagues wrote in their recent NEJM paper, these therapies "have not generated survival curves with a plateau in patients with multiple myeloma, and most patients are likely to have an eventual relapse."

When, eventually, most patients do experience disease progression following BCMA-directed CAR T-cell therapy, the treatment options are limited, highlighting a significant need for a next-line therapy like MCARH109.

Possible dual-targeting approach

Beyond the possibility that MCARH109 might offer multiple myeloma patients another option after BCMA-directed CAR T-cell therapy, Brentjens suggested there might be a role for combined CAR T-cell infusions that target both BCMA and GPRC5D.

"The idea is that, if the tumor can somehow dodge one CAR T cell by, for example, decreasing or losing expression of BCMA well, it's a lot more difficult to get rid of both targets at the same time," Brentjens said. "If target antigen loss is a reason why patients get relapsed disease, one would predict that that would occur less frequently than if you're going after two targets rather than one on the tumor cell."

Clinical trials evaluating this approach are already underway in the academic setting, Brentjens said. He and his colleagues at MSK have recently begun enrolling patients into a Phase I trial combining BCMA- and GPRC5D-targeted CAR T-cell therapy for relapsed or refractory multiple myeloma patients after at least three prior treatment lines.

Investigators exploring the dual receptor targeting approach will need to be extra careful about patient toxicity, Brentjens acknowledged. "You would think that the toxicity would be additive, so the toxicity you see with one therapy would be seen at the same time as the toxicity you see with the other but biology can sometimes surprise us," he said. "You need to be vigilant to look at whether there is a synergistic degree of toxicity if you get both [CAR T-cell therapies] at the same time."

As far as the efficacy of the dual-targeting approach goes, Brentjens said that the data he and colleagues have generated to date "certainly justifies trying both at the same time."

"I'm very excited about it," he said of the new combined CAR T-cell trial. "I think we're one of the first to try to see if this approach might be feasible, and hopefully we'll see that the remissions are longer term when compared to one or the other treatment alone."

Brentjens also suggested he could see a future situation in which patients could have their cells analyzed prior to undergoing CAR T-cell therapy, and a higher expression of one versus the other target be it BCMA or GPRC5D could determine which therapy a patient receives. That said, because BCMA-targeted CAR T-cell therapy is currently FDA approved whereas GPRC5D-directed CAR T-cell therapy is not, the prospect of that sort of biomarker-directed approach to sequencing cell therapies is not right around the corner; clinical trials would first need to provide enough support for MCAR109 to score regulatory approval.

This may well be on the horizon, though. BMS has recently launched a dose-escalation study of MCARH109 at nine sites across the country and is planning to enroll 77 relapsed or refractory multiple myeloma patients. Participants in this trial must have three or more prior therapies, though prior BCMA-targeted CAR T-cell therapy is not a requirement for enrollment.

BMS did not provide further information about this trial or its overall approach to studying MCARH109.

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Early Data on GPRC5D-Directed CAR T-Cell Therapy Open Doors for New Myeloma Treatment Strategies - Precision Oncology News