Evaluating Allogeneic CAR-T P-BCMA-ALLO1 in R/R Multiple Myeloma
Bhagirathbhai R. Dholaria, MD, an associate professor of medicine in malignant hematology & stem cell transplantation at Vanderbilt University Medical Center, discussed interim data from the phase 1/1b clinical trial evaluating Poseida's CAR-T.
Bhagirathbhai R. Dholaria, MD
Poseida Therapeutics is currently evaluating P-BCMA-ALLO1, an allogeneic BCMA-directed chimeric antigen receptor T-cell (CAR-T) therapy, in an ongoing phase 1/1b clinical trial (NCT04960579) for the treatment of relapsed/refractory (r/r) multiple myeloma (MM). The company recently presented data from the trial at the 21st International Myeloma Society (IMS) Annual Meeting, held September 25 to 28, in Rio de Janeiro, Brazil.
CGTLive® followed up with trial investigator Bhagirathbhai R. Dholaria, MD, an associate professor of medicine in malignant hematology & stem cell transplantation at Vanderbilt University Medical Center, after the conference to interview him about the findings presented. Dholaria discussed what makes P-BCMA-ALLO1 unique and went over the key safety and efficacy results presented and their potential implications.
CGTLive: Can you give some background context about P-BCMA-ALLO1 and what it is?
Bhagirathbhai R. Dholaria, MD: P-BCMA-ALLO1 is an off-the-shelf allogenic CAR T-cell therapy manufactured from healthy donor T-cells. The way it is different than other myeloma CAR-T therapies is that it is manufactured using a nonviral gene editing platform, as opposed to cilta-cel or ide-cel, which use virus-based vectors. [But] it also targets the BCMA protein, similar to other CAR T-cell therapies.
Can you give an overview of the recently announced data from the phase 1/1b clinical trial?
At the recent IMS meeting, we presented the data on a phase 1 trial using P-BCMA-ALLO1 at a different cell dose and a different lymphodepletion regimen. Overall, this looked at the data on 72 patients. These are heavily pretreated MM patients. Half of them had high-risk cytogenetics, and around 43% of the patients actually had prior other BCMA-targeted therapy or talquetamab, which is a GPRC5D-targeted bispecific antibody therapy. Several of these patients also had other CAR T-cell therapy before coming on this trial.
Overall, 100% of the intention-to-treat patients actually ended up receiving the P-BCMA-ALLO1 infusion. The primary end point of this trial was the safety of P-BCMA-ALLO1. Looking at the safety aspect of the trial results, no graft versus host disease was reported. It is important, given that this is an off-the-shelf allogeneic T-cell being infused in the recipient. The risk of cytokine release syndrome (CRS) was relatively low. Only around 27% of the patients had this event. Most of the events were grade 1 or grade 2. No patient actually had grade 3 or higher CRS or neurotoxicity or immune effector cell-associated neurotoxicity syndrome. There were some infections seen, but the risk of grade 3 or higher infection was relatively low.
Looking at the in vivo kinetics, we noticed that with higher lymphodepletion we noticed better in vivo expansion and persistence of P-BCMA-ALLO1. That actually correlated with the antimyeloma activity of this agent compared to the standard lymphodepletion, where overall response rate (ORR) was only 21%. We noticed that in arms with enhanced lymphodepletion, such as arms A, B, and C, we noticed increasing ORR of 42%, 72%, and 91% respectively. Arm C, which is using cyclophosphamide 750 mg/m2/day is currently selected for phase 1b expansion, where we saw a 91% ORR, even in heavily pretreated MM patients.
How would you summarize the big-picture implications that doctors and the broader healthcare community should take away from these findings?
This is still a very early study. I think we definitely need a larger patient cohort with longer follow-up to accurately understand the safety and more importantly the efficacy of this agent. However, in current era of bispecific antibodies and CAR T-cell therapies, there is still a huge unmet need of patients who have failed other bispecific antibody therapies, or patients who have failed or are not eligible for standard-of-care CAR T-cell therapy such as cilta-cel or ide-cel. Among those patients, I think this treatment can offer a good option if it turns out to be good enough and safe enough. Given the fact that this is an allogenic product, it's readily available. There is no leukapheresis needed. There is no waiting for manufacturing, which is a huge issue in autologous BCMA-targeted CAR T-cell therapy, which is takes anywhere from 4 to 6 weeks from the time of leukapheresis to actual cell infusion. Many of our high-risk patients are not able to wait that long, and they end up requiring bridging therapy, which none of the patients on this trial needed because P-BCMA-ALLO1 was available right away. So I think that this agent has potential to address that unmet need in high-risk, aggressively-progressing, extramedullary MM patients or high-risk MM patients who had failed other standard-of-care myeloma therapies.
Have there been any challenges in the study and/or are there any areas of interest for further research?
In terms of challenges, of course very early on, like I said, we realized that the standard lymphodepletion was just not good enough to have a better expansion, persistence, and efficacy of this drug. But we appear to have overcome that now. We actually did a very systemic dose escalation of the Cytoxan dose along with the cell dose expansion also, and we learned that there is a sweet spot—not the highest lymphodepletion, but we picked kind of the intermediate dose lymphodepletion, which is cyclophosphamide, cyclophosphamide 750 mg/m2/day, where we saw kind of the right balance of safety and efficacy. That's what we are currently expanding, both in patients who had prior BCMA-targeted therapies and patients who had no prior BCMA-targeted therapies. We are also exploring multiple cell dose infusions to improve the durability of the responses.
This transcript has been edited for clarity.
