Coming Soon: An Off-the-Shelf CAR T Therapy for Myeloma

The wonders of chimeric antigen receptor (CAR) T-cell therapy cannot escape a simple fact: for some patients, the wait required for the manufacturing process is simply too long.

For years now, investigators have explored allogeneic CAR T-cell treatments, made with T cells from healthy donors, which would eliminate both the wait times and the high-wire act of the manufacturing process for individual therapies. The challenge, of course, has been overcoming the risk of graft vs host disease (GVHD).

Attendees at the International Myeloma Society (IMS) 21st Annual Meeting & Exposition got an early look at data for Poseida Therapeutics’ investigational allogeneic product, P-BCMA-ALLO1, which uses both a stem-cell rich CAR and endogenous T cell receptor gene editing to prevent GVHD.

Bhagirathbhai R. Dholaria, MBBS | Image credit: Poseida Therapeutics

At IMS 2024, trial investigator Bhagirathbhai R. Dholaria, MBBS, associate professor of medicine, Malignant Hematology & Stem Cell Transplantation at Vanderbilt University Medical Center in Nashville, Tennessee, presented results from a phase 1 study involving 34 patients; this was designed to evaluate lymphodepletion strategies and establish a maximum tolerated dose. The process established doses of 750 mg/m2/day and fludarabine 30 mg/m2/day and a P-BCMA-ALLO1 dose of 2x106 cells/kg for further study (Arm C).

The median age of the patients is 66 years, with 5 median prior lines of therapy. Median time to enrollment to treatment is just 2 days, and 100% of the intent-to-treat population received P-BCMA-ALLO1. No patient required bridging therapy; the investigational product was well tolerated with no GVHD or dose-limiting toxicity. The most common treatment-related adverse events of grade 3 or higher were: neutropenia (61%), leukopenia (55%), lymphopenia (45%), thrombocytopenia (39%), anemia (30%) and febrile neutropenia (24%). Ten of the 34 patients (29%) developed cytokine release syndrome of at least grade 2 and 1 patient developed grade 2 immune effector cell-associated neurotoxicity syndrome.

Dholaria answered questions about the study from The American Journal of Managed Care^® (AJMC^®) via email. His responses appear below.

AJMC: Can you describe the most important ways in which P-BCMA-ALLO1 is constructed differently from earlier CAR T-cell therapies?

Dholaria: P-BCMA-ALLO-1 is fundamentally different from approved CAR T-cell therapies because it is an allogeneic CAR T manufactured from healthy donor T cells, instead of from a patient’s own cells. This allows it to be available as an off-the-shelf, readily available therapy vs several weeks required to deliver autologous CAR T. In addition, the non-viral technology that Poseida uses to manufacture P-BCMA-ALLO1 uniquely enables a product that is rich in stem cell memory T cells, or Tscm, while also efficiently adding multiple different functions and genes into the cells to support several potential safety benefits and a lower production cost.

AJMC: Discuss the importance of the stem cell memory T cells in this therapy.

Dholaria: Tscm have great promise for allogeneic CAR T treatment because of their enduring nature and ability to differentiate into diverse T-cell subsets. This “stemness” is important because in CAR T it has been shown to correlate with product efficacy, depth and durability of response.

AJMC: As you noted in your presentation, because this is an allogeneic therapy, there is no bridging therapy; the time to treatment once a decision is made is about one day. How does this affect patient outcomes?

Dholaria: 100% of enrolled patients received P-BCMA-ALLO1 and no patients needed a bridging therapy, despite having a very aggressive relapsed refractory multiple myeloma. In myeloma, bridging therapy can be something like a triplet combination of chemotherapy and expensive targeted monoclonal antibodies. I think avoiding bridging therapy is a huge advantage that will allow us to treat patients who really need this therapy—those who have aggressive disease, have relapsed or have not responded to other therapies. And for many of these patients that previously tried a T-cell engager therapy, there is no good way to give them autologous CAR T because after the prior T cell engager exposure, the quality of autologous CAR T is not as robust, the response rates are low, and the duration of response has been suboptimal.

In addition, autologous CAR T requires at least 6 to 8 weeks from the time we make a decision to treat a patient to when they actually get the CAR T therapy. Many of our myeloma patients, including the majority of who were treated in the P-BCMA-ALLO1 trial, would not have been able to stay stable for that long. And given the fact that P-BCMA-ALLO1 can be administered in an outpatient setting, smaller academic programs and community practices can potentially use it in their office, greatly expanding access. Our experience treating patients in the trial entirely in the outpatient setting has been very positive.

AJMC: You were able to enroll a diverse patient population for this trial, especially relative to what we have seen in some recent high-profile trials. What was your strategy for recruiting a diverse population?

Dholaria: I am encouraged that this study included a racially diverse population, which is important as patients of color have historically had poorer clinical outcomes. The diversity in the trial was driven in part by the location of the clinical trial sites, and also the ability to administer P-BCMA-ALLO1 in an outpatient setting, which can be helpful for minority populations that may be challenged by the requirements for autologous CAR T and other biologics that require significant time commitments pre- and/or posttreatment.

AJMC: Can you briefly discuss the results for Arm C and the next steps?

Dholaria: Arm C has enrolled 21 patients who received cyclophosphamide 750 mg/m2/day and fludarabine 30 mg/m2/day and approximately 2x106 cells/kg P-BCMA-ALLO1. The data from this arm is still relatively early and needs time to mature, but the early efficacy is encouraging—the overall response rate was 91%, with the majority being either complete response or very good partial response. For the patients I personally treated, I was very impressed with the rapid responses and the safety profile of this therapy compared to other CAR T-cell therapies, which was quite manageable and enabled us to treat most of our patients on a completely outpatient basis.

More broadly, we saw an overall consistent and compelling emerging safety profile across all the trial arms, which included a diverse, heavily pretreated, refractory and high-risk patient population. Given these results, we have now entered the phase 1b expansion phase of the study, using the Arm C lymphodepletion regimen across 2 dosing cohorts.

Reference

Dholaria B. A phase 1 study of P-BCMA- ALLO1, a non-viral, allogeneic BCMA directed CAR-T in relapsed/refractory multiple myeloma (RRMM). Presented at: International Myeloma Society 21st Annual Meeting & Exposition, Rio de Janiero, Brazil; September 27, 2024. Abstract OA – 04.