Trial Begins Dosing of ‘Off-the-shelf’ CAR T-cell Therapy for Multiple Myeloma

The first patient has been dosed in a Phase 1/2a trial investigating Precision BioSciences‘ new CAR T-cell therapy candidate, PBCAR269A, for people with relapsed or refractory multiple myeloma.

The dose-escalation trial (NCT04171843) is expected to recruit 48 participants at five clinical sites in the U.S. Enrollment is now active at City of Hope, in California, and at Columbia University Irving Medical Center, in New York. More information on enrollment is available here.

“There remains significant unmet need for a broadly available and well-tolerated treatment for patients with relapsed or refractory Multiple Myeloma,” Chris Heery, MD, chief medical officer of Precision BioSciences, said in a press release.

“We are committed to improving the access of CAR T therapies for more patients. We appreciate the commitment of our clinical sites to start enrollment ahead of schedule, even during these difficult times, and the willingness of patients to take part in this trial,” he added.

Traditional CAR T-cell therapy is a type of immunotherapy in which a patient’s own T-cells — a type of immune cell — are collected and genetically modified in the lab to better fight cancer, after which they are expanded and infused back into the patient.

While autologous (patient-derived) CAR T-cell therapies have shown promise in multiple cancer types, researchers aren’t always able to collect enough cells from a patient to create the treatment. A donor-derived treatment could thus improve availability and reduce costs.

PBCAR269A is an allogeneic CAR T-cell approach that uses T-cells from healthy donors, allowing for the production of an “off-the-shelf” treatment that may potentially be used in numerous patients.

Specifically, PBCAR269A contains T-cells engineered to produce a man-made chimeric antigen receptor, or CAR, that helps them recognize and kill cells containing the B-cell maturation antigen — a protein found at high levels on the surface of multiple myeloma cells — while leaving healthy cells unharmed.

One drawback of allogeneic therapy is the risk of graft-versus-host disease, a potentially life-threatening reaction in which the donor’s immune system sees the patient’s cells and organs as threats, and launches damaging attacks against them.

To avoid this reaction, Precision uses its genetic engineering technique, called the ARCUS system, to eliminate the graft-versus-host disease response. This system allows the replacement of the gene coding for a key protein involved in T-cell recognition, called T-cell receptor, for the CAR gene.

PBCAR269A has been granted orphan drug status by the U.S. Food and Drug Administration for the treatment of multiple myeloma.

The ongoing Phase 1/2a trial is recruiting patients with relapsed or refractory myeloma who failed to respond to two prior therapies, including an immunomodulatory agent and a proteasome inhibitor.

Participants will first receive a chemotherapy regimen, which eliminates white blood cells to create room for the engineered T-cells and reduce immune reactions against these cells. Then, they will receive a single infusion of ascending PBCAR269A doses, in an attempt to determine the optimal dose for additional testing.

After this dose is established in Phase 1 of the trial, additional patients will be enrolled in Phase 2a to continue studying the treatment’s safety and efficacy, including the proportion of patients who respond to the therapy and the duration of such responses.

Changes in circulating tumor cells, the amount of CAR T-cells in circulation at given time points, and measures of immune system activation will also be examined as exploratory efficacy measures.

Participants will be followed for up to 15 years in a separate, long-term study after completing this trial.

“PBCAR269A is our third off-the-shelf CAR T candidate to advance into the clinic; the second within the last two months,” said Matt Kane, CEO and co-founder of Precision Biosciences.

In addition to PBCAR269A, the company is testing PBCAR0191 (NCT03666000) in patients with B-cell acute lymphoblastic leukemia and non-Hodgkin’s lymphoma; as well as PBCAR20A (NCT04030195) in people with non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, and small lymphocytic lymphoma.

“Despite the uncertain impact of COVID-19 on patients and the healthcare community at large, we maintained our focus and dedication that have enabled continued execution during the pandemic,” Kane added.