HOUSTON—Bellicum Pharmaceuticals reported in early March interim clinical data of BPX-501 in pediatric patients with acute myeloid leukemia (AML) and primary immunodeficiencies (PIDs). BPX-501 is an adjunct T cell therapy incorporating CaspaCIDe administered after haploidentical hematopoietic stem cell transplant (haplo-HSCT) for the treatment of hematologic cancers and inherited blood diseases.
According to a Bellicum spokesperson, “BPX-501 are donor T cells engineered with a safety switch. The T cells are added to a T cell-depleted haploidentical stem cell transplant to support immune recovery and to potentially clean up any remaining cancer cells after the transplant.”
BPX-501 is designed to provide a safety net to eliminate alloreactive BPX-501 T cells (via administration of activator agent rimiducid), should uncontrollable graft-versus-host disease (GvHD) or other T cell-mediated complications occur. This enables physicians to more safely perform stem cell transplants by administering BPX-501 engineered T cells to speed immune reconstitution, provide control over viral infections and enhance graft-versus-leukemic effect without unacceptable GvHD risk. The ongoing BP-004 clinical study of BPX-501 is being conducted at transplant centers in the United States and Europe.
CaspaCIDe (also known as inducible Caspase-9, or iC9), the company’s safety switch, consists of the chemical induction of dimerization (CID) binding domain coupled to the signaling domain of Caspase-9, an enzyme that is an integral part of the apoptotic cell death pathway.
“If donor T cells with CaspaCIDe result in the immune disorder graft-versus-host disease, a small-molecule activation agent can be administered, causing rapid apoptosis and cell death to the toxic T cells. In studies, this has cleared the GvHD,” says the Bellicum spokesperson. “CaspaCIDe is also being evaluated in a CAR T cell to see if it can shut down toxicities through this mechanism.”
Data from the ongoing Phase 1/2 BP-004 trial suggest that BPX-501 T cells may contribute to a durable antileukemic effect in patients with AML. In the study, 38 pediatric AML patients in their first or second complete response underwent a haplo-HSCT, followed by treatment with BPX-501. With a median follow-up of one year, rates of relapse-free survival and overall survival were 91.5 percent and 97.3 percent, respectively. This compares to one-year rates reported in the literature in pediatric AML patients undergoing alternate-donor HSCT of 60 percent to 80 percent.
“The recurrence of cancer is one of the most serious risks to AML patients receiving a stem cell transplant. These impressive results in children with AML suggest that BPX-501 may be effectively reducing or eradicating residual cancer cells following a haplo-transplant procedure,” said Dr. Neena Kapoor, director of the Blood and Marrow Transplantation Program at Children’s Hospital of Los Angeles and an investigator in the BP-004 trial.
Also from the BP-004 study, Bellicum reported high rates of disease-free survival and overall survival in pediatric patients with PIDs, including severe combined immunodeficiency (“bubble boy disease”), Wiskott-Aldrich syndrome, chronic granulomatous disease and other rare immune deficiencies. Of 59 pediatric PID patients undergoing a haplo-HSCT and treatment with BPX-501, disease-free survival was reported at 88.1 percent and overall survival was reported at 88.6 percent, with a median follow-up of one year.
Kapoor noted, “Delayed immune reconstitution can lead to severe infectious complications, a major cause of morbidity and mortality in PID patients who undergo a T-depleted haplo-HSCT. BPX-501 donor T cells administered after a transplant support immune recovery in these patients, and the CaspaCIDe safety switch engineered into BPX-501 may provide a critical safety net to address the risk of uncontrolled GvHD from donor T cells.”
“[BPX-501] may make transplants safer and more accessible for patients who lack a matched family member stem cell donor. BPX-501 has the potential of making haploidentical transplants, which are available to almost anyone, safer and more effective. Bellicum also has an activation switch being tested in CAR-T cells. An activation switch may make CAR-T cells more effective against solid tumor cancers through a sustained and controlled attack. And in 2019, [Bellicum] will begin clinical trials of two different CAR-T cells using a dual switch, containing both safety and activation switches in the same product candidate,” the Bellicum spokesperson concludes.
Based on the BPX-501 clinical data, Bellicum is working with the investigators and the U.S. Food and Drug Administration to develop a protocol for a potential U.S. registration study in pediatric patients. Pending regulatory clearances, the company expects to initiate the study by the end of 2018. These clinical data have been submitted for presentation at an upcoming medical meeting.