The trials are designed to determine whether that laboratory activity can be translated into a useful clinical strategy, rather than to establish efficacy at their outset. Ultra-high-risk multiple myeloma is an aggressive form of blood cancer in which patients often have poor outcomes despite existing treatments, including bone marrow transplantation, and the cancer frequently returns after treatment. CAR T-cell therapy is already an option for some patients whose myeloma has recurred, but the proposed trial asks whether a second agent can improve the activity of those engineered immune cells.

Opaganib will be given after CAR T-cell therapy, with the aim of helping the modified cells continue attacking the cancer. Yubin Kang, M.D., an OU Health hematologist-oncologist and chief of Hematology, Bone Marrow Transplant and Cellular Therapy at OU Health Stephenson Cancer Center, said the research is needed because patients in this high-risk group continue to fare poorly with current care. CAR T-cell therapy takes a patient’s T cells and genetically modifies them so that they can recognize and attack cancer cells before the cells are returned to the patient.

In the planned OU studies, opaganib is intended to alter the environment in which the CAR T cells operate. According to the University of Oklahoma, opaganib blocks SK2, a protein that appears to act as a brake on the immune system’s cancer-fighting T cells. When SK2 was absent or blocked in mice, the T cells multiplied more effectively and killed myeloma cells better.

The trial hypothesis is therefore specific: administration of opaganib after CAR T-cell infusion may support sustained cellular activity in patients with ultra-high-risk disease. The studies will test that hypothesis directly; the grant award itself provides no clinical evidence that the combination is effective. In mouse models receiving both opaganib and CAR T-cell therapy, tumors were controlled better and for longer than in comparison groups, the University of Oklahoma reported.

These observations led to the human research program. “Those studies led to this new grant and the opportunity to test the combination of CAR T-cell therapy and opaganib in humans,” Kang said. The distinction between the models and the planned trials is important: the animal findings supplied the rationale for the grant, but the safety, dosage and clinical effects of the sequence in people remain to be evaluated. The Phase 1b trial is the first of the two stages.

It is planned to enroll as many as 18 patients with ultra-high-risk multiple myeloma. According to the grant description, investigators will evaluate the safety of administering opaganib after CAR T-cell therapy and determine the appropriate dosage for subsequent study. This initial stage therefore addresses whether and at what dose the combination can be administered under a clinical-trial protocol.

The planned Phase 2 stage will enroll up to 21 additional patients and seek early evidence of effectiveness. Because this is a small, grant-funded program, its results will be preliminary; the source does not describe a randomized comparison or establish whether either stage can demonstrate that the combination is superior to other treatments. Opaganib is being developed as a combination agent for multiple treatment settings, including oncology.

Mark Levitt, chief scientific officer at RedHill Biopharma, said prior preclinical and clinical work has indicated that opaganib can reduce cancer-cell survival proteins such as c-Myc and Mcl-1. The company, which is partnering with OU on the trials and will supply opaganib, described those observations as evidence that the drug may have a role in combination treatment for multiple myeloma. “Opaganib has shown promise in preclinical studies as a potential combination therapy in a number of oncology and other indications,” Levitt said. The OU project will examine the drug in a defined sequence with CAR T-cell therapy in ultra-high-risk myeloma.

It will not, by itself, resolve the broader question of whether opaganib is effective across other cancers or disease indications. The project will also test a new local manufacturing workflow at OU. Cells currently sent by the university to an out-of-state company require four to six weeks for genetic engineering and cost nearly half a million dollars, according to Kang.

He said OU believes it can manufacture CAR T cells on campus in six to nine days for less than $100,000. These production times and costs are the university’s stated expectations for the new facility, not results already demonstrated in the planned trials. Kang also said the infrastructure created for the project could potentially support other cellular-therapy studies in the future.

Miltenyi Biotec, which developed the CAR construct used in the program, is helping enable local production by supplying good manufacturing practice-grade lentiviral vector for CAR T-cell manufacturing on the CliniMACS Prodigy system. The collaboration combines three elements of the planned trial: OU’s campus manufacturing operation, Miltenyi’s lentiviral vector and CAR construct, and RedHill’s provision of opaganib. The source describes this as a coordinated effort to translate the preclinical combination into human trials.

It does not report that the complete workflow has yet been clinically validated or that the projected six-to-nine-day production time has already been achieved. The overall question is whether opaganib can safely follow CAR T-cell therapy and provide an early clinical signal consistent with the improved tumor control seen in mice. The Phase 1b study will address safety and dose selection, while the Phase 2 study is intended to look for early effectiveness evidence in an additional group of patients.

If either stage produces information useful to investigators, that information will come from a limited sample and will require further study before broader clinical conclusions could be drawn. No results are available at the time of the award announcement. The NCI-supported project, identified as award No.

R01CA293516-01A1, instead represents a planned test of whether blocking SK2 can extend the cancer-fighting activity of CAR T cells in people with ultra-high-risk multiple myeloma.

Subject of Research: Clinical trials of opaganib after CAR T-cell therapy for ultra-high-risk multiple myeloma

Article Title: OU researcher to study CAR T-cell and opaganib combination in clinical trials for ultra-high-risk multiple myeloma

Article References: OU researcher to study CAR T-cell and opaganib combination in clinical trials for ultra-high-risk multiple myeloma. Original publication (Bibliographic details unavailable.)

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Keywords: multiple myeloma, CAR T-cell therapy, opaganib, SK2, clinical trials, National Cancer Institute, Yubin Kang, cellular therapy, cancer research, OU Health, researcher, T-cell