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Phase I/II clinical trial of in-house BCMA CAR T-cell therapy and opaganib in ultrahigh risk multiple myeloma

Award Number: R01CA293516
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/18/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2031

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Phase I/II clinical trial of in-house BCMA CAR T-cell therapy and opaganib in ultrahigh risk multiple myeloma - Our long-term goal is to develop novel therapeutic approaches to improve the outcomes and survival of patients with ultrahigh risk multiple myeloma (uHRMM). uHRMM encompasses 15-20% of all multiple myeloma diagnoses and is associated with a very poor prognosis. The median overall survival for patients with uHRMM is only about 2 years, and a significant portion of patients with uHRMM die within 6-12 months of the diagnosis. Autologous hematopoietic stem cell transplantation does not provide a sustained response for patients with uHRMM, highlighting an unmet need to develop more effective therapeutic approaches for this population of patients. In this application, we describe a protocol in which we will manufacture in-house BCMA CART-cells using a closed system device, and treat uHRMM patients with BCMA CART-cells for consolidation following standard induction therapy, Additionally, to further improve the efficacy of BCMA CART-cell therapy, we propose the use of the sphingosine kinase 2 inhibitor opaganib after CAR T-cell infusion. Sphingolipid metabolism is increasingly being recognized as a key pathway in tumor biology and anti-tumor immunity. Sphingosine kinases (SK1 and SK2) offer a potential target for modulating tumor cell proliferation and apoptosis, as well as immune responses. We recently found that SK2 plays a critical but suppressive role in CD8 T-cell-mediated anti-tumor activity. CD8 T-cells isolated from SK2-1 - KO mice were more proliferative and more cytotoxic against myeloma cells. Compared to CART-cells generated from WT mice, anti-BCMA CART-cells generated from SK2-1 - KO mice exhibited enhanced anti-myeloma activities in vivo in our preclinical CAR T mouse model, Moreover, the combination of opaganib and BCMA CART-cell therapy resulted in much improved tumor control in our NSG myeloma xenograft CAR T mouse model, The obiective of this application is to determine the safety and preliminary efficacy of BCMA CART-cell therapy in combination with SK2 inhibition in the treatment of uHRMM. Our central hypothesis is that opaganib, administered following CART therapy, will enhance CART-cell function and reduce CART-cell exhaustion, resulting in a deeper and more sustained response for patients with uHRMM. We have two specific aims. Aim 1 is to perform a phase lb clinical trial to determine the safety, pharmacokinetics, and pharmacodynamics of opaganib in combination with in-house BCMA CART cell therapy in uHRMM following standard induction therapy, Up to 18 patients will be enrolled in phase lb study. Aim 2 is to perform a phase II clinical trial to determine the preliminary efficacy of opaganib in combination with inhouse BCMA CAR T cell therapy in uHRMM. Up to 21 additional patients will be enrolled at the recommended phase 2 dose to confirm safety and to investigate preliminary efficacy in this population of patients. We anticipate that this clinical trial will have significant implications for the treatment of uHRMM. The proposed studies constitute a focused approach for developing a novel treatment for patients with uHRMM, a disease with a high unmet clinical need. If positive, these data will provide justification for a larger, multi-center phase Ill study. Project Summary/Abstract


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $628,602 )
2026	2026	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 560	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cancer Treatment Research	000	1	8/18/2026	NEW	$628,602
														Subtotal = $628,602

Grand Total All Awards = $628,602

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Phase I/II clinical trial of in-house BCMA CAR T-cell therapy and opaganib in ultrahigh risk multiple myeloma

Award Number: R01CA293516

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/18/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2031

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