University of Pittsburgh scientists have identified that including Compound 991 (c991) in the preparation of cellular therapies it can increase the anticancer activity of subsequent therapies in vivo. This novel compound can easily be incorporated into existing protocols to improve anticancer efficacy against a variety of malignancies and could improve patient outcomes across a wide array of conditions.
Description
Hematological cancers account for roughly 8% of all adult cancers, with 5-year survival rates of less than 50%. Current treatments can be costly with a continuing need to find the most effective treatment options. With chimeric antigen receptor (CAR) T cells increasingly being used to tackle difficult-to-treat cancers, inclusion of c991 in the preparative CAR T cell regimen alters the metabolic profile of the CAR T cells, enhancing in vivo efficacy and potentially increasing survival rates for some of the deadliest cancers.
Applications
• Leukemia
• Car T Cells Targeting Solid Tumors
• Improved Efficacy of Tumor-Infiltrating Lymphocyte (TIL) Therapies
• Improved Performance of Regulatory T Cells in vivo
• Enhancement of Additional Immune Cell Effector Functions (NK and NK-T Cells)
Advantages
CAR T cell therapies, where a patient’s T cells are cultured ex-vivo and re-infused into the patient, have revolutionized the treatment of many conditions, including cancer. However, treatment is not 100% effective, and relapses occur in up to half of leukemia patients receiving CAR T cell therapies. Previous research demonstrated that CAR T cells with a more oxidative phenotype persisted longer in vivo persistence were more effective in targeting leukemia cells. However, efforts to consistently develop more oxidative T cells in the numbers necessary for clinical application have been unsuccessful.
Compound 991 overcomes this challenge. When applied to CAR T cells during the ex vivo expansion phase, the oxidative metabolism of these cells increased without negatively impacting cell growth. Treated cells also showed a marked increase in anti-leukemia activity in vivo. A huge advantage of this approach is that c991 can be CAR T cells briefly during the ex vivo expansion phase, reducing the risk of on-target/off-tissue effects that might be expected if in vivo systemic administration was required.
Invention Readiness
Various efforts to promote AMP-activated protein kinase (AMPK) activity were studied to increase oxidative metabolism. Treatment of leukemia-targeting CAR T cells with an optimized dosing schedule of the an AMPK agonist, c991, increased their oxidative metabolism without disrupting their in vitro expansion. In vivo testing in animal models of leukemia found that mice receiving c991-treated CAR T cells (c991-CART) survived significantly longer than recipients of untreated CAR T cells, with 80% of c991-CART treated mice leukemia free at the end of the study (compared to 0% in the control group). Further work is required to delineate c991 benefits for other immune-based therapies.
IP Status
https://patents.google.com/patent/WO2025101276A1
