Saturday, May 17, 2025
5/17/2025
Next Generation Engineered NK Cells for Lymphoma Patients after CD19 CAR-T Cell Failure. - Summary: CD19 directed CAR-T cells have transformed the treatment landscape of B-cell lymphoid malignancies. However, despite high initial complete remission rates, relapses occur within the first year of therapy in approximately 50% of patients who receive commercially available autologous CAR19 T-cells. Relapses can be classified into two patterns: CD19-positive relapse related to CAR T-cell exhaustion and senescence, or CD19- negative relapse related to target antigen loss. Patients who relapse after CAR19 T-cell therapy have poor prognosis; hence, there is an urgent need to develop the next-generation of CAR engineered immune effector cells that target tumors with efficacy and with minimal toxicity. There is growing interest in natural killer (NK) cells as a candidate for CAR therapy as they may prevent antigen escape through their innate ability to kill tumor cells and they are safe and well-suited for use in the allogeneic therapy setting. In a first-in-human study, our group showed the safety and promising activity of cord blood (CB) derived CAR-NK cells targeting CD19 in patients with B-lymphoid malignancies (Liu et al NEJM 2020). This proposal aims to build on this platform to develop the next-generation NK cell therapies by enhancing NK cell potency and persistence through optimal costimulatory signaling, cytokine armoring and checkpoint inhibition. We have identified CD70, as a novel therapeutic target in patients with B-NHL after CAR19 T-cell failure and developed a novel strategy to target CD70 by genetically modifying CB-NK cells with a retroviral vector (iC9-CD27-DAP10-CD3ζ-IL-15) that incorporates (i) the gene for a truncated human CD27 (the natural receptor for CD70) to redirect their specificity; (ii) DAP10 as an NK-specific costimulatory domain linked to a CD3ζ signaling endodomain; (iii) IL-15 to support their survival and proliferation, and (iv) inducible caspase-9 (iC9) as a suicide gene. Our preliminary data show the efficacy and safety of this approach in vitro and in vivo and support its translation to the clinic. In addition, we have developed a robust strategy to cryopreserve CAR-NK cells, allowing for the generation of a biobank of off-the-shelf engineered NK cells, thus reducing cost and increasing accessibility. Finally, we have devised a novel strategy to target the immune checkpoint CIS in our CAR-NK cells to modulate their metabolic fitness and potency. We hypothesize that targeting CD70 with iC9/CAR27D10ζ/IL-15 NK cells will greatly improve outcomes in patients with NHL after CAR19 T-cell failure and that by targeting the immune checkpoint CIS we can further enhance the CAR-NK cells’ metabolic fitness and potency. These concepts will be evaluated in three specific aims: In Aim 1 we will conduct a Phase I/II clinical trial to test the safety and efficacy of iC9/CAR27D10ζ/IL-15 NK cells in patients with CD70+ NHL who have failed CAR19 T-cell therapy (FDA approved, IND #27757). In Aim 2 we will apply innovative single-cell proteomic and transcriptomic studies to comprehensively characterize the fate of the CAR-NK cells and to identify key mechanisms of efficacy and resistance. In Aim 3, we will perform mechanistic studies to elucidate how CIS deletion enhances the metabolic fitness of CAR-NK cells and will perform IND enabling studies in preparation for the next-generation clinical studies testing CIS deficient iC9/CAR27D10ζ/IL-15 NK cells.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).