Off-the-Shelf Immune Effector Cells for Hematological Malignancies

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PROJECT SUMMARY/ABSTRACT Immune effector cells (IECs) targeting tumor associated antigens, such as with chimeric antigen receptors (CARs) and bi- and tri- specific antibodies, offer unprecedented results in patients previously considered incurable. The number of cellular immunotherapies for solid tumors and hematological malignancies has dramatically increased. CAR T cells are now being considered early in the patient’s treatment plan as in children with CD19+ acute lymphocytic leukemia (ALL), no longer reserved for salvage therapy. However, as experience grows, a number of issues need to be addressed urgently. The grand challenges of adoptive IEC therapy include: on-target/off-tumor toxicities, T cell exhaustion, tumor escape by antigen loss, immunosuppressive tumor microenvironment, variable persistence, and time and cost of individualized product manufacture, limiting global access. To this end, there are 5 important research themes woven throughout the 3 Projects and 4 Cores, specifically, 1) the need for safe and effective allogeneic off-the-shelf IECs, 2) IECs that can target multiple tumor antigens to minimize tumor escape, 3) development of drug regulatable CARs for greater control, limiting on- target/off-tumor adverse effects and T cell exhaustion, 4) more selective cytokine stimulation to enhance IEC persistence and potency with minimal systemic side effects, and 5) translation of new engineering methods for industrial-scale manufacturing. During the current funding period, there have been key discoveries that will drive the next 5 years of this grant, specifically: the finding that (a) Tregs are effective cancer IECs which can be engineered to effectively target and kill cancer comparable to conventional T cells, (b) ability to generate iPSC- derived CD8 iTregs as a renewable starting cell source, readily amenable to genetic engineering and ex vivo expansion, (c) iPSC-derived NK cells engineered to express a high-affinity, non-cleavable CD16a (hnCD16) and membrane-bound IL-15/IL-15R without expression of CD38 enhances in vivo persistence and NK fitness and permits use of anti-CD38 antibody for in vivo depletion of regulatory cells, (d) the construction of antibodies that engage multiple targets, i.e. NK cells and tumor cells, with a stimulatory cytokine increase anti-tumor efficacy, and, (e) large scale IEC manufacturing, providing 100s to 1000s of cell doses, is possible. These discoveries will be further optimized and tested in relevant model systems in support of clinical translation. Project 1 will test the hypothesis that engineered allogeneic CD4 Tregs can be engineered to express synthetic stimulatory receptors and drug inducible CARs for maximum safety and reduced risk of exhaustion. Project 2 we will test the hypothesis that off-the-shelf CD83 CAR iPSC CD8 iTregs can be engineered to avoid rejection and exhaustion but retain potent tumoricidal activity against AML. And, Project 3 will test the hypothesis that the combination of iNK genetic engineering and antigen specific targeting with TriKEs and CARs will enhance specificity, potency, persistence for maximal AML killing.