Off-the-shelf engineered NK cells for the treatment of AML

Abstract: The coronavirus (COVID-19) pandemic has spread rapidly and globally to infect over 3 million individuals, withno effective therapeutic options for patients with serious and life-threatening complications. The impact of thisinfection is likely to be especially serious in patients undergoing hematopoietic stem cell transplant (HSCT), inparticular umbilical cord blood transplant (CBT) recipients or those receiving chimeric antigen receptor (CAR)T or NK cell therapies, given their immunocompromised state, presence of medical comorbidities, and concernsfor higher infection-related severity and mortality. Our team has developed robust clinical banks of HLA-typedGMP-grade viral-specific T lymphocytes (VSTs) targeting cytomegalovirus (CMV), BK virus (BKV) andadenovirus. We have treated over 100 HSCT recipients, 49% of whom had received CB or haploidenticaltransplants, with these partially HLA-matched and off-the-shelf VSTs on FDA-approved clinical protocols with a>80% response rate and no toxicity. We have successfully applied this platform to establish the protocols for themanufacture of GMP-grade COVID-19 specific T cells. We propose to generate a biobank of COVID-19 specificT cells from donors who have recovered from COVID-19 infections using IRB-approved protocols (MDACCLab02-0630) in the MDACC GMP Facility. We will then conduct a phase I/II clinical trial to evaluate the safety,feasibility and antiviral activity of third-party, off-the-shelf, most closely HLA-matched COVID-19 specific T cellsin HSCT including CBT/haploidentical transplant or cell therapy recipients with severe COVID-19 infections (Aim1). To expedite the approval of this trial for our patients, we recently amended another VST protocol to includetreatment with COVID-19 specific T cells (MDACC #2017-0350, IND 17761).One of the most severe manifestations of the COVID-19 viral infection is acute respiratory distress syndrome(ARDS), often requiring mechanical ventilation and high dose corticosteroid therapy due to respiratory failure.Indeed, there is increasing evidence that the use of corticosteroids may reduce mortality in patients with COVID-19 related ARDS, especially if administered early in the treatment algorithm. However, COVID-19 specific T-celltherapy is not an option in such patients as corticosteroids induce apoptosis of adoptively transferred T cells,thus, significantly limiting the efficacy of this approach. To address this challenge, our group has developed anefficient and novel strategy to inactivate the glucocorticoid receptor (GR) in viral-specific T cells, using CRISPR-Cas9 gene editing of the Nuclear Receptor Subfamily 3 Group C Member1 gene (NR3C1- the gene encodingthe GR). In Aim 2 of this proposal, we will perform the IND-enabling studies for the production of GMP-gradeNR3C1 knockout COVID-19 specific T-cells in preparation for a subsequent phase 1 trial, to be funded throughalternative sources. Given our track-record of generating clinically effective viral-specific T-cells, we areoptimistic that our approach of adoptive immunotherapy with COVID-19 specific T cells will be successful inHSCT or cell therapy recipients with life-threating COVID-19 related infections.