Novel Combinatorial Targeted Chimeric Antigen Receptor Natural Killer Cell-Based Cellular Immunotherapy with Adjuvant Immunomodulation in Patients with AML
Abstract
Topic Area and Military Focus: This addresses the Fiscal Year 2020 (FY20) Peer Reviewed Cancer Research Program (PRCRP) Topic Area of blood cancers, specifically acute myeloid Leukemia (AML). A second Topic Area could include childhood, adolescent and young adult cancer. The FY20 PRCRP Military Health Focus will be to enhance mission readiness by reducing the gaps in AML prognosis (dismal outcomes) and create novel targeted immune cells (natural killer) (NK) therapy and medications that enhance the immune response in patients with high-risk AML (immunomodulatory effects). We therefore anticipate that this combinatorial cellular and immunomodulatory therapy will significantly improve the health and well-being of active military Service Members, Veterans, their beneficiaries, and the general public with high-risk AML. Rationale and Scientific Objectives: High-risk AML has a dismal prognosis (25% or less overall survival) in patients who relapse from their initial treatment, develop progressive disease on chemotherapy treatment, relapse after stem cell transplantation, and/or have underlying risk factors such as certain subtypes, and/or have specific genetic risk factors. Importantly, military Service Members, their beneficiaries, and Veterans are at significantly higher risk of developing AML secondary to their prior exposure to radiation and/or toxins. Specific immune cell therapy (NK cells) has been demonstrated to be effective against high-risk AML, but has had limited utilization in the past due to normal low numbers of circulating NK cells in the blood stream, poor targeting of NK cells to AML cells, and lack of NK cell persistence after infusion. Our group has developed novel methods to significantly expand NK cell numbers by up to 35,000-fold and utilize innovative technologies to target these expanded NK cells to significantly improve their ability to target and kill AML cells. Furthermore, we have investigated new methods to enhance and modulate the function of NK cells with a variety of new therapeutic immunomodulatory drugs. We therefore propose the following three overarching objectives for this advanced preclinical research grant: (1) To determine and maximize the expansion and targeting of human immune NK cells and test them with respect to their safety and efficacy, both in the laboratory and in the animals with high-risk AML; (2) To maximize the effects of these expanded and targeted NK cells against high-risk AML by the addition of immunomodulatory drugs and also determine the cause of resistance to this combinatorial immunological approach; and (3) to manufacture and validate clinical grade expanded and targeted NK cells from both family members and from universal donors, and ultimately obtain Food and Drug Administration (FDA) approval for a future early-phase clinical trial of these expanded and targeted NK cells in patients with high-risk AML. Near-Term Impact and Clinical Applicability: The near-term impact of this approach is to investigate a novel cellular therapeutic approach that is anticipated to be associated with reduced toxicity in patients with high-risk AML. The populations that will benefit the most with this innovative approach include the general public with high-risk AML; patients with AML with serious co-morbidities such as elderly Veterans, who would benefit from this therapy because of its low toxicity profile; military Service Members with high-risk AML, which would also simultaneously enhance mission readiness; and importantly, the elderly (Veterans) with high-risk AML. The proposed benefits include enhancing the remission rate and overall survival rates of patients with high-risk AML, especially those with evidence of resistance to chemotherapy, relapsing after stem cell transplantation, and/or those with co-morbidities. The potential risks of this expanded and targeted NK cellular therapy approach include potential infusion reactions following the administration of these expande
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110841
Entities
People
- Mitchell S Cairo
Organizations
- New York Medical College
- United States Army