Developing allogeneic iNKT cell adoptive therapy to improve outcomes for HSCT indications

Summary This Phase I STTR application addresses the NIAID high-priority area: "Immunomodulatory agents to prevent graft rejection and biomarkers to predict transplantation outcomes". Specifically, this project will advance a novel immunotherapeutic for improving outcomes of hematopoietic stem cell transplantation (HSCT). MiNK Therapeutics, a clinical-stage biopharmaceutical company in Lexington (MA), has developed a cellular immunotherapy product, "agenT-797", composed of invariant Natural Killer T (iNKT) cells. Due to the conserved structure of their T cell receptors and non-polymorphic activating ligands, iNKT cells can be used for adoptive cellular immunotherapy in an allogeneic manner without engineering. agenT-797 is designed as an 'off-the-shelf' product, administered without lymphodepletion or HLA matching, and has shown excellent safety in three completed US phase 1 trials (one for acute respiratory distress syndrome and two in oncology). Results from these studies suggested that agenT-797 has significant immunomodulatory properties impacting endogenous immune cells in patients. In collaboration with Professor Jenny Gumperz's laboratory at the University of Wisconsin School of Medicine and Public Health, this project will conduct pre-clinical studies to evaluate agenT-797's efficacy in reducing graft-versus-host disease (GvHD) and improving immune engraftment post-hematopoietic stem cell transplantation (HSCT). Previous research indicates that human iNKT cells can perform both pro- and anti-inflammatory roles and identifies two main subsets (CD4+ and CD4–) with distinct functional profiles and substantially varying frequencies among healthy individuals. CD4– iNKT cells are more oriented towards cytolysis and pro-inflammatory functions, while regulatory functions are largely associated with the CD4+ subset. Therefore, we hypothesize that CD4+ iNKT cells are likely to be most important for improving HSCT outcomes. This study will utilize murine xenotransplant models developed by the Gumperz lab to assess the impact of agenT-797 batches containing either high or low CD4+ iNKT frequency on human HSCT outcomes. Aim 1 will employ quantitative milestones to rigorously evaluate whether agenT-797 treatment significantly reduces the incidence or severity of GvHD and improves the efficiency of human hematopoietic engraftment, and to determine whether CD4hi and CD4lo batches differ significantly in their effects. Additionally, we will assess whether circulating levels of two anti-inflammatory soluble factors (IL-1RA and IL-4), previously linked to agenT-797 treatment in a clinical trial, can serve as biomarkers for reduced GvHD risk. Aim 2 will determine the efficacy of agenT-797 immunotherapy following pre-transplant myeloablative conditioning. Since such pre-conditioning regimens are often used in clinical HSCT protocols, and are known to produce cellular damage that is highly inflammatory, it is crucial to demonstrate that the regulatory effects of agenT-797 can withstand this challenge. Accomplishing the milestones for each of these Aims will provide the rationale to support a clinical trial to test agenT-797 for improved outcomes in HSCT.