First-in-Human Phase I Trial of Adoptive Immunotherapy with Ex Vivo Expanded and Activated Γδ T Cells Following Haploidentical Bone Marrow Transplantation and Post-BMT Cyclophosphamide

INTRODUCTION: HAPLO BMT combined with cyclophosphamide infusion on days +3 and +4 following BMT (PTCy) for patients that lack an HLA-matched donor provides effective graft versus host disease (GVHD) prophylaxis but with a heightened risk of disease recurrence likely due to prolonged immunodeficiency. Multiple studies have shown that increases in circulating donor-derived gamma delta (γδ) T cells during the early post-transplant period is strongly associated with significant improvement in disease-free survival (DFS). We developed a clinical protocol to engineer this effect by infusing escalating doses of ex vivo expanded and activated donor γδ T cells (EAGD) during this period of immunodeficiency as prophylaxis against disease recurrence. As innate immune effectors γδ T cells immediately recognize and kill malignant cells in a broad-based non-MHC restricted manner and do not initiate GVHD.

STUDY DESIGN AND METHODS: This single-center Phase I clinical trial of allogeneic haploidentical BMT + EAGD (NCT03533816), currently underway at the Kansas University Cancer Center, represents the first time BMT patients have received a large infusion of EAGD from a haploidentical donor during the early post-transplant time period. Subjects ≥18 years of age with AML, ALL, CML or MDS either in morphologic complete remission with high risk features, in first complete remission, or chronic phase (CML) eligible for BMT are enrolled in a 3 x 3 design with escalating EAGD doses from 1 x 10⁶/kg to 3 x 10⁶/kg to 1 x 10⁷/kg. Subjects must have adequate organ function and a KPS ≥70. Any subjects with central nervous system neoplastic involvement, HIV infection, or a life expectancy <12 weeks are excluded. Haploidentical donors provide an initial non-mobilized leukapheresis product from which EAGD are manufactured and an unmanipulated bone marrow harvest as the source of hematopoietic stem cells. Closed system EAGD manufacturing is performed in the Miltenyi Prodigy® bioreactor by expansion of γδ T cells in conjunction with αβ T cell depletion. Specimens for composition, viability, sterility, identity, and purity are obtained prior to cryopreservation and results obtained prior to infusion. Subjects undergo standard of care conditioning therapy with fludarabine and cyclophosphamide followed by BMT and post-BMT cyclophosphamide (Cy). The EAGD product is thawed and infused directly within 5 days of neutrophil engraftment (ANC >500/mL for 3 consecutive days). Peripheral blood is collected at screening, pre and post EAGD infusion, then monthly thereafter through Day 100 with additional samples collected every 6 months through 1 year and annually thereafter. Biologic parameters include leukemia phenotype and genomics, multiparameter peripheral blood immunophenotyping, single-cell and serum Th1/Th2/Th17 cytokine analysis, and immunogenomics for both peripheral blood and the EAGD cell product. Primary endpoints include the following safety assessments; laboratory parameters, viral monitoring, physical exams, acute and chronic GVHD, as well as biopsy pathology. Relapse and overall survival will be measured as secondary endpoints. Descriptive statistics under each specific dose will be used to summarize baseline characteristics, safety variables and efficacy outcomes. Kaplan-Meier curves and summary statistics will be used to summarize time-to-event outcomes.

STATUS: To date, 3 female subjects (age range, 44 - 54) with AML have been enrolled with 2 subjects receiving the EAGD infusion. To have no treatment-related adverse events have been recorded