Inb-100: Pilot Study of Donor Derived, Ex-Vivo Expanded/Activated Gamma Delta T Cell Infusion Following Haploidentical Hematopoietic Stem Cell Transplantation and Post-Transplant Cyclophosphamide

Background: Gamma-delta (γδ) T cells engage heme malignancies via innate sensing of multiple ligands such as PVR, B7-H6, DNAM-1, and the NKG2DL family. These MHC unrestricted cells do not initiate graft-versus-host disease (GvHD), are anti-leukemic and may address the ~50% incidence of relapse following haplo-reduced intensity conditioning (RIC) stem cell transplantation. Infusion of donor-derived allogeneic ex vivo activated γδ T cells (EAGD) post-transplant may reduce relapse without severe GvHD. We present updated clinical and correlative data from dose-escalation and recommended phase 2 dose (RP2D) cohort. Methods: Adults with newly diagnosed or relapsed ALL, CML, AML, or MDS undergoing first HSCT with RIC received EAGD cells after neutrophil engraftment. Three dose levels (DL) of 1x106, 3x106 and 1x107 cells/kg were planned. Primary endpoints included dose-limiting toxicities (DLT), grade (G) 3-4 adverse events (AE's) including GvHD, with secondary endpoints of relapse-free (RFS) and overall survival. Immunophenotyping and cytokine analysis were conducted over the one year post-HSCT. Results: 14 subjects enrolled, 10 treated (4 treated at DL1, 6 treated at the RP2D of DL2). Untreated subjects included a screen failure, manufacturing failure, one subject who died prior to dosing, and a subject who received an out of study specification product. Dosed subjects were 60% male, 90% white, median age 68, and primarily AML subjects in CR1. RP2D was defined by an acceptable toxicity profile, no DLT's, prolonged RFS and elevated γδ levels. Most common AE's included platelet count decrease, anemia, decreased ANC (92% each), WBC count decrease (83% ), hypomagnesemia (75%), maculopapular rash (67%) and blood creatinine increased, hypokalemia, nausea, diarrhea and decreased lymphocyte count (58% each). EAGD related toxicities were primarily G1-2, included maculopapular rash (50% incidence with 10% G3 events), acute GvHD (G2 in 70%) and 31% chronic GVHD. Treatment related serious AE's in 23% of patients included G3 nausea (8%), G2 rash (15%). No DLTs, neurotoxicity, cytokine release syndrome or treatment related deaths were reported. At median follow-up of 19.0 months (mos), 15.3 mos median duration of morphologic complete remission (CR) was observed in 10 evaluable subjects. Seven of 10 evaluable subjects remain in CR with one subject receiving intermittent hypomethylating therapy for emergence of recipient chimerism. Of the seven, three subjects remain relapse free beyond 3 years, including 2 with trisomy 8 and del 7 along with IDH and/or FLT-3 mutation. One patient died relapse free due to idiopathic pulmonary syndrome unrelated to EAGD cells at 15.5 mos, and 2 subjects with TP53 mutations (an MDS/MPN overlap and an ALL subject) relapsed at 12.5 and 14.7 mos, respectively, despite the ALL subject having received 7 prior induction regimens. Peripheral lymphodepletion persisted through d100 post-transplant followed by T cell recovery, where CD8+ T cells shift from central memory to effector memory and terminal effector memory T cells (TEMRA) CD45RA/CD27 phenotypes. Continued γδ T cell expansion is observed in DL2 at 60-365d post-BMT vs. DL1 and historical haplo/PTCy patients, p = <0.05 suggesting durability of the anti-leukemic effect and continued leukemic surveillance. Summary: EAGD cells demonstrated manageable safety with no severe acute GvHD. Durable RFS ≥ 12mos was achieved in 100% of subjects followed for a year despite historical ~50% relapse rates at 1 year. This, along with evidence of γδ T cells expansion post-HSCT suggests this therapy may be effective in mitigating relapse after haplo-HSCT and warrants on-going study continuation. Based on preliminary data, a registrational trial in AML patients is forthcoming. NCT03533816