Gamida Cell (Israel)

Background: Natural killer (NK) immune effectors are being explored for cancer immunotherapy. GDA-201 is a novel nicotinamide ex-vivo expanded metabolically fit allogeneic NK cell product with augmented resistance against exhaustion. We conducted a phase 1 study of GDA-201 (NCT03019666) and reported 19 patients (pts) with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL). Methods: R/R NHL patients (10 follicular lymphoma, 8 DLBCL, 1 MCL) received lymphodepleting chemotherapy followed by 2 infusions of GDA-201 (days 0, 2) combined with rituximab and low dose IL2. We performed comprehensive analysis of the host innate immunity and T cell repertoire using CyTOF and Clonoseq. “On treatment” lymphoma biopsies obtained between 4 and 16 days after GDA-201 infusion were examined using CODEX spatial proteomic profiling and CyTOF. Results: We previously reported that the best overall response rate for 19 NHL patients was 74% and 62% achieved complete response. The median duration of response was 16 months (range 5–36 months). GDA-201 cells persisted in peripheral blood for 7–14 days (2–92% NK cells were GDA-201) but were no longer detected after day 14. At baseline, number of classical monocytes varied widely (266–730 cells/uL) among patients. Responders had lower levels of classical monocytes and PMN myeloid derived suppressor cells (MDSC) at baseline compared to non-responders (monocytes median 342 vs. 624 cells/uL; p = 0.093; PMN-MDSC 0.04 vs. 0.6 cells/uL; 0.049). At day 7 after GDA-201, we observed expansion of host T cell subsets, particularly regulatory T cells, CD8 effector memory and CD4 effector memory subsets characterized by high Ki67 expression. CD4 cells had increased expression of CCR4 and CXCR3 chemokines. T cell clonality data will be presented. Tumor tissue biopsies obtained 4–16 days after GDA-201 revealed a low number of viable B-cell lymphoma cells with areas of necrosis. CODEX analysis demonstrated NK cells in lymphoma tissue increased from <1% at baseline to 10% after GDA-201 infusion. Remarkably, host T cells comprised most of cells at tumor sites (∼ 50–65% of cellularity). Both CD8 and CD4 subsets have been detected, including regulatory T cells (10–25%). Tumor infiltrating T cells were predominantly characterized by terminal effector or effector memory phenotype, activation (↑ HLA-DR, CD69), expression of suppressive receptors TIGIT, PD1 and increased expression of chemokine receptors CXCR3 and CCR4. The high proportion of CXCR4+ CD4+ T cell in both blood and tissues suggests a role for chemokine recruitment and trafficking. Conclusion: Overall, our findings showed that responses after allogeneic NK cell therapy are influenced by levels of pre-treatment monocytes and PMN MDSCs. Our results suggest that immune microenvironment changes after allogeneic NK therapy stimulate influx of host T cells into tumor sites and support cross-talk between innate and the adaptive arms to enhance lymphoma elimination. The research was funded by: This research was partially funded by Gamida Cell. Trial is an investigator initiated trial sponsored by Gamida Cell Keywords: Cellular therapies, Microenvironment Conflicts of interests pertinent to the abstract. V. Bachanova Research funding: Gamida Cell R. Simantov Employment or leadership position: Gamida Cell Ltd. R. D. Mazor Employment or leadership position: Gamida Cell ltd B. Grzywacz Research funding: Gamida Cell

Delayed hematopoietic recovery is a major drawback of umbilical cord blood (UCB) transplantation. Transplantation of ex vivo-expanded UCB shortens time to hematopoietic recovery, but long-term, robust engraftment by the expanded unit has yet to be demonstrated. We tested the hypothesis that a UCB-derived cell product consisting of stem cells expanded for 21 days in the presence of nicotinamide and a noncultured T cell fraction (NiCord) can accelerate hematopoietic recovery and provide long-term engraftment. In a phase I trial, 11 adults with hematologic malignancies received myeloablative bone marrow conditioning followed by transplantation with NiCord and a second unmanipulated UCB unit. Safety, hematopoietic recovery, and donor engraftment were assessed and compared with historical controls. No adverse events were attributable to the infusion of NiCord. Complete or partial neutrophil and T cell engraftment derived from NiCord was observed in 8 patients, and NiCord engraftment remained stable in all patients, with a median follow-up of 21 months. Two patients achieved long-term engraftment with the unmanipulated unit. Patients transplanted with NiCord achieved earlier median neutrophil recovery (13 vs. 25 days, P < 0.001) compared with that seen in historical controls. The 1-year overall and progression-free survival rates were 82% and 73%, respectively. UCB-derived hematopoietic stem and progenitor cells expanded in the presence of nicotinamide and transplanted with a T cell-containing fraction contain both short-term and long-term repopulating cells. The results justify further study of NiCord transplantation as a single UCB graft. If long-term safety is confirmed, NiCord has the potential to broaden accessibility and reduce the toxicity of UCB transplantation. Clinicaltrials.gov NCT01221857. Gamida Cell Ltd.