Gda-201, a Novel Metabolically Enhanced Allogeneic Natural Killer (NK) Cell Product Yields High Remission Rates in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma (NHL): 2-Year Survival and Correlation with Cytokine IL7
Authors: Bachanova Veronika , Maakaron Joseph E. , Cichocki Frank , McKenna David H. , Cao Qing , DeFor Todd E. , Janakiram Murali , Wangen Rose , Cayci Zuzan , Grzywacz Bartosz , Simantov Ronit , Lodie Tracey , Miller Jeffrey S. 
Published: November 2021

Abstract
Background: The innate capacity of natural killer (NK) cells to kill tumor targets has been translated into cancer immunotherapy. GDA-201 represents a novel class of metabolically enhanced ex-vivo expanded allogeneic NK cells with acquired capacity for improved organ trafficking, augmented resistance against exhaustion and in vivo proliferation. We conducted a phase 1 study of GDA-201 in combination with rituximab (NCT03019666) in patients (pts) with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) and report 2-year outcomes and cytokine biomarkers associated with survival.
Methods: Following donor apheresis, CD3-depleted mononuclear cells were cultured for 14-16 days with NAM (5mM) and IL-15 (20ng/ml), resulting in a 40-fold increase in NK cells and increased expression of CD62L from 2.9% to 21%. GDA-201 contained ~98% NK cells, and CD3 content was low at &lt;0.5% (&lt;5x10 5/kg/dose). Pts with R/R B-cell NHL received lymphodepleting (LD) chemotherapy with cyclophosphamide (400mg/m 2 IV x 3d) and fludarabine (30 mg/m 2 /d IV x 3d), followed by GDA-201 (days 0 and 2) and low-dose IL-2 (6 million units sc x 3 doses at days 0,2,4). Pts also received rituximab (375 mg/m 2) x 3 weekly infusions (days -8,+1 and +11).
Results: 20 NHL pts were enrolled: 1 mantle cell, 10 follicular [FL], 9 diffuse large cell lymphoma [DLBCL]) 16 pts received the maximum target dose (median dose 12.4 (range 2.0-26.0) x 10 7 GDA cells/kg. The most common grade 3/4 adverse events were thrombocytopenia (n=9), hypertension (n=9), neutropenia (n=4), febrile neutropenia (n=4), and anemia (n=3). There were no CRS, neurotoxic events, GVHD or marrow aplasia. One patient died of E-coli sepsis.
Among 19 NHL pts evaluable for response, the median age 64 (range 48-83 years), most were multiply relapsed (median lines of therapy 3 (range 1-8) or refractory (n=3) and 87% had advanced stage. Thirteen patients (65%) had complete response (CR), 1 pt had partial response (PR) with the best overall response rate of 74%. Two of these patients underwent allogeneic hematopoietic stem cell transplantation and are doing well at 3 years post GDA-201. One patient underwent autologous HSCT and is well at 18 months. Four NHL patients underwent re-treatment with GDA-201 without LD chemotherapy; 2 patients (FL and transformed DLBCL) had further deepening of response from PR to CR. Median duration of response was 16 months (range 5-36 months). At median follow-up of 11 months (range 1-36 months), progression-free survival (PFS) at 1 and 2 years was estimated at 50% (95% CI 27-69%) and 35% (95% CI 14-58%). OS at 2 years was 78% (95%CI 51-91%).
Flow cytometry confirmed the persistence of donor NAM-NK in peripheral blood up to day 7-14 (day 7 range 2-92% GDA 201 cells), as well as enhanced in vivo proliferation (median Ki67 99%). Lymphopenia following LD chemotherapy is known to result in a surge of endogenous cytokines IL7 and IL15. The median IL-7 plasma levels at baseline, day 7 and 14 were 5.12pg/dl (range 1.7-16), 11.7pg/dl (range 3.5-20) and 9.66 pg/dl (5.4-18.5). Increased delta of IL7 between days 14 and day 0 positively correlated with survival. Delta IL7 serum level increase by each 1 pg/dl was associated with improved 1-year PFS with HR 0.63 (95% CI; 0.41-0.96); p=0.03) and 1-year OS with HR 0.42 (95%CI 0.40-0.85; p=0.02).
Conclusions: Cellular therapy using GDA-201 with rituximab is well-tolerated, and demonstrated significant clinical activity in heavily pre-treated pts with advanced NHL. A cytokine surge following LD chemotherapy appears to be associated with clinical activity. Phase II studies in aggressive and indolent NHL cohorts are planned.

Disclosures
Bachanova: FATE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding; KaryoPharma: Membership on an entity's Board of Directors or advisory committees. Cichocki: Fate Therapeutics, Inc: Patents & Royalties, Research Funding; Gamida Cell: Research Funding. McKenna: Qihan Bio: Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics: Other: all manufacturing of cell therapy products for clinical trials; Intima: Other: all manufacturing of cell therapy products for clinical trials; Gamida: Other: all manufacturing of cell therapy products for clinical trials; Magenta: Other: all manufacturing of cell therapy products for clinical trials. Janakiram: FATE, Nektar Therapeutics: Research Funding; Bristol Meyer Squibb, Kyowa Kirin, ADCT Therapeutics: Honoraria. Grzywacz: Gamida: Research Funding. Simantov: Gamida: Current Employment. Lodie: Gamida Cell: Current holder of stock options in a privately-held company, Ended employment in the past 24 months. Miller: Fate Therapeutics, Inc: Consultancy, Patents & Royalties, Research Funding; GT Biopharma: Consultancy, Patents & Royalties, Research Funding; Vycellix: Consultancy; ONK Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Magenta: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Wugen: Membership on an entity's Board of Directors or advisory committees.

OffLabel Disclosure:
IL-2, Rituximab both in combination with GDA-201