POST-TRANSPLANT NIVOLUMAB PLUS UNSELECTED AUTOLOGOUS LYMPHOCYTES IN REFRACTORY HODGKIN LYMPHOMA PATIENTS: A SAFE AND EFFECTIVE THERAPY ASSOCIATED WITH EXPANSION AND MATURATION OF NK CELLS

Hodgkin Lymphoma (HL) is a B-Cell neoplasia with a favourable outcome in responding patients. However, despite the efficacy of first line therapy about 30% of patients eventually relapse or are refractory (R/R). Recently, the immune checkpoint inhibitor (CI) nivolumab demonstrated good activity in R/R HL patients although the complete response (CR) rate was less than 20%. The efficacy of nivolumab is strictly related to the host degree of immune competence, which is greatly impaired in heavily pre-treated HL patients after autologous stem cell transplantation (ASCT). To enhance the activity of CI, we explored the feasibility of the infusion of autologous lymphocytes (ALI) in combination with the pre-emptive administration of nivolumab, early post-ASCT, in patients affected by R/R HL. Eight patients (median age 29, range 18-56) with active R/R disease, who had already failed at least two chemotherapy lines and Brentuximab, were eligible for the trial. HL patients underwent early lymphocyte apheresis, with a target cell dose of 5x107 CD3+/kg. All patients then received ASCT with FEAM conditioning followed by ALI at a median time of 14 days after infusion, starting with 1x104 CD3+ cells/kg in the first infusion to a maximum of 1x107cells/kg in the fourth and last infusion. Each ALI was followed after 48 hours by the administration of nivolumab 240 mg flat dose. As a control cohort, two patients, in CR after second line chemotherapy, were given ALI only, without nivolumab. No grade 3 or 4 adverse events were recorded. All treated patients achieved negative PET scan after immunotherapy and are alive and disease-free after a median follow-up of 20 months. Two patients did receive allogeneic stem cell transplantation while in CR. Notably, compared to control patients, a faster expansion/reconstitution of highly differentiated NK cells was observed as well as a quicker T-cell recovery. These data suggest the potential role of PD-1 receptor in the direct or indirect control of NK cell maturation/development and, probably, NK anti-tumor activity. Thus, the combination of adoptive cell therapy with CI may represent a novel approach for chemorefractory HL patients.