Adoptive Cell Therapy and Immune Check Points Inhibitors As a Salvage Treatment for Patient Affected By Relapsed/Refractory Hodgkin's Lymphoma
Authors: Guolo Fabio , Minetto Paola , Ballerini Filippo , Tedone Elisabetta , Contini Paola , Mangerini Rosa , Bo Alessandra , De Luigi Maria Carla , Carlier Paolo , Serio Alberto , Strada Paolo , Luchetti Silvia , Gobbi Marco , Marcenaro Emanuela , Lemoli Roberto Massimo 
Published: November 2019

BACKROUND: Hodgkin Lymphoma (HL) is characterized by a high degree of response to chemotherapy and an overall favorable outcome in responding patients. Despite the efficacy of first line therapy, however, about 30% of patients affected by HL eventually relapse or are refractory (R/R) to first or second line therapy followed by autologous hemopoietic stem cell transplantation (ASCT).
Recently, the clinical application of immune checkpoint inhibitors (CI), in particular the PD-1 targeting antibody Nivolumab, has dramatically improved the prognosis of patients affected by advanced phase solid tumours. In HL, Nivolumab has shown good activity in the difficult setting of patients relapsing after ASCT; however, complete response (CR) rate was less than 20%. Many studies in the solid tumours field have shown that the efficacy of CI is strictly related to the host degree of immune competence, which is greatly impaired in heavily pre-treated HL patients who received ASCT. Therefore, there is a strong rationale in enhancing the activity of the CI with the co-infusion of autologous lymphocytes (ALI), that have been collected in the early phase of therapy, and that are functionally activated.
AIMS OF THE STUDY: Primary endpoint of this prospective trial was the evaluation of the efficacy of ALI in combination with pre-emptive CI administration early post ASCT in patients affected by R/R HL. Secondary pre-clinical endpoint was the study of the peripheral blood lymphocyte subpopulation, pre and post adoptive immune cell therapy and CI administration.
METHODS: HL patients under the age of 60 with active R/R disease who have already failed at least two chemotherapy lines and Brentuximab (BV) were eligible for the trial. All enrolled patient underwent early lymphocyte apheresis, with a target cell dose of 5x107 CD3+/kg. All patients then received ASCT with FEAM conditioning. After ASCT, the first ALI was delivered 7 days after engraftment. ALI dosing was incremental, one logarithm at each step, starting from 1x104/kg in the first infusion to a maximum of 1x107/kg in the fourth and last infusion. Each ALI was followed after 48 hours by the administration of Nivolumab 240 mg flat dose. The second ALI dose was administered at 14 days after the first one. The third and the fourth were given every 21 days. Lymphocyte subpopulations were extensively studied on peripheral blood samples before and after each ALI and each Nivolumab administration, by 8-colours flow cytometry. Clinical response was evaluated 21 days after completion of the fourth ALI + Nivolumab.
RESULTS: Six R/R HD patient have completed treatment so far and one is currently being treated. All patients failed to achieve CR with chemotherapy and then progressed during BV therapy. PET scan before ASCT showed progressing disease in all patients, with multiple-extra nodal involvement in 5 of them. All patients achieved complete hematological engraftment after a median of 10 days (8-12) from ASCT.
Overall, infusion of ALI resulted in significantly higher lymphocyte counts at day 90, as compared to HL patients receiving the same conditioning without ALI (p <0.05), especially in the T-lymphocyte effector-memory (CD45RA-, CD68L-, CD27+) compartment (p<0.03). After ALI administration, naïve (CD45RA+, CD62L+, CD27+, CD28+) CD8+ cell (p<0.03) and cytotoxic (CD56+,CD16+,CD57+) NKcells (Fig. 1, p<0.05) showed a significant consistent increase. Nivolumab administration determined only a modest and transient increase in T-effector-memory population. No grade 3 or 4 adverse events were recorded so far.All treated patients so far achieved negative PET scan after the procedure and are alive and disease free after a median follow-up of 18 months.
CONCLUSIONS: Post-ASCT ALI proved to be feasible and effectivein a heavily-pre-treated population,resulting in a quicker immune recovery and in a complete response in all treated patients. Immunotherapy as post-ASCT consolidation therapy might improve the CR rate expected with anti-PD1 blockade alone, providing a more effective option for refractory patients, who are usually considered not candidate for ASCT. The observed expansion of NK cell compartment may suggest that NK cell have a primary role in response to CI in HL patients. This is consistent with the observation that lack of Reed Sternberg cells lack HLA I expression, which excludes a T-Cell mediated killing. Functional experiments are underway to test this hypothesis.
Figure 1

Disclosures
No relevant conflicts of interest to declare.