Targeted immunotherapy for relapsed/refractory Hodgkin lymphoma

For patients with relapsed/refractory classical Hodgkin lymphoma (HL) after induction treatment, standard of care is 2nd-line combination chemotherapy followed by autologous hematopoietic cell transplantation (AHCT). Complete response (CR) at the time of AHCT is the strongest indicator of post-AHCT prognosis1; thus, we have designed a clinical trial investigating enhanced 2nd-line therapy to increase the proportion of patients in CR at the time of AHCT. The PD-1 inhibitor nivolumab (NIVO) has recently been approved for use in HL patients relapsing post-AHCT. In Specific Aim 1 we propose a multicenter phase II study evaluating NIVO followed by response-adapted addition of standard ifosfamide, carboplatin, etoposide (ICE) chemotherapy as a bridge to AHCT. This regimen, NICE, is designed to maximize CR rates pre-AHCT. In Specific Aim 2 we augment the AHCT conditioning regimen with targeted radioimmunotherapy (RIT) to improve AHCT outcomes. This single-center phase II study combines standard BEAM (BCNU, etoposide, Ara-C, melphalan) chemotherapy with an Yttrium-90 (90Y)-labeled anti-CD25 antibody, basiliximab. Basiliximab directly targets radiation to CD25+ Reed Sternberg (RS) cells, as well as activated T cells and regulatory T cells (Tregs) throughout the HL tumor microenvironment (TME). The crossfire effect of 90Y kills nearby cells including CD25-negative RS and immune cells in the tumor. The two studies are complementary, with NICE participants eligible for enrollment to the aTac-BEAM trial. The overarching goal of this project is to improve overall outcomes for patients with relapsed/refractory HL, via separate clinical trials to improve pre-AHCT CR rates and post-AHCT survival. Gene expression and tumor spatial analysis studies will help to elucidate the role of the TME in responses to anti-PD-1-based therapy.