Patients with high-risk relapsed/refractory Hodgkin lymphoma have only a 20-50% chance of cure. This project addresses this problem in 2 independent, but sequentially compatible clinical trials. In Specific Aim 1, we propose the NICE trial, a phase II study of response-adapted sequential therapy using nivolumab (NIVO) +/- ICE chemotherapy as second-line therapy following induction failure or early relapse. Patients who achieve a complete response (CR) after 12 weeks of the PD-1 inhibitor NIVO proceed directly to autologous hematopoietic cell transplantation (AHCT). We will combine NIVO with ICE chemotherapy for 6 more weeks in patients not in CR after 12 weeks of NIVO, or who have not achieved at least a partial response after 6 weeks of NIVO. This approach, utilizing an innovative PET response-adapted treatment sequence, is designed to increase the proportion of patients who are in CR at the time of AHCT, and is expected to spare those patients transplanted after NIVO alone, from the toxicity of additional chemotherapy. It also offers a unique opportunity to examine the effect of PD-1 inhibitors on the Hodgkin lymphoma tumor microenvironment, through extensive correlative studies of paired biopsies taken just prior to therapy and after the first 6 weeks of NIVO treatment. These studies include 1) microarray gene expression profiling to identify differentially expressed genes and pathways in the tumor microenvironment, as well as signatures that may be associated with response to treatment; 2) spatially mapping the density/distribution of different T-cell and macrophage subsets associated with response to therapy, using a 7-color multiplexed immunofluorescence spatial analysis imaging platform; and 3) CD25 and PD-1/PD-L1 immunohistochemistry;. Specific Aim 2 addresses the dilemma that, as the field advances, patients treated with upfront immunotherapy may experience relapsed or progressive disease that is more intractable, necessitating potent AHCT regimens that are agnostic to prior immunotherapies. We have developed at City of Hope, a 90Y-labeled anti-CD25 antibody immunoconjugate to augment BEAM AHCT conditioning. This aTac-BEAM regimen takes advantage of the susceptibility of Hodgkin lymphoma to radiation, and targets that radiation to the CD25 antigen found on many Reed-Sternberg cells and on activated T cells and Tregs in the tumor microenvironment. Preliminary data from our phase I trial (funded by NCI R21CA185875-02) indicates that the regimen is feasible, remarkably well tolerated, and has promising efficacy. In the phase II trial proposed here, the anti-lymphoma activity of the aTac-BEAM AHCT conditioning regimen will be assessed by 2-year progression-free survival. The two studies will accrue simultaneously, and patients may enroll in them both; we suspect that reactivating T cells with NIVO may increase CD25 expression, amplifying the number of targets for aTac-BEAM. Patients will also include those referred for AHCT after other second-line regimens. A further objective in Specific Aim 2 is establishing a consortium and standard operating procedures for exporting the aTac-BEAM regimen for a multi-center randomized trial.