PROJECT SUMMARY: Recent insights into the B-cell origin of the Reed-Sternberg (RS) cell point to new immunotherapeutic targets for classical HL (cHL). It has been appreciated that many cancers are comprised of cells that may be functionally divided into two groups: 1) relatively differentiated cells that form the bulk of the tumor, and 2) cells that may be quite distinct phenotypically but retain the capacity to self- renew. In vitro studies by our group suggest a role for rituximab in cHL as a potential cancer stem cell targeting agent. The first clinical trial integrates vaccine and antibody therapies for relapsed cHL, exploring the cancer stem cell concept as well as the possible role for tumor vaccines for cHL following high dose therapy. The second trial expands upon the concept of cancer stem cell targeting in newly diagnosed cHL patients and explores DNA markers for assessing the clinical impact of stem cell therapies. The long-term overall objective is to investigate novel immunotherapies for cHL based on the concept of cancer stem cell targeting, and the hypothesis that the HL cancer stem cell is biologically and phenotypically distinct from the RS cell and expresses CD20. Specific Aim 1: Conduct a pilot study of rituximab, high dose cyclophosphamide, and an allogenic tumor vaccine for relapsed cHL; determine whether cellular responses to a tumor vaccine can be generated after high dose therapy and rituximab; and evaluate whether an EBV reporter system is useful in monitoring these responses. Specific Aim 2. Conduct a multicenter clinical trial of rituximab-ABVD for newly diagnosed cHL, and investigate DNA biomarkers for assessing the effectiveness of stem cell targeting agents.