The objective of this application is to approach the problem of AIDS- lymphomas by developing integrated clinical and laboratory programs that 1) conduct therapeutic Phase II clinical trials to test the clinical hypothesis that curative chemotherapy can be administered to patients with AIDS-lymphoma when toxicity is minimized by colony stimulating factors, anti-viral agents, and prophylactic antibiotics; and 2) conduct preclinical laboratory studies with biopsy specimens or derived cell lines to test four critical aspects of a model of the pathogenesis of the AIDS-lymphoma. Each preclinical study may result in biologically based future treatment strategies. The clinical and laboratory studies will be compared and contrasted with the applicants' extensive experience in the treatment of lymphomas that occur in the immunocompetent host and the post-transplant patient. Initial clinical trials will treat a) aggressive AIDS-lymphomas with a reduced dose and shortened course of ProMACE-CytaBOM accompanied by low dose trimethoprim-sulfamethoxazole, AZT, and GCSF; b) primary CNS lymphomas with irradiation followed by the previously described chemotherapy program; and c) relapsed systemic AIDS- lymphomas with a novel platinum-based salvage protocol aimed at minimizing immunosuppression. End-points for each of these trials will be response, survival, and quality of life. Preclinical studies will determine a) the pretreatment immunophenotype of AIDS-lymphomas focusing on cell surface molecules involved in growth regulation, cell trafficking, and host recognition; b) the role of B cell stimulatory cytokines in the autocrine or paracrine growth regulation of the AIDS- lymphoma; 3) the ability of antitumor agents to inactivate the translocated c-myc oncogene in AIDS-lymphomas; and 4) whether specific immunoglobulin variable regions are preferentially expressed on the malignant B cells suggesting expansion of the B cell is induced by antigen.
