The success of autologous marrow transplantation (AMT) for the treatment of patients ,with leukemia or lymphoma in limited largely by the high incidence of recurrence of the malignancy after AMT. Interleukin-2 (IL-2), alone or in conjunction with adoptively transferred lymphocytes, has been effective against cancer in animal models. Similarly, in preliminary clinical trials, immunotherapy in the form of recombinant human IL-2 used alone or with ex vivo-generated lymphokine activated killer (LAK) cells, has induced regression of advanced cancer in some patients. Animal data attest to the curative potential of adoptive immunotherapy for hematologic malignancies. Although little is known about responsiveness of patients with hematologic malignancies to treatment with IL-2/LAK, human leukemia and lymphoma cells are known to be susceptible to LAK cytotoxicity in vitro. IL-2/LAK therapy could potentially represent a treatment modality which would be non-cross resistant with chemoradiotherapy and AMT in the treatment of this group of patients. IL-2 + LAK has been used mostly in the presence of large tumor burdens and have induced predominantly partial regressions. Our goal is to use this approach in a setting of minimal residual disease, such as in selected patients who have no evidence of disease after undergoing AMT but who are at very high risk for recurrence. Accordingly, the specific aims of this project are as follows: (1) to determine the kinetics of appearance of circulating IL-2 responsive LAK precursor cells after chemoradiotherapy and AMT; (2) to phenotypically and functionally characterize LAK precursor and effector cells after AMT; (3) to assess the toxicity and immunomodulatory effects of systemically administered IL-2 after AMT in a Phase Ib clinical trial for patients with leukemia and lymphoma; and (4) based on data anticipated from specific aims 1- 3, to design and perform a Phase II clinical trial using a combination of systemically administered IL-2 and ex vivo generated autologous LAK cells in patients who have undergone AMT for resistant or relapsed lymphoma. The results might lead to an effective new treatment modality to be used in the context of AMT for hematologic malignancies.
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