This project is designed to develop a novel, more effective means of immunotherapy for patients with hematologic and non-hematologic malignancies. Cancer immunotherapy has largely concentrated on methods to augment the host's immune system with only modest success. This proposal will test the ability of allogeneic, rather than autologous, immunotherapy to induce a """"""""graft-vs-tumor"""""""" reaction in patients with cancer. The anti- tumor potential of donor immune cells has been demonstrated in both animal models and bone marrow transplantation (BMT) where donor immune cells, included in the marrow graft, are critical for the cure of patients with leukemia. The current proposal is further based on studies demonstrating that a striking anti-leukemic reaction is induced in patients who relapse after allogeneic BMT by administering interferon-alpha (IFN-alpha) and donor MNC infusions. Similar therapy is effective for patients with post- transplantation B-cell lymphomas. It may now be possible to harness the immune potential of these donor cells to treat patients with other malignancies without a prior BMT. This will be a phase I/II trial of HLA-matched sibling donor mononuclear cell (MNC) infusions combined with IFN-alpha to treat patients with malignancies who have not had a prior BMT.
The first aim of the proposal is to determine the toxicity of this therapy including the risk of graft- vs-host-disease and marrow aplasia. The second goal is to evaluate the survival of the infused MNC in the patient. Presumably, an anti-tumor reaction will result only if the infused MNC are not be rapidly rejected by the relatively normal host immune system. The trial will test for donor cell survival using molecular analysis of polymorphic DNA sequences to distinguish and quantitate donor vs host cells. IFN-alpha and 4 MNC infusions will be given in the first phase. If no response, toxicity, or donor cell survival is noted, transient immuno-suppression with chemotherapy will be used prior to a second course of donor MNC infusions in an effort to enhance donor cell survival and allow time for a significant anti-tumor effect to occur. The third and ultimate aim is to identify potential graft-vs-tumor effects provided by donor MNC. Supportive laboratory studies are designed to shed light on possible anti- tumor mechanisms by studying potential effector cells, and possible tumor cell antigens mediating an anti-tumor response. This therapy will initially be appropriate for diseases historically responsive to immuno-modulation, such as CML, melanoma, renal cell carcinoma, and lymphoma that will be incurable with standard therapies. If effective, this therapy may have tremendous impact for these patients with a uniformly poor prognosis. If effective for patients with CML, one can envision a potentially curative therapy without the need for bone marrow transplantation. We hope to gain new insight into the intricate relationship between cancer cells and the immune system, and will be able to study graft-vs-host disease in a non-transplant setting. Ultimately, this trial may begin to define a novel immunologic approach to cancer therapy.
| Porter, D L; Antin, J H (1998) Infusion of donor peripheral blood mononuclear cells to treat relapse after transplantation for chronic myelogenous leukemia. Hematol Oncol Clin North Am 12:123-50 |
