This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.This GCRC application will focus on answering several important questions in NK cell biology. The main hypothesis to be tested in this study is that inhibitory NK cell receptors play a role in the therapy of cancer and transplantation. It is now well known that NK cells express inhibitory receptors that recognize class I MHC molecules. Engagement of these receptors by their MHC ligands provides an inhibitory signal which protects targets from being lysed. Therefore, it follows that therapy will allogeneic NK cells bearing receptors mismatched for class I MHC ligands may provide more effective anti-tumor therapy than autologous NK cells. This will be tested in a clinical trial (Sub-Study 1). Sub-Study 1 will test the hypothesis that clearance of lymphoid space is required for homeostatic expansion of NK cells, which will be required for efficacy. Sub-Study 1 will be stratified among two patient populations, AML and renal cell carcinoma. In poor prognosis AML patients, an intense preparative regimen using in-patient chemotherapy that has activity against acute leukemia will be used. This degree of intensity is not clinically warranted in renal cell carcinoma. Therefore, a modified, less intense regimen using out-patient chemotherapy will be tested. In addition, during NK cell development, the acquisition of NK cell reconstituting after allogeneic transplant is unknown. Sub-study 2 will focus on answering this question with the hypothesis that NK cell receptors reconstituting early after transplant will exhibit a paucity of receptors which will be of physiologic relevance and correlate wil clinical outcomes. Understanding this process in transplantation may allow maipulation of donor grafts or donor selection to enhance optimal therapy of cancer. Sub-Study 1: 'MT2003-01: Allogeneic natural killer cells in patients with reapse of acute myelogenous leukemia and renal cell carcinoma'. This is a clinical trial in advanced patients with AML who fail to achieve remission after standard induction chemotherapy or have metastatic renal cell carcinoma. This trial is a direct extrapolation of a phase I clinical trial performed in the GCRC (Protocol #679) which is nearing completion of its study goals. From that phase I cell dose escalation study, we conclude that haploidentical allogeneic NK cell infusions are safe, that the preparative regimen of low-dose cytoxan and high-dose methylprednisolone is unable to suppress recipient mixed lymphocyte reactivity and that donor cells can be found in recipient peripheral blood for approximately five days but that do not persist long term and do not expand in vivo. One of the main hypotheses for this study is that for allogeneic NK cells to be efficacious they must expand in vivo during the two week period of IL-2 administration. Failure to achieve this goal in the phase I study may be due to 1) inadequate suppression of the preparative regimen and 2) inadequate clearance of lymphoid space, now known to be important in homeostatic expansion of adoptively transferred lymphocytes in vivo. This clinical trial will address both of those hypotheses. The choice of AML as a target population for this study is based on recent bone marrow transplant studies showing that the ability of haploidentical transplants to protect against AML reapse is associated with mismatched NK cell receptors and their presumed MHC class I ligands. Patients on this study will receive a preparative regimen which is more immunosuppressive using two active leukemia drugs: cyclophosphomide and fludarbine. The choice of including renal cell carcinoma is based on new data showing activity after allogeneic transplant and the fact that this tumor is historically immune responsive. Haploidentical NK cells will be selected and activated in the GCRC Cell Therapy Core under GMP conditions. As a part of understanding the role of allogeneic haploidentical NK cells, laboratory studies will be performed on donor NK cells and patient blood at several time points to understand their persistence, expansion and immunologic response.
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