Approximately 80% of patients with chemo-resistant intermediate grade non-Hodgkin's lymphoma (NHL) will relapse following high-dose chemotherapy with autologous stem cell transplantation (ASCT). Our ability to further intensify chemotherapy to improve the outcome of ASCT has reached a plateau, necessitating a need for development of novel therapeutic strategies. Rituximab is a chimeric monoclonal antibody directed against CD20, found on most B-cell NHL. As a single agent, rituximab is modestly effective with <10% complete responses in patients with relapsed lymphoma. Although other mechanisms have been proposed for the activity of rituximab, recent work has established that antibody dependent cytotoxicity (ADCC) is critical for its in vivo activity, a process involving the interaction of the Fc portion of the antibody with Fc-gamma receptors (Fc-gamma-R) on cells of the innate immune system, particularly natural killer (NK) cells and monocytes. Furthermore, our results in a mouse model of human B cell lymphoproliferation show that the efficacy of rituximab is improved when it is given in combination with low dose interleukin (IL)-2, further suggesting an important interaction between rituximab and IL-2-responsive FcR bearing cells. We propose to build on these results and investigate a novel immunotherapy approach using rituximab with adoptive innate immune cellular therapy in NHL patients undergoing ASCT, and in effect clinically test the notion that Fc-gamma-R is critical to effective ADCC against lymphoma cells in vivo. Specifically, our aims are: (1) To conduct a safety and feasibility study of immunotherapy combining concurrent rituximab with high-dose chemotherapy, ASCT, followed by innate immune cellular therapy using NK cells and monocytes collected after in vivo expansion with IL-2 and GM-CSF prior to transplantation, (2) To perform phenotypic and functional analyses, including ADCC potential, of immune effector cells collected following cytokine priming, and (3) To characterize the expression of activating and inhibitory Fc-gamma-R subtypes on NK cells and monocytes following priming with the combination of IL-2 and GM-CSF. The overall hypothesis is that priming with IL-2 and GM-CSF will result in significant in vivo expansion of FcR, bearing immune effectors, and that these collected cells when infused in the presence of circulating rituximab, given with high-dose chemotherapy, will create an environment that will promote ADCC of residual lymphoma cells that escaped killing by high-dose chemotherapy. The clinical and laboratory data derived from this trial will form the basis for future phase II studies to investigate the efficacy of this immunotherapy approach.
