As both basic laboratory research and clinical research become increasingly complex, development of novel therapeutic strategies for patients with B-cell malignancies requires collaborative efforts between clinical researchers and basic scientists. During the proposed funding period, a formal didactic program, dedicated team of mentors with a history of training investigators, and a supportive, enthusiastic environment should allow the applicant to achieve an independent research career as such a """"""""translational"""""""" investigator in the field of lymphoma therapy. Patients with advanced stage follicular non-Hodgkin's lymphoma (NHL) are generally accepted to be incurable with conventional treatment, and the median survival has not changed significantly in the past thirty years. Novel approaches with minimal toxicity are therefore needed. Rituximab, a chimeric CD20 monoclonal antibody, has significant, albeit limited activity as a single agent for treatment of follicular NHL. Immunostimulatory DNA oligonucleotides (ISS) are novel compounds that have pleotropic immunological effects, including enhancement of antigen presentation and costimulatory molecule expression, stimulation of dendritic cell maturation, and induction of cytokines resulting in enhanced antibody-dependent cell-mediated cytotoxicity (ADCC). Through these effects on both the adaptive and innate immune response, ISS have significant promise as synergistic agents with monoclonal antibody therapy such as dtuximab, with minimal added toxicity. Given a favorable safety profile, and evidence of biologic activity in an ongoing phase I study of ISS (1018) with rituximab, this project proposes to test the efficacy of rituximab in combination with 1018 ISS in a phase II study for patients with relapsed follicular NHL Detailed analysis of the immunological effects of this combination both in vivo and in vitro, including evaluation of effector cell number and function, dendritic cell maturation, and changes in the tumor microenvironment, will allow optimization of this rational combination for further clinical development.
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