Developing Immune Based Therapies

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The first major accomplishment of this project was a publication documenting the clinical results of the second trial of rhIL-7 in humans (Sportes et al Clin Cancer Res. 2010 Jan 15;16(2):727-35) . Our previous publication (2008, J Exp Medicine) provided extensive biologic insight into the basis through which IL-7 therapy can augment immune reconstitution and broaden repertoire diversity. This manuscript provided the clinical results of the same trial that are essential for further clinical development rhIL7. The manuscript provides pharmacokinetic parameters, the demonstration that rhIL7 induces a reversible expansion in early B cell progenitors within the bone marrow, as well as changes in peripheral blood lymphocyte subsets. A second major accomplishment of this project during FY2010 was the completion of extensive work demonstrating that a clinical grade master cell bank (KT64.41BBL) is able to support expansion of NK cells from peripheral blood. The CD137L/IL15 NK cells mediate high level tumor cytotoxicity and are not inhibited substantial by KIR signaling. We further demonstrated that the killing activity of CD137L/IL15 NK cells can be predicted based upon the level of expression of the natural cytotoxicity receptors (NKp30, NKp40, NKp44). A manuscript summarizing this work has been submitted. Furthermore, this work has served as the basis for a clinical trial of adoptive therapy with activated NK cells following HLA matched hematopoietic stem cell transplantation that has completed NCI Scientific Review, has been reviewed by the NCI IRB and is expected to open shortly. An IND has been filed with the FDA and is under review. A third major accomplishment of this project during FY2010 was continued enrollment onto a clinical trial that directly translates our basic studies into an immune based therapy trial for patients with high-risk pediatric sarcomas. This work follows closely on our preclinical studies (Cui et al, BLOOD 2009) demonstrating that the combination of Treg depletion plus homeostatic cytokines is a potent combination for supporting antitumor based adoptive cell therapy. NCI 07-c-0206 seeks to induce Treg depletion during the period of immune reconstitution by administering T cells that have been depleted of Tregs (via a CD25 selection column). Furthermore, an amendment in December 2009 incorporated rhIL7 into this trial. Thus, this is the first study of rhIL7 in children and allows us to directly test our hypothesis that the combination of rhIL7 plus Treg depletion is a potent maneuver for supporting immune based therapies. Thus far, a total of 25 patients have been enrolled, with 26 patients enrolled and 11 having initiated immunotherapy, whereas the other 15 are still receiving standard therapy. Preliminary results show promising disease free survival, good tolerability and significant Treg depletion compared to previous studies in patients with profound lymphopenia.