This Program Project Grant (PPG) competitive renewal application stresses innovative clinical cancer immunotherapy trials to a broad array of patients with hematopoietic and solid malignancies. There is also a strong, ongoing basic investigation among four highly integrated principal investigators focused entirely on human innate immune effector cell function in preparation for subsequent, more refined clinical cancer immunotherapy trials. Project 1 is focused on chronic lymphocytic leukemia (CLL) by targeting an alternative B-cell antigen, CD37, with a novel engineered small modular immune pharmaceutical (SMIP) that directly promotes apoptosis of CLL cells as well as SMIP-directed cell cytotoxicity. Project 1 uses the preclinical SCID-human chimeric mouse model of human B cell lymphoma to assess combination of the CD37-SMIP with a novel immune activator, IL-21, and will explore the direct and specific pro-apoptotic effect of IL-21 on CLL. Project 2 continues with elegant basic investigative work on Fc-gammaR signaling in human monocytes with broad application to natural killer (NK) and B cell biology as well as antibody dependent cellular cytotoxicity that is relevant to Projects 1, 3 and 4. Project 3 investigates the role of transforming growth factor-beta (TGF-beta) in dampening NK development and NK functions. These in vitro studies are complemented by two clinical trials assessing NK development and function in vivo while cancer patients with melanoma, renal cell carcinoma and pancreatic cancer will receive a "first in man" infusion of a humanized monoclonal antibody (mAb) that neutralizes TGF-beta. Project 3 will perform a clinical trial in patients with multiple myeloma infusing an antibody that recognizes a common epitope on inhibitory killer immunoglobulin like receptors (KIRs) in an effort to, 1) learn more about in vivo human NK development;2) assess efficacy of NK killing against primary myeloma in the presence of KIR blockade;Project 4 utilizes both a preclinical murine model of breast cancer and a clinical trial in breast cancer to study the combination of IL-21 and trastuzumab (anti-HER2), while elucidating the signaling events behind synergy observed with IL-21 and Fc-gammaRllla activation in human NK cells. Collectively, in the first four years of progress, members of this P01 have accrued 248+ patients to clinical trials and have co-authored 75% of their 52 original, peer-reviewed publications. This work has broad application to cancer prevention and cure.