It is now clear that treatment of certain solid and liquid tumors with targeted monoclonal antibodies (mAb) can improve clinical outcome for many patients. It is also clear that in many instances this mAb therapy requires participation from the innate immune system. Nonetheless, tumors themselves exploit innate immune tolerance so as to weaken effective participation by the latter, thereby contributing to the fact that mAb therapy is still not curable today. In this competing renewal application we hypothesize that a better understanding of how the tumor exploits innate immune effector cell tolerance will lead to novel therapeutic options that largely reverse this process and enhance mAb therapy of cancer. To achieve this Project 1 (PI: J Byrd) plans to disrupt human B cell signaling in chronic lymphocytic leukemia with two novel compounds, examine innate immune effector cell function, and move to the clinic combining these agents with mAb B cell therapy;Project 2 (PI: S Tridandapani) will explore negative regulators of human monocytes / macrophage Fc? receptor signaling, as well as immune activators that reverse such negative regulators in order to improve antibody dependent cellular cytotoxicity (ADCC) of both liquid and solid tumors. Project 3 (PI: M Caligiuri) examines the mechanisms by which human natural killer (NK) cells acquire Fc?Rlll, and characterizes negative regulators of NK ADCC. Two clinical trials will then inhibit this negative signaling in order to enhance NK ADCC against lymphoma and NK cytotoxicity against multiple myeloma;Project 4 (PI: W Carson) examines the mechanism by which myeloid derived suppressor cells suppress innate effector cell ADCC, and explores different mechanisms to deplete these suppressor cells in order to enhance ADCC in the laboratory and in the solid tumor clinic. These four projects are served by the unique resources provided by Core A (Administration), Core B (Biostatistics) and Core C (Mouse Modeling and Animal Development). For the past 4.5 years, investigators within this P01 have published 51 collaborative manuscripts and have accrued 815 patients to clinical trials emanating from this P01. The next 5 years of work will result in improved clinical outcome of cancer patients undergoing with mAb therapy.

Public Health Relevance

Monoclonal antibody (mAb) therapy of cancer has improved clinical outcome for patients with both liquid and solid tumors, but by-in-large it is not curative. This program projec grant will elucidate how tumors weaken the immune system, thereby preventing more effective mAb therapy of cancer. Several clinical trials will be undertaken that will reverse this suppression in order to see if mAb therapy of cancer can be strengthened.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA095426-11
Application #
8269416
Study Section
Special Emphasis Panel (ZCA1-RPRB-B (J1))
Program Officer
Merritt, William D
Project Start
2002-02-01
Project End
2017-08-31
Budget Start
2012-09-19
Budget End
2013-08-31
Support Year
11
Fiscal Year
2012
Total Cost
$2,058,483
Indirect Cost
$708,658
Name
Ohio State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Gautam, Shalini; Fatehchand, Kavin; Elavazhagan, Saranya et al. (2016) Reprogramming Nurse-like Cells with Interferon γ to Interrupt Chronic Lymphocytic Leukemia Cell Survival. J Biol Chem 291:14356-62
Mani, R; Yan, R; Mo, X et al. (2016) Non-immunosuppressive FTY720-derivative OSU-2S mediates reactive oxygen species-mediated cytotoxicity in canine B-cell lymphoma. Vet Comp Oncol :
Freud, Aharon G; Keller, Karen A; Scoville, Steven D et al. (2016) NKp80 Defines a Critical Step during Human Natural Killer Cell Development. Cell Rep 16:379-91
Duggan, Megan C; Jochems, Caroline; Donahue, Renee N et al. (2016) A phase I study of recombinant (r) vaccinia-CEA(6D)-TRICOM and rFowlpox-CEA(6D)-TRICOM vaccines with GM-CSF and IFN-α-2b in patients with CEA-expressing carcinomas. Cancer Immunol Immunother 65:1353-1364
Byrd, John C; Harrington, Bonnie; O'Brien, Susan et al. (2016) Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med 374:323-32
Markowitz, Joseph; Abrams, Zachary; Jacob, Naduparambil K et al. (2016) MicroRNA profiling of patient plasma for clinical trials using bioinformatics and biostatistical approaches. Onco Targets Ther 9:5931-5941
Latchana, Nicholas; Regan, Kelly; Howard, John Harrison et al. (2016) Global microRNA profiling for diagnostic appraisal of melanocytic Spitz tumors. J Surg Res 205:350-8
Scoville, Steven D; Mundy-Bosse, Bethany L; Zhang, Michael H et al. (2016) A Progenitor Cell Expressing Transcription Factor RORγt Generates All Human Innate Lymphoid Cell Subsets. Immunity 44:1140-50
McMichael, Elizabeth L; Jaime-Ramirez, Alena C; Guenterberg, Kristan D et al. (2016) IL-21 enhances natural killer cell response to cetuximab-coated pancreatic tumor cells. Clin Cancer Res :
Mundy-Bosse, Bethany L; Scoville, Steven D; Chen, Li et al. (2016) MicroRNA-29b mediates altered innate immune development in acute leukemia. J Clin Invest 126:4404-4416

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