Stimulation of antigen-presenting cells through their CD40 receptors can induce antitumor T cell responses in some murine tumor models. We have recently shown that an agonistic anti-CD40 mAb can also induce antitumor effects via activation of natural killer (NK) cells, even in the absence of T cells. Our preliminary results suggest that macrophages activated via CD40 ligation may also kill tumor cells in vivo. We also hypothesize that the T cells or NK cells activated by CD40 ligation will cause augmented antitumor destruction when combined with immunotherapeutic reagents designed to activate antitumor T cells (tumor vaccines) or NK cells (immunocytokine fusion proteins), respectively. The purpose of this project is to determine the mechanisms inducing T cell dependent or T cell independent antitumor effects in response to anti-CD40 mAb treatment, identify the specific cells and cytokines involved in these responses, and evaluate the adjuvant antitumor efficacy of anti- CD40 mAb when combined with other forms of immunotherapy. Specifically, we will accomplish this through the following 3 aims: 1. Determine the mechanisms accounting for preferential activation of T cells or NK cells in response to anti-CD40 mAb. 2. Evaluate NK cell and macrophage-mediated mechanisms of antitumor effects induced by anti-CD40 mAb. 3. Determine the role of anti-CD40 mAb in augmenting effects of immunotherapies against poorly immunogenic tumors. Together, these studies will characterize the novel, T cell-independent mechanisms of the antitumor effects induced by anti-CD40 mAb. Furthermore, they will determine how anti-CD40 mAb-activated cells may be used to further augment the antitumor effects of tumor vaccines and mAb-IL2 fusion proteins. These results may be directly implemented into the design of clinical trials potentially combining CD40 ligation with different forms of immunotherapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA087025-04
Application #
6920821
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Muszynski, Karen
Project Start
2002-08-01
Project End
2007-07-31
Budget Start
2005-08-01
Budget End
2007-07-31
Support Year
4
Fiscal Year
2005
Total Cost
$258,990
Indirect Cost
Name
University of Wisconsin Madison
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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Shi, Yongyu; Felder, Mildred A R; Sondel, Paul M et al. (2015) Synergy of anti-CD40, CpG and MPL in activation of mouse macrophages. Mol Immunol 66:208-15
Goldberg, Jacob L; Sondel, Paul M (2015) Enhancing Cancer Immunotherapy Via Activation of Innate Immunity. Semin Oncol 42:562-72

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