ZIA BC 009262 (ZIA) | |||
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Title | Immunophysiological Mechanisms in the Biological Therapy of Cancer | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Wiltrout, Robert | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $545,663 | Project Dates | 10/01/1982 - 00/00/0000 |
Fiscal Year | 2014 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Digestive Diseases (30.0%) Metastasis (20.0%) |
Breast (10.0%) Kidney Cancer (50.0%) Kidney Disease (50.0%) Liver Cancer (30.0%) Lung (10.0%) Urinary System (50.0%) |
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Research Type | |||
Systemic Therapies - Discovery and Development Application of Model Systems |
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Abstract | |||
Successful development of new approaches for the immunotherapy of cancer requires an understanding of complex, interdependent activities of early innate response elements with subsequent powerful adaptive immune responses. We are taking several novel approaches to maximize the host's ability to mount an effective antitumor response. These approaches include optimizing antigen presenting capability through the ligation of CD40, a TNF superfamily receptor that serves as a potent trigger for dendritic cells and macrophages, which provide a key interface between innate and adaptive responses. The potency of dendritic cell stimulation by agonist CD40 antibodies is enhanced when used in conjunction with IL-2 or IL-15 and the combination of agonist anti-CD40 plus either IL-2 or IL-15 shows enhanced antitumor activity against metastatic kidney cancer in mice. We have analyzed leukocytes contained within the primary tumors that develop in the kidney as well as those in the lungs and livers, which serve as primary and secondary sites of tumor metastases, respectively. After treating tumor-bearing mice with IL-2/anti-CD40 or IL-15/anti-CD40, we have identified the recruitment of macrophages and T cells that appear to be critical mediators of anti-tumor responses. Once present at the developing tumor site, these cells are capable of producing many different soluble mediators, such as interferon gamma (IFNg), nitric oxide, and VEGF that may influence tumor progression. By regulating the ability of these cell types to accumulate within tumors, we are identifying the role that these cells play during both primary tumor progression and metastasis to distant organs. Our data have illustrated the potential for dramatic mechanistic differences in biological effects mediated by anti-CD40 alone versus its use in combination with IL-2 that includes the synergistic upregulation of IFNg and nitric oxide expression that controls tumor burden. To date, we have shown IL-2/anti-CD40 induces enhanced antitumor responses that depend on the infiltration of established tumors by effector CD8+ T cells and a concomitant IFNg-dependent reduction in CD4+/FoxP3+ regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSC) and Th2 chemokine expression within the tumor-microenvironment. These results may help to explain the limited clinical efficacy of anti-CD40 as a single agent based on its inability to remove Tregs and MDSC specifically from within the tumor microenvironment and they suggest that anti-CD40 may be more beneficial in combination with other selected immune agents, such as IL-2. Our ongoing work is investigating the mechanisms underlying the selective loss of regulatory T cells and MDSC within the tumor microenvironment. Our data indicates that IL-2/anti-CD40 induces the expression of Fas on these cell populations, as well as the infiltration of primary tumors by Fas ligand expressing CD8+ T cells and other leukocytes. This process elicits Fas-dependent cell death, or apoptosis, of Tregs and MDSC. Our data demonstrates the critical importance of Fas-mediated Treg and MDSC removal towards the anti-tumor efficacy of IL-2/anti CD40 combination therapy. Furthermore, they suggest that immunotherapeutic strategies, such as IL-2/anti CD40, that target the susceptibility of Tregs and MDSC to Fas-mediated cell death hold promise for further development as cancer treatment strategies. Our current and future studies seek to clarify the cellular and molecular events critical for the observed biological effects of aCD40, and the potential for complementary use of anti-CD40 with rationally selected molecularly targeted agents. In one such approach, we have combined anti-CD40 with an ATP competitive mTOR drug, AZD8055, developed by AstraZeneca. The rationale for this strategy is two-fold. First, mTOR inhibition represents is currently a leading clinical target for RCC. We also hypothesized that combining AZD8055 with aCD40 antibody would induce more efficie" |