The current treatment options for metastatic colon carcinoma are limited. Our preclinical research indicates that immune-modulatory gene therapy may be effective for the treatment of advanced metastatic colorectal cancer. Using an orthotopic murine model for pre-established hepatic colon carcinoma, we have shown that intratumoral injection of an adenoviral vector expressing murine interleukin-12 (Adv/mIL-12) and 4-1BB, a co-stimulatory molecule normally found on activated dendritic and T cells, can induce dendritic cell and CD8+ T cell activation and proliferation. This leads to tumor regression and prolonged survival of treated mice. However, this therapeutic effect is significantly compromised by large tumor burdens (>8x8-10x10mm2). Significant accumulation of myeloid suppressor cells (MSC) and T regulatory cells (Treg) were found in animals bearing large tumors. The lack of proper antigen presentation and Treg mediated immune suppression are two of the main means by which tumor cells evade the immune system and present the major obstacles for cancer immune therapy. We found that CD 40 engagement greatly improved the long-term survival rate of mice bearing large tumors when used in conjunction with IL-12 + anti-4-lBB combination therapy. Furthermore, agonistic anti-CD40 antibody prevented MSC-mediated Treg induction. We hypothesize that CD40 activation by agonistic antibody or Ig-CD40 ligand fusion protein can enhance anti-tumor responses through multiple mechanisms: 1) CD40 ligation can prevent Treg induction through CD40 signaling on MSC;2) CD40 activation can induce the differentiation of MSC into dendritic cells and downregulate the inhibitory receptors, PIR-B (paired Ig-like receptor B) and gp49b, which are highly expressed on MSC and immature DCs.
Three specific aims will be pursued in order to understand the mechanisms underlying the CD40 mediated regulation of MSC function and reversion of immune suppression in the large tumor setting: 1) Study the mechanisms underlying the prevention of MSC-induced Treg development by anti-CD40 ligation;2) Investigate the negative receptor signals as the potential mechanism behind the ineffective anti-tumor response to synergistic IL-12 and 4-1BB activation in mice with large tumor burdens;3) Determine the therapeutic effect of blocking negative inhibitory receptors and reversing immune suppression by co-stimulatory molecules on the persistence of an effective anti-tumor response following immune activation in the large tumor bearing host. The completion of these studies will not only provide a new insight into the mechanisms of tumor mediated suppression and tolerance, but also facilitate effective clinical translation of our immune enhancing therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA070337-14
Application #
7793536
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Muszynski, Karen
Project Start
1996-04-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2012-03-31
Support Year
14
Fiscal Year
2010
Total Cost
$287,106
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Chen, Hui-Ming; Ma, Ge; Gildener-Leapman, Neil et al. (2015) Myeloid-Derived Suppressor Cells as an Immune Parameter in Patients with Concurrent Sunitinib and Stereotactic Body Radiotherapy. Clin Cancer Res 21:4073-4085
Shen, Jin; Chen, Xiaojuan; Wang, Zhenxing et al. (2014) Downregulation of CD40 expression contributes to the accumulation of myeloid-derived suppressor cells in gastric tumors. Oncol Lett 8:775-780
Eisenstein, Samuel; Coakley, Brian A; Briley-Saebo, Karen et al. (2013) Myeloid-derived suppressor cells as a vehicle for tumor-specific oncolytic viral therapy. Cancer Res 73:5003-15
Ma, Ge; Pan, Ping-Ying; Eisenstein, Samuel et al. (2011) Paired immunoglobin-like receptor-B regulates the suppressive function and fate of myeloid-derived suppressor cells. Immunity 34:385-95
Meseck, Marcia; Huang, Tiangui; Ma, Ge et al. (2011) A functional recombinant human 4-1BB ligand for immune costimulatory therapy of cancer. J Immunother 34:175-82
Kao, Johnny; Ko, Eric C; Eisenstein, Samuel et al. (2011) Targeting immune suppressing myeloid-derived suppressor cells in oncology. Crit Rev Oncol Hematol 77:12-9
Boros, Peter; Ochando, Jordi C; Chen, Shu-Hsia et al. (2010) Myeloid-derived suppressor cells: natural regulators for transplant tolerance. Hum Immunol 71:1061-6
Pan, Ping-Ying; Ma, Ge; Weber, Kaare J et al. (2010) Immune stimulatory receptor CD40 is required for T-cell suppression and T regulatory cell activation mediated by myeloid-derived suppressor cells in cancer. Cancer Res 70:99-108
Yin, Bingjiao; Ma, Ge; Yen, Chun-Yu et al. (2010) Myeloid-derived suppressor cells prevent type 1 diabetes in murine models. J Immunol 185:5828-34
Ozao-Choy, Junko; Ma, Ge; Kao, Johnny et al. (2009) The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immune-based cancer therapies. Cancer Res 69:2514-22

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