Successful eradication of solid tumors and metastatic disease by immunotherapy requires systemic and persistent functional anti-tumor cytotoxic T lymphocytes (CTL). Dendritic cells (DC), as the pivotal initiator and regulator of immune responses, have become the major targets and candidates for tumor immunotherapy. However, the therapeutic efficacy of ex vivo manipulated DCs is limited by their inefficient homing to the lymphoid compartments where T cell activation occurs. To enhance the sustained high numbers of activated tumor antigen presenting DCs in relevant lymphoid compartments, we propose that lentiviral vector modified DC progenitors, after transplantation, can provide a constant reservoir for in vivo generation of large numbers of antigen expressing DCs with appropriate activation regimens. We have already demonstrated that these modified DC progenitors, in combination with DC activation regimens markedly activate systemic antigen specific immunity and significantly improve tumor-free survival in the treatment of aggressive, established murine hematological and epithelial tumors carrying a model tumor antigen. Hypothesis: Significant therapeutic benefits in treating solid tumor and metastatic disease can be achieved by using an optimal combination of early DC engraftment progenitors, reduced toxicity of conditioning regimen, fresh lymphocyte infusion, and optimal DC activation regimens to stimulate systemic and sustained CTL activation in the context of weakly immunogenic natural tumor antigens.
The Specific Aims will focus on the following aspects to examine the underlying mechanisms that support sustained CTL function and maximal therapeutic efficacy: (1) To test the hypothesis that proper combinations of DC stimulatory and activation regimens will provide not only great number of in vivo derived tumor antigen expressing DCs, but also optimal DC subsets for appropriate cytokine production and class of immune responses. These DCs will dictate the polarization of antigen specific immune responses and support sustained, systemic activation of antigen specific CTL effector function in multiple lymphoid compartments in antigen-naive and antigen-tolerant hosts; (2) To test the hypothesis that the enhanced, systemic CTL activation will result in sustained recruitment of functional tumor specific CTL to multiple tumor draining lymphoid compartments and tumor sites, and thus enable successful treatment of solid tumors and metastatic disease.
| Guo, Gang; Marrero, Luis; Rodriguez, Paulo et al. (2013) Trp53 inactivation in the tumor microenvironment promotes tumor progression by expanding the immunosuppressive lymphoid-like stromal network. Cancer Res 73:1668-75 |
| Kibe, R; Zhang, S; Guo, D et al. (2012) IL-7Rýý deficiency in p53null mice exacerbates thymocyte telomere erosion and lymphomagenesis. Cell Death Differ 19:1139-51 |
| Agarwal, N; Tochigi, Y; Adhikari, A S et al. (2011) MTBP plays a crucial role in mitotic progression and chromosome segregation. Cell Death Differ 18:1208-19 |
| Zhang, Shuzhong; Zheng, Mingquan; Kibe, Ryoko et al. (2011) Trp53 negatively regulates autoimmunity via the STAT3-Th17 axis. FASEB J 25:2387-98 |
| Zhang, X; Zhao, P; Kennedy, C et al. (2008) Treatment of pulmonary metastatic tumors in mice using lentiviral vector-engineered stem cells. Cancer Gene Ther 15:73-84 |
