IBMS零壹讲堂学术报告系列之一
----New concept of T-APC and its application of T cell-based vaccines
报 告 人：Prof. Jim Xiang （University of Saskatchewan，Canada）
报告时间：09:00-10:30，2011.09.08
报告地点：独墅湖校区一期703栋4楼3401学术报告厅
Prof. Jim Xiang (Senior Scientist)
Research Unit, Saskatchewan Cancer Agency, Department of Oncology, University of Saskatchewan, Saskatoon, SK, S7N 4H4, Canada.
Research Interests
His major research work is in the area of molecular tumor immunology. Recent advances in understanding of the molecular and genetic alterations of tumor as well as in tumor immunology and biotechnology has made it possible to specifically target the tumors by tumor-specific immunotherapeutics leading to induction of anti-tumor immune responses. Therefore, tumor-targeted immunotherapy becomes a new frontier in combating human malignancy. I have developed a strong research program on “Tumor-targeted, genetic and cellular immunotherapy”, which includes both basic research and development of novel molecular immunotherapeutic strategies for treatment of cancer.
1. Basic research:
Dendritic cells, the most potent APCs play a critical role in initiation and regulation of immune responses including Th cell-dependent and -independent CTL responses. Two previous models have been raised to explain the Th cell-dependent CTL responses. These include the passive model of three cell interation and a dynamic model of sequential two cell interactions by APCs. We have recently developed a new dynamic model of sequential two cell interactions by CD4 Th-APCs. We have found that CD4 Th cells acquired MHC class I/peptide complexes and costimulatory molecules from APCs and then functioned as CD4 Th1-APCs in stimulation of CD8 CTL responses in vitro and in vivo. This finding opens a new revenue in study immune responses. It will not only direct research in antitumor immunity, but also immune tolerance and autoimmunity. DC subsets play a distinct role in regulation of immune responses.
2. Applied research:
(A) Dendritic cell vaccines: Dendritic cell (DC) vaccine has become a new exciting area in cancer immunotherapy. Its efficiency, which is still limited to induction of prophylactic antitumor immunity only, needs to be greatly enhanced before use in clinic. To enhance the antitumor immunity, we have developed a new DC vaccine strategy by using DCs with phagocytosis of apoptotic tumor cells. We have shown that it can induce more efficient antitumor immunity than DCs pulsed with tumor peptide. In addition, we demonstrated the critical importance of DC maturation in activation of T cells in vitro and in vivo, and induction of efficient antitumor immunity in three different DC vaccine systems. These include the use of (i) LPS-treated DCs, (ii) DCs engineered to express transgene CD40L and FLt3L. Therefore, our findings thus make significant contribution to the molecular mechanisms of DC maturation and its relationship to the antitumor immunity. More recently, we have provided evidence that (i) the anti-HER2/neu immunity can be obtained and enhanced in a transgenic tumor model expressing the human HER2/neu antigen by AdVHER2/neu and TNF-engineered DC vaccine and (ii) DC vaccine is superior to DNA vaccination in induction of stronger antitumor humoral and cellular immune responses. This may offer new DC vaccine strategies in treatment of HER2/neu-positive human breast cancer.
(B). Adoptive T-cell therapy: Adoptive T-cell therapy is another exciting field in cancer immunotherapy. To date, however, it only demonstrates its treatment of tumors in very early stages in animal models and low response rates in humans. Thus, a strategic goal of current research has been focused on the induction of stronger antitumor immune responses. Chemokines play critical roles in chemotaxis of leukocyte migration. Recently, we have provided the first evidence of chemoattractic effect of C chemokine lymphotactin (Lptn) on neutrophils expressing XCR1 receptor. Recently, we have systemically analyzed gene profiles of activated antitumor CTLs and further developed a novel adoptive T-cell therapy strategy by combining Lptn or IP-10 transgene expression and adoptive T-cell therapy. For the first time, we have demonstrated an interesting synergy of Lptn or IP-10 transgene expression on the therapeutic efficiency of adoptive T cell therapy. More recently, we have found that tumor-specific Th cells greatly enhanced Tc-cell immunotherapy in conjunction of chemokine transgene expression and further elucidated the mechanisms of Th1 effect in prolonging Tc1 survival, reducing apoptosis formation and facilitating its tumor localization.
(C) Cancer gene therapy:
Adenovirus-mediated gene therapy represent a new direction in cancer therapy. We have previously shown that intratumoral adenovirus-mediated TNF gene transfer can cure murine tumors in early stages. Recently, we have displayed that a combinational therapy with adenovirus-mediate TNF gene therapy and engineered tumor and DC vaccines can cure some tumors in an intermediate stage. We have also demonstrated that a double gene (IP-10 and IL-18) therapy can synergistically enhance the antitumor immunity and cure large size tumors.