| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2005: ¥2,300,000 (Direct Cost: ¥2,300,000)
|
|---|
| Research Abstract |
(1) Efficacy of immunothetrapy with the receptor tyrosine kinase EphA2 derived peptides-pulsed dendritic cells in mouse liver tumor.
The receptor tyrosine kinase EphA2,a new tumor-associated antigen, is broadly expressed in diverse cancer, especially in advanced-stage cancer or metastatic cancer. In this study, we evaluated the effectiveness of the immunization with EphA2 derived peptide-pulsed DCs in mouse subcutaneous and liver tumor. IFN-Υ ELISPOT assays revealed that EphA2 derived peptides-specific CTLs could be generated in vivo by immunization of EphA2 peptide pulsed DCs (Eph-DCs). MC38 subcutaneous or liver tumor-bearing mice were treated with Eph-DCs or unpulsed DCs. MC38 subcutaneous tumor growth in the mice treated with Eph-DCs was significantly inhibited compared with that in the-mice treated with unpulsed DCs. In contrast, MC38 liver tumor growth was significantly inhibited in the mice treated with both Eph-DCs or unpulsed DCs. In vivo depletion study revealed that CD8+ T ce
… More
lls mainly, not NK cells, played critical roles for antitumor effect of Eph-DCs treatment in subcutaneous tumor. In liver tumor model, not only CD8+ T cells but also NK cells played critical roles in antitumor effect of Eph-DCs. These results demonstrated that immunization of Eph-DCs activated acquired immunity in subcutaneous tissue and both innate and acquired immunity in the liver, suggesting the therapeutic potential of Eph-DCs vaccine against EphA2-expressing subcutaneous and liver tumor.
(2) Injection of IL-12 gene-transduced dendritic cells into mouse liver tumor lesions activates both innate and acquired immunity
Dendritic cells (DCs) based vaccines have been applied clinically in the setting of advanced-stage cancer. To date, the clinical efficacy of these vaccines has been limited, possibly due to the impairment of transferred DC function in cancer bearing-patients. In this study, we examined the therapeutic efficacy of IL-12 gene-transfected DCs isolated from tumor bearing hosts against liver tumor. The endogenous DCs isolated from subcutaneous CMS4 tumor-bearing mice (CMS4DC) exhibited decreased DC function compared with DCs isolated from normal mice. Adenoviral transfection of IL-12 gene into CMS4DC (AdIL12DC) restored the decreased DC function. Intratumoral (i.t.) delivery of AdIL12DC resulted in complete rejection of intrahepatic CMS4 tumors and activation of innate and acquired immune cells. I.t. treatment of AdIL12DC also resulted in long-term protection against s.c. rechallenge with CMS4 tumor cells. These results revealed that IL-12 gene transfer is capable of improving the impaired functions of DC isolated from tumor bearing hosts, and support the preclinical therapeutic efficacy of intrahepatic injection of AdIL12DC.
(3) Intrahepatic delivery of α-Galactosylceramide pulsed dendritic cells (αGCDC) suppresses liver tumor.
α-Galactosylceramide mediates interaction of DCs and NKT cells, leading to activation of both innate and acquired immunity. For cancer treatment, conventional DC-based vaccine has been tried, but its clinical efficacy is limited against liver cancer. Intrahepatic injection of αGCDC has not yet been tested in the liver that contains abundant immune cells such as NK, NKT and T cells. We examined the efficacy of αGCDC administration in comparison with p53 peptide-pulsed DCs using a well-established murine CMS4 tumor model. Injection of αGCDC into CMS4 liver tumors resulted in complete tumor rejection and established long-term survival of the animals, while injection of p53_<232-240>o peptide-pulsed DCs (pepDC) only partially suppressed tumor growth in the liver. Hepatic NK cells were efficiently activated by αGCDC injection and played a critical role in liver tumor rejection as evidenced by an in vivo antibody-mediated NK cell depletion study. Injection of αGCDC into liver tumor led to higher p53_<232-240> peptide-specific CD8+ T cell response than that of pepDC. The mice that had been protected from CMS4 liver tumor by αGCDC injection became resistant to subcutaneous CMS4 rechallenge, but not to Colon26 rechallenge. These results demonstrate that αGCDC injection into the liver can efficiently activate NK cells that in turn reject liver tumors to establish potent acquired immunity against the original tumor. Less
|
