Induction of CTL responses by simultaneous administration of liposomal peptide vaccine with anti-CD40 and anti-CTLA-4 mAb

Activation of APC via CD40-CD40 ligand pathway induces up-regulation of cos timulatory molecules such as B7 and production of IL-12, Interaction betwee n B7 on APC and CD28 on naive T cells is necessary for priming the T cells. On the other hand, interaction between B7 on APC and CTLA-4 on activated T cells transduces a negative regulatory signal to the activated T cells. In the present study, we attempted to generate tumor-specific CTL by s.c. adm inistration of antigenic peptides encapsulated in multilamellar liposomes ( liposomal peptide vaccine) with anti-CD40 mAb and/or anti-CTLA-4 mAb. Lipos omal OVA(257-264) and anti-CD40 mAb or anti-CTLA-4 mAb were administrated t o C57BL/6 mice and the splenocytes were cocultured with OVA(257-264) for 4 days. The splenic CD8(+) T cells showed a significant cytotoxicity against EL4 cells transfected with cDNA of OVA, In addition, administration of both anti-CD40 and anti-CTLA-4 mAb enhanced the CTL responses. Considerable CTL responses were induced in MHC class II deficient mice by the same procedur e. This finding indicated that CTL responses could be generated even in the absence of Th cells. When BALB/c mice were immunized with pRL1a peptide th at are tumor-associated Ag of RL male 1 leukemia cells using the same proce dure, significant CTL responses were induced and prolonged survival of the BALB/c mice was observed following RL male 1 inoculation. These results dem onstrate that anti-CD40 mAb and anti-CTLA-4 mAb function as immunomodulator s and may be applicable to specific cancer immunotherapy with antitumor pep tide vaccine.