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. 1996 Jun 15;56(12):2832-6.

Costimulation enhances the active immunotherapy effect of recombinant anticancer vaccines

R S Chamberlain  1 , M W Carroll, V Bronte, P Hwu, S Warren, J C Yang, M Nishimura, B Moss, S A Rosenberg, N P Restifo
Affiliations

Costimulation enhances the active immunotherapy effect of recombinant anticancer vaccines

R S Chamberlain et al. Cancer Res. .

Abstract

Activation of T lymphocytes in the absence of a costimulatory signal can result in anergy or apoptotic cell death. Two molecules capable of providing a costimulatory signal, B7-1 (CD80) and B7-2 (CD86), have been shown to augment the immunogenicity of whole-tumor cell vaccines. To explore a potential role for costimulation in the design of recombinant anticancer vaccines, we used lacZ-transduced CT26 as an experimental tumor and beta-galactosidase (beta-gal) as the model tumor antigen. Attempts to augment the function of a recombinant vaccinia virus (rVV) expressing beta-gal by admixture with rVV expressing murine B7-1 were unsuccessful. However, a double recombinant vaccinia virus engineered to express both B7-1 and the model antigen beta-gal was capable of significantly reducing the number of pulmonary metastases when administered to mice bearing tumors established for 3 or 6 days. Most important, the double recombinant vaccinia virus prolonged the survival of tumor-bearing mice. These effects were antigen specific. The related costimulatory molecule B7-2 was found to have a similar, although less impressive enhancing effect on the function of a rVV expressing beta-gal. Thus, the addition of B7-1 and, to a lesser extent, B7-2 to a rVV encoding a model antigen significantly enhanced the therapeutic antitumor effects of these poxvirus-based, therapeutic anticancer vaccines.

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Figures

Fig. 1
Fig. 1
An admixture of rVV fails to elicit antitumor immune responses. BALB/c mice (five per group) were given i.v. injections of 5 × 105 CT26.CL25 tumor cells. A, 3 days later, mice were vaccinated i.v. with 107 PFUs B7-1β-gal rVV (B7-1β-gal), MHAβ-gal rVV (MHAβ-gal), B7-1NP rVV (B7-1NP), an admixture of both B7-1NP rVV and MHAβ-gal rVV (107 PFUs each), or HBSS. Mice were randomized and then sacrificed 12 days after tumor injection (A and B). P value reflects comparison between designated group and HBSS; *, P < 0.0001. B, in addition to the experimental groups in A, an admixture of B7-1NP rVV and MHAβ-gal rVV was given in ratios of 3:1, 1:1, and 1:3 (107 PFUs total). P value reflects comparison between designated group and HBSS: *, P < 0.0001.
Fig. 2
Fig. 2
Vaccination with B7-1β-gal rVV treats tumor established for 6 days. BALB/c mice (five per group) were given i.v. injections of 5 × 105 CT26.WT or CT26.CL25 tumor cells. Three days later, mice were vaccinated i.v. with 107 PFUs B7-1β-gal rVV (B7-1β-gal), MHAβ-gal rVV (MHAβ-gal), B7-1NP rVV (B7-1NP), or HBSS. Mice were randomized and then sacrificed 12 days after tumor injection. All mice inoculated with CT26.WT had large tumor burdens (data not shown). Vaccination with B7-1β-gal rVV mediated a significant reduction in tumor burden compared to all other treatment groups (*, B7-1β-gal rVV versus HBSS, P < 0.008). Duplicate experiments confirmed these results.
Fig. 3
Fig. 3
Vaccination with B7-1β-gal rVV prolongs the survival of tumor-bearing animals. BALB/c mice (10/group) were given i.v. injections of 5 × 105 CT26.WT or CT26.CL25 tumor cells. Three days later, mice were vaccinated i.v. with 107 PFUs B7-1β-gal rVV (B7-1β-gal), MHAβ-gal rVV (MHAβ-gal), B7-1NP rVV (B7-1NP), or HBSS. Survival was monitored on a daily basis. Vaccination with B7-1β-gal rVV significantly prolonged the survival of mice versus other treatment groups (B7-1β-gal versus HBSS, P < 0.0001). All mice inoculated with CT26.WT were dead by day 43 after tumor injection (data not shown). Duplicate experiments confirmed these results.
Fig. 4
Fig. 4
Efficiency of costimulation with B7-1 versus B7-2. BALB/c mice (10/group) were given i.v. injections of 5 × 105 CT26.WT or CT26.CL25 tumor cells. Three days, later, mice were immunized i.v. with either 107 PFU B7-1β-gal rVV (B7-1β-gal), B7-2 β-gal rVV (B7-2β-gal). B7-1B-2β-gal rVV (B7-1B7-2β-gal), MHAB7-2β-gal rVV (MHAB7-2β-gal), MHAβ-gal rVV (MHAβ-gal), B7-1NP rVV (B7-1NP). HBSS. Mice were randomized and then sacrificed 12 days after tumor injection. Lungs were harvested and stained, and pulmonary metastases were enumerated in a blinded fashion. All mice inoculated with CT26.WT had large tumor burdens (data not shown). Mice treated with HBSS alone or B7-1NP rVV showed no therapeutic effect (data not shown). P values reflect comparison between the designated group and the HBSS group; *, P < 0.0014; **, P < 0.0018; ***, P < 0.0018, and ****, P < 0.0018). This figure represents data pooled from two distinct, but identically performed experiments.
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