Therapy of Established Tumors in a Novel Murine Model Transgenic for Human Carcinoembryonic Antigen and HLA-A2 with a Combination of Anti-idiotype Vaccine and CTL Peptides of Carcinoembryonic Antigen

Abstract

Induction of potent and sustained antitumor immunity depends on the efficient activation of CD8 + and CD4 + T cells. Immunization using dendritic cells loaded with tumor antigens constitute a powerful platform for stimulating cellular immunity. Our previous studies suggested that vaccination with an anti-idiotype antibody 3H1, which mimics a specific epitope of carcinoembryonic antigen (CEA), has the potential to break immune tolerance to CEA and induce anti-CEA antibody as well as CEA-specific CD4 + T-helper responses in colon cancer patients as well as in mice transgenic for human CEA. Here, we have combined the anti-idiotype 3H1 with the CTL peptides of CEA to augment both T-helper and CTL responses in a clinically relevant mouse model, which is transgenic for both CEA and HLA-A2. We have evaluated the potential of two different HLA-A2-restricted epitopes of CEA pulsed into dendritic cells in a therapeutic setting. The overall immune responses and survival were enhanced in groups of mice immunized with agonist peptide for CEA 691 (YMIGMLVGV)-pulsed dendritic cells or CAP1-6D (YLS-GADLNL, agonist peptide for CAP-1)-pulsed dendritic cells. Mice immunized with peptide-pulsed dendritic cells along with 3H1-pulsed dendritic cells resulted in significant increase in survival compared with mice immunized with peptidepulsed dendritic cells alone (P < 0.02). IFN-; ELISPOT and 51 Cr-release assays showed that HLA-A2-restricted, CEAspecific CTL responses were augmented by combined dendritic cell vaccinations. The combined vaccination strategy resulted in increased antigen-specific proliferation of splenocytes and secretion of Th1 cytokines by CD4 + T cells that correlated with increased survival. These results suggest the potential use of this vaccination strategy for future clinical applications. [Cancer Res 2007;67(6):2881-92]

Cancer Immunotherapy UsingIn vitroGenetically Modified Targeted Dendritic Cells

“…Because antigen-negative variants may arise after antigenpositive tumor cells are destroyed, immune responses to additional undefined TAAs may be crucial to the ultimate success of DC vaccination. The results are also consistent with the reports using different DC vaccination strategies or non-DC vaccination protocols (42,43).…”

“…It is possible that the cytokines produced by the transferred CD4 + T cells is required for the maintenance of transferred CD8 + T cells and/or activation of host CD4 + or CD8 + T cells. Several recent studies have documented that CD4 + T-cell help is critical for the maintenance of CD8 + T-cell population (43)(44)(45). Taken together, we designed a TAA-targeted DC activation system that couples DC maturation with DC migration in tumor.…”

Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality

“…Mixed lymphocyte reaction. DCs were generated as described previously (83). Briefly, BM cells isolated from BALB/c mice were cultured with recombinant mouse GM-CSF and recombinant mouse IL-4 for 7 days.…”

α‐Galactosylceramide‐loaded, antigen‐expressing B cells prime a wide spectrum of antitumor immunity

“…51 Crlabeled YAC-1 was coincubated with the indicated effectors for 4 hr. The 51 Cr radioactivity of supernatants was determined in a Wallac 1470 Wizard TM automatic g-counter. Specific lysis (%) was calculated as [(experimental release 2 spontaneous release)/ (maximal release 2 spontaneous release)] 3100.…”

“…Antibody-dependent cellular cytotoxicity assay 51 Cr-labeled SK-BR-3 cells were incubated at 37°C with the sera for 1 hr, and then naive splenocytes were added as effectors (effector:target 5 100:1). After an additional 4 hr, the supernatants were harvested and 51 Cr radioactivity was determined in a Wallac 1470 Wizard TM automatic g-counter.…”