pf-3512676 and Leukemia--Myeloid--Acute

T cells with specificity for antigens derived from Wilms Tumor gene (WT1), Proteinase3 (Pr3), and mucin1 (MUC1) have been demonstrated to lyse acute myeloid leukemia (AML) blasts and multiple-myeloma (MM) cells, and strategies to enhance or induce such tumor-specific T cells by vaccination are currently being explored in multiple clinical trials. To test safety and immunogenicity of a vaccine composed of WT1-, Pr3-, and MUC1-derived Class I-restricted peptides and the pan HLA-DR T helper cell epitope (PADRE) or MUC1-helper epitopes in combination with CpG7909 and MontanideISA51, four patients with AML and five with MM were repetitively vaccinated. No clinical responses were observed. Neither pre-existing nor naive WT1-/Pr3-/MUC1-specific CD8+ T cells expanded in vivo by vaccination. In contrast, a significant decline in vaccine-specific CD8+ T cells was observed. An increase in PADRE-specific CD4+ T helper cells was observed after vaccination but these appeared unable to produce IL2, and CD4+ T cells with a regulatory phenotype increased. Taken into considerations that multiple clinical trials with identical antigens but different adjuvants induced vaccine-specific T cell responses, our data caution that a vaccination with leukemia-associated antigens can be detrimental when combined with MontanideISA51 and CpG7909. Reflecting the time-consuming efforts of clinical trials and the fact that 1/3 of ongoing peptide vaccination trails use CpG and/or Montanide, our data need to be taken into consideration.

Topics: Adolescent; Antigens, Neoplasm; Cancer Vaccines; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Female; Humans; Leukemia, Myeloid, Acute; Male; Mannitol; Mucin-1; Multiple Myeloma; Myeloblastin; Neoplasm Staging; Neoplasm, Residual; Oleic Acids; Oligodeoxyribonucleotides; Peptides; Pilot Projects; Treatment Outcome; WT1 Proteins

To investigate whether syngeneic BM-derived DCs generated in vitro and fused with syngeneic C1498 tumor cells (murine AML line) could induce a better antitumor protective effect compared to similarly generated DCs pulsed with C1498 lysate with or without co-injection of a class B CpG oligodeoxynucleotide (CpG 7909) in vivo.. DCs were pulsed with C1498 lysate prior to intravenous administration 14 and 7 days prior to tumor challenge. Separate cohorts received DCs electrically fused to irradiated C1498 cells. Cohorts were administered DCs that were lysate-pulsed or fused with tumor cells on days 14 and 7 prior to tumor injection. Some cohorts were co-injected with CpG 7909 at the time of DC administration.. All DC vaccines significantly improved survival (p < 0.01) vs nonvaccinated controls. There was no difference in the antitumor protective response between mice that received pulsed vs fused DCs (47% vs 45% survival). Both DC vaccines generated a fivefold increase in splenic tumor-reactive cytotoxic T-lymphocyte precursor cells and significantly (p < 0.05) higher mean frequencies of IFN-gamma-producing splenocytes compared to controls. CpG 7909 improved the survival of mice receiving the fused DCs (p < 0.05) but not the pulsed DCs. Surviving mice were rechallenged and found to be resistant to lethal tumor injection.. DC vaccine strategies may be effective in generating anti-AML responses. No advantage was observed between lysate-pulsed and tumor cell-fused DCs. CpGs may provide an adjuvant effect depending on the type of DC vaccine administered.

Topics: Adjuvants, Immunologic; Animals; Antigens, Neoplasm; Cancer Vaccines; Cell Line, Tumor; Cell-Free System; Dendritic Cells; Female; Interferon-gamma; Leukemia, Myeloid, Acute; Mice; Neoplasm Transplantation; Neoplasms, Experimental; Oligodeoxyribonucleotides; Spleen; T-Lymphocytes; Vaccination