Pitfalls of vaccinations with WT1-, Proteinase3- and MUC1-derived peptides in combination with MontanideISA51 and CpG7909

Abstract

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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00262-010-0929-7) contains supplementary material, which is available to authorized users.

Regulatory T cells in acute myelogenous leukemia: is it time for immunomodulation?

“…88 Although patient numbers were very limited in these studies, their results imply that immunologic responses might be inversely correlated with Treg frequencies. 81,87 Therefore, Treg depletion before vaccination might help augment antileukemic responses. Berneman et al demonstrated that WT1-targeted DC vaccination can prevent relapse by augmenting CD8 ϩ immune response without an increase in Tregs.…”

“…In vivo, a few vaccination studies monitored Treg frequencies before and after vaccination. 80,81,87,88 Vaccination with allogeneic or autologous AML cells transduced with a lentivirus expressing CD80 and IL-2 (ie, LV-CD80/IL-2) increased Treg frequencies. 88 Although patient numbers were very limited in these studies, their results imply that immunologic responses might be inversely correlated with Treg frequencies.…”

The Immune Microenvironment of Myeloma

“…Many studies have investigated the use of these target antigens as possible vaccine strategies in other hematologic malignancies [119,120]. However, a recent study showed that these vaccine strategies employed on advanced stage cancer patients could not produce T cells that proliferated nor secreted cytokines upon peptide stimulation and in fact T cells were depleted rather than rescued after vaccination [118].…”

“…Another candidate tumor antigen is the mucin 1 protein (MUC1) [118]. Many studies have investigated the use of these target antigens as possible vaccine strategies in other hematologic malignancies [119,120].…”

An autologous leukemia cell vaccine prevents murine acute leukemia relapse after cytarabine treatment

“…However, administration of a vaccine without a suitable adjuvant is unlikely to elicit an effective immune response and may lead to tolerance. 21,22 The glycolipid a-galactosylceramide (a-GalCer) has recently been shown to be a useful adjuvant for whole tumor cell vaccination by eliciting stimulatory interactions between dendritic cells (DCs) and natural killer T (NKT) cells. [23][24][25][26] When DCs acquire cellular material from irradiated tumor cells that have been treated with a-GalCer, the protein content is presented as peptides via major histocompatibility complex (MHC) molecules to CD4 1 and CD8 1 T cells, whereas the a-GalCer is presented via the MHClike molecule CD1d to NKT cells.…”