Cancer patients treated with high-dose chemotherapy (HDC) experience long-lasting T cell defects that can make tumor vaccination futile. Yet, vaccines inducing antitumor T cell responses mediated by CD4+ T cells and CD8+ cytolytic T cells (CTLs) might represent an effective treatment combined with HDC. Vaccines would eradicate minimal residual disease when tumor burden is at its lowest. This project will define if it is possible to successfully immunize in conjunction with HDC and autologous stem cell transplantation. Dendritic cells (DCs) are antigen-presenting cells that are essential for priming immune responses, and like T cells, DCs seem to be affected by chemotherapy. We hypothesize that there will be an association between numbers of DCs, as well as of native T cells present at the time of vaccination and the ability to successfully immunize. As a corollary, we predict that changing numbers of DCs or of naive T cells in a nonspecific manner will impact on the success of a concurrent vaccination. We will use two experimental approaches to test this hypothesis. First, in an ongoing Phase I clinical study at our institution, we will determine, 1) if patients undergoing high-dose chemotherapy can be immunized; 2) if there is an association between the ability to specifically immunize and the numbers of naive T cells or of dendritic cells in the blood; 3) if the stem cell graft can serve as a source of immune cells for therapy. Breast cancer patients undergoing HDC and stem cell transplantation will be vaccinated against tetanus toxoid and against the tumor-associated Muc-1 peptide. Antigen-specific humoral and T cell-mediated immune responses will be measured. Second, we will use a preclinical mouse model using MHC Class I-restricted TCR transgenic mice to specifically test how CTL-mediated antitumor responses can be elicited by DCs after bone marrow transplantation. Levels of naive T cells and of different types of DCs will be manipulated to measure CTL-dependent antitumor response. Antigen-specific T cells will be directly measured, to test if failure to immunized is caused by a lack of T cells or of DCs or due to vaccine-induced tolerization. Altogether, results obtained in this project will help regulate the immune recovery posttransplantation to improve the current treatment of metastatic breast cancer.
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