Results from successful immune therapy approaches, for various human and murine cancers, have shown that antitumor effects can be mediated by T cells, which is proof-of-principle that the immune system, and in particular, T cells, can reject tumor. Overall, however, the complete clinical response rate for T cell mediated immunotherapies has been low. There are at least two possibilities to explain why this may be the case. First, tumor reactive T cells may not traffic to tumors. Second, tumor reactive T cells may not have adequate effector function within the tumor microenvironment. Neither of these hypotheses has been adequately explored, though there are data suggesting that either or both may represent obstacles to successful immune therapy. In order to improve upon the clinical response rate with vaccines, we need to address the questions of whether vaccine-induced T cells traffic to tumor and exhibit effector function within the tumor. Specifically for breast cancer, there are opportunities for targeting T cells against primary tumors with the intent of providing immune protection early in the disease course. The proposed will address two fundamental questions related to peptide-based breast cancer vaccines. First, are vaccine-induced T cells trafficking to and penetrating into tumor and second, are the activated T cells maintaining their effector function. The following hypotheses will be tested in the proposed clinical trial: (1) the number of peptide-specific T cells increases at the site of tumor following 3 vaccinations, (2) vaccine-induced CD8+ T cells in the periphery and within the tumor express CXCR3 and a4?1 integrins, (3) CXCL9, CXCL10, and CXCL11 are expressed in breast tumors, (4) vaccination induces appropriate activation of CD8+ T cells in the periphery with transient expression of CD69, CD137, and sustained expression of GITR, (5) vaccination induces CD8+ T cells in the periphery with a fully differentiated effector phenotype (CD27-CD28-), (6) vaccine- induced T cells within the tumor exhibit markers of recent activation (CD69, CD137, and GITR), (7) vaccine- induced T cells within the tumor are fully differentiated effector cells (CD27-CD28-), and (8) vaccine-induced T cells in the blood and within the tumor have effector function as determined by IFN? production. These hypotheses will be evaluated under the following Specific Aims:
Aim 1 : Determine whether a multi-peptide vaccine induces T cells that traffic to and penetrate into human primary breast cancers.
Aim 2 : Determine whether T cells induced by vaccination are differentiated effector cells, both in the peripheral blood and within the tumor microenvironment. Very little is known about whether breast cancer vaccines induce T cells that traffic to tumor and whether the vaccine-induced T cells are functional within the tumor microenvironment. The results from these analyses will help guide us in the development of more effective vaccine therapies for the treatment of breast cancer.
Resistance of tumor cells to standard treatment is thought to be the major cause of long term failure of current breast cancer therapies thus, there is a need for new strategies that may add to or replace existing therapy. Very little is known about whether breast cancer vaccines induce T cells that can traffic to tumor and whether the vaccine-induced T cells are functional within the tumor microenvironment. The data from the proposed clinical trial will provide answers to the key questions regarding T cell trafficking and functionality following vaccination, and the results from these analyses will help guide us in the development of more effective vaccine therapies for the treatment of breast cancer.
|Carroll, Kathleen M; Ball, Samuel A; Jackson, Ron et al. (2011) Ten take home lessons from the first 10 years of the CTN and 10 recommendations for the future. Am J Drug Alcohol Abuse 37:275-82|