Recent clinical trials have demonstrated that advanced melanoma can be treated with a combination of nonmyeloablative chemotherapy and autologous adoptive T cell immunotherapy (AIT) to achieve a 50% clinical response rate. Such clinical responses are not, however, consistently durable. Cytotoxic T cells (CTL) are shortlived in the absence of T cell help (Th), with limited persistence after infusion. Furthermore, antigen (Ag) negative variants develop after infusion of CD8+ predominant tumor specific T cell lines, suggesting tumors readily escape from focused therapy. Our goal is to optimize and extend AIT to advanced breast cancer by providing functionally characterized tumor Ag-specific CD4+ Th1 cells as a central component of the infused product. Tumor Ag-specific CD4+ Th1 cells can home to tumor and secrete inflammatory cytokines, modulating the microenvironment to enhance the function of local antigen presenting cells (APC). The resultant increased processing of endogenous tumor cells results in epitope spreading. By providing a robust CD4+ Th1 immune response, tumor Ag-specific CD8+ T cells will be elicited, and the response generated will be long lived.
We aim to promote tumor-specific, epitope spreading, Th1-type CD4+ responses as an essential component of effective AIT. This strategy has been validated by our own vaccine trials for Stage III/IV patients with HER-2/neu (HER2)-overexpressing breast cancer. Patients vaccinated with MHC Class II-binding HER2-derived peptides evidenced a significant survival advantage if they achieved not only enhanced CD4+ T cell responses to vaccine peptides, but also T cell responses to additional HER2 epitopes expressed by their tumors but absent from the vaccine. In animal studies we observe that the inclusion of autologous dendritic cells (DCs) during T cell culture can markedly improve T cell therapeutic performance at the time of re-infusion. Moreover, appropriately activated DCs can promote the expansion of T cells with higher functional avidity, including CD8+ cytolytic T cells that can directly lyse MHC-restricted tumors. We propose to develop a clinically relevant method to expand HER2 specific T cells ex vivo, using optimally activated autologous DC generated simultaneously in the same cultures as the T cells to be activated. We will also assess whether these culture methods increase epitope spreading.
We have observed that vaccination with the breast cancer-associated protein HER2neu is associated with unexpectedly long survival in a group of breast cancer patients. To give such patients the maximum therapeutic benefit, we will develop better ways to grow out T lymphocytes which recognize HER2neu as well as associated proteins and give these expanded armies of lymphocytes back to the patients.
