Optimized ex vivo expansion of anti-tumor Th1 and Tc1 for adoptive immunotherapy.

点击翻译按钮获取中文摘要

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.