Vaccines for pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDA) remains a highly lethal disease; new therapeutic modalities are urgently needed. A number of immunotherapies tested in preclinical models have shown promise. Early-phase clinical trials have demonstrated evidence of immune activation that in some cases correlates with clinical response. Moreover, recent evidence delineates the intricate role of inflammation in PDA, even at its earliest stages. Pancreatic ductal adenocarcinoma is thus ripe for immunotherapy; however, significant challenges remain before success can be realized. Future studies will need to focus on the discovery of novel PDA antigens and the identification of the multiple immune suppressive pathways within the PDA tumor microenvironment that inhibit an effective PDA-targeted immune response. Technologies are now available to rapidly advance discovery. Rapid translation of new discoveries into scientifically driven clinical trials testing combinations of immune agents will likely continue to shift the procarcinogenic tumor environment toward the most potent anticancer response.

Figure 1

A. TAAs are expressed as small peptide fragments on HLA molecules and presented to T cells for recognition and activation and is referred to as T cell signal 1. However, tumor cells cannot effectively activate T cells alone because they do not express the co-stimulatory molecules such as B7.1 and B7.2 which provide signal 2. Vaccines are designed to deliver TAAs to antigen presenting cells which naturally upregulate both signal 1 and signal 2. Dendritic cells are the most efficient antigen presenting cells due to their ability to readily process tumor antigen and present them on both MHC I and II surface molecules which then bind to T cell receptors on both CD4⁺ and CD8⁺ T cells. DCs also upregulate B7-1/B7-2 expression (signal 2) for efficient T cell activation. Members of immune regulatory cell surface receptors on T cells such as CTLA-4 turn off activated T cells by competing with activating receptors (signal 2) for the same ligand, allowing the tumor to evade immune recognition. Cytokines produced by T cells mediate both activating and inhibitory immune responses. B. Examples of different family members of both co-stimulatory and inhibitory signals on antigen presenting cells that interact with T cells. TCR = T cell receptor MHC = Major histocompatibility complex

Figure 1

A. TAAs are expressed as small peptide fragments on HLA molecules and presented to T cells for recognition and activation and is referred to as T cell signal 1. However, tumor cells cannot effectively activate T cells alone because they do not express the co-stimulatory molecules such as B7.1 and B7.2 which provide signal 2. Vaccines are designed to deliver TAAs to antigen presenting cells which naturally upregulate both signal 1 and signal 2. Dendritic cells are the most efficient antigen presenting cells due to their ability to readily process tumor antigen and present them on both MHC I and II surface molecules which then bind to T cell receptors on both CD4⁺ and CD8⁺ T cells. DCs also upregulate B7-1/B7-2 expression (signal 2) for efficient T cell activation. Members of immune regulatory cell surface receptors on T cells such as CTLA-4 turn off activated T cells by competing with activating receptors (signal 2) for the same ligand, allowing the tumor to evade immune recognition. Cytokines produced by T cells mediate both activating and inhibitory immune responses. B. Examples of different family members of both co-stimulatory and inhibitory signals on antigen presenting cells that interact with T cells. TCR = T cell receptor MHC = Major histocompatibility complex

Figure 2. Methods of Tumor Antigen Identification

Differential gene analysis, exome sequencing and proteomics are three different methods of identifying tumor TAAs in PDA. Immunoassays conducted on T cells from vaccinated PDA patients determine the presence of antigen specific cytotoxic CD8⁺ T cells. These antigens can then be used to develop more potent antigen specific immunotherapies.

Figure 3

Combinatorial Immunotherapies Target Distinct Steps for an Optimal Anti-Tumor Immunity