Class II artificial antigen presenting cells for cancer immunotherapy

Project Summary Adoptive cell therapy (ACT) has become an increasingly attractive method for treating patients with solid tumors due to its impressive response rate; that said, the costs and complexity of current cellular approaches for expansion of tumor-specific T cells have limited accessibility of this therapy.

Significant progress has been made in scalable, acellular technologies for expanding tumor-specific CD8 T cells.

However, no analogous acellular platforms for expansion of CD4 T cells exist, despite overwhelming preclinical and clinical evidence that CD4 T cells are central to antitumor immune responses and can augment CD8- based therapies.

The goal of the proposed project is to investigate the application of a novel Class II artificial antigen presenting cell (aAPC) for expansion of functional, polyclonal endogenous tumor-specific CD4 T cells for ACT as well as potential synergies with endogenous CD8 T cells.

The platform, which consists of a 50 nm paramagnetic iron dextran nanoparticle conjugated with Class II Major Histocompatibility Complex proteins and costimulatory molecules, will allow us 1) to enrich and expand rare murine and human tumor-specific CD4 T cells to clinically relevant levels, and 2) to facilitate dendritic cell (DC) independent T cell help.

In turn, the Class II aAPC will allow us for the first time to monitor both the antitumor efficacy and T cell receptor dynamics of ACT with polyclonal CD4 or combined CD4 and CD8 T cells in mice. To accomplish these goals, the project will proceed in three phases.

First, we will investigate the in vitro function and in vivo antitumor efficacy of aAPC-expanded polyclonal CD4 T cells specific to foreign and self-antigens, OVA and Trp1 with B16-OVA and B16-F10 melanoma models, respectively.

Second, we will apply a modular human Class II aAPC, capable of expanding a range of antigen-specific CD4 T cells through HLA molecules loaded with thrombin-cleavable peptides, to expand functional tumor-antigen NY-ESO-1 specific CD4 T cells from HLA DR1 and DP4 donors.

Finally, we will combine the Class I and Class II aAPC technologies to investigate DC independent in vitro and in vivo antitumor synergies of combined antigen-specific mouse and human CD4 and CD8 culture, using B16-OVA and B16-F10 for mouse T cells, and the human SK-MEL-37 (A2+/NY-ESO-1+) melanoma cell line for human T cells.

If successful, this proposal will deliver a novel acellular approach for polyclonal CD4 or combined CD4 and CD8 ACT and will provide insight into alternative mechanisms of T cell help, with potential clinical ramifications for ex vivo CD8 T cell expansion.