Collaborating Investigator: Yonghong Wan
Affiliation: McMaster University, Ontario, Canada

Funding Source: Canadian Cancer Society
Project Period: 08/01/17-07/31/20

Summary

The goal of SP #2 is to establish new approaches for ex vivo expansion of circulating endogenous antigen-specific T cells for oncolytic immunotherapy. We will push TR&D1 optimized aAPC for expansion of tumor-specific T cells that Dr. Wan will study in their models of oncolytic virus therapy.

Specific Aim 1. Delivering a protocol that allows local manufacturing of T cells against broadly expressed tumor antigens. Use of leukapheresis products to optimize our culture conditions and evaluate T cell functions in vitro and in vivo (adoptive transfer to NRG/A2 mice followed by oncolytic vaccination).

Specific Aim 2. Further streamlining the enrichment/expansion (E+E) process with nano-artificial APC and simultaneously producing multi-antigen specific T cells. We have requested aAPC from Jonathan Schneck to develop an E+E strategy using nanoscale aAPC and forms the basis of this SP. This approach will be integrated with our culture conditions to optimize cell number and function.

Approach

Aim 1. Endogenous T cells for commonly expressed tumor antigens such as WT-1, NY-ESO-1 and MAGE family antigens are relatively rare (<1:10,000) and the possibility to enrich/expand these T cells using our culture conditions, optimized for CMV, remains to be established. We will use leukapheresis products (increase the starting number) from different patient donors (increase the diversity) to test/optimize our culture conditions and evaluate T cell functions both in vitro and in vivo (adoptive transfer to NRG/A2 mice followed by oncolytic vaccination).
Aim 2. To reduce the cost and shorten the manufacturing time, we will obtain aAPC from TR&D1 for simultaneous generation of multi antigen-specific T cells from a single naïve T cell population, offering a possibility to reduce the likelihood of tumor immune escape due to down-regulation of a single antigen. We will integrate this enrichment technology with our culture conditions to not only accelerate the generation of large numbers of tumor-specific T cells in a cost-effective fashion but to also improve the quality of T cells for their in vivo responses to oncolytic vaccines. We will evaluate this combination approach in several murine tumor models and simultaneously test its ability to enrich/expand human T cells. We have constructed a rhabdoviral vector expressing 5 different epitopes, which will be used to test in vivo expansion and antitumor benefit of adoptively transferred multi-antigen specific T cells.