Collaborative Project #2 : Regulation of memory CD8 T cell development
Collaborating Investigator: Susan Kaech
Affiliation: Salk Institute
Funding Source: NIH
Grant Number: R37AI066232
Project Period: 05/01/05-01/31/23
Checkpoint blockade immunotherapies are currently some of the most promising strategies for fighting cancer. PD-1/PD-L1 blockade induces measurable responses in 13-26% of patients with many types of cancer by increasing anti-tumor T cell responses 1. In some cases, PD-1/PD-L1 blockade results in rapid and durable anti-tumor responses. Despite the effectiveness of PD-1/PD-L1 blockade, many patients are unresponsive to therapy 2-4. There are two major factors that contribute to poor prognosis: 1) Tumors poorly elicit CD8 T cell responses and 2) if T cell responses are formed, they often fail to infiltrate the tumor or are functionally exhausted 5-7. T cell exhaustion is associated with increased T cell expression of inhibitory receptors such as PD-15.
Recently, a phase I clinical trial evaluating a novel NY-ESO vaccine (CDX-1401, CellDex Therapeutics)demonstrated that targeting antigen-presenting cells to present NY-ESO antigen to T cells was capable of promoting tumor regression in 53% of patients 12. A new phase II trial that the Kaech lab will be contributing to aims to evaluate the benefits of PD-L1 blockade after CDX-1401 therapy.We hypothesize that either priming anti-tumor CD8 T cells by vaccination with tumor antigens would augment the effectiveness of PD-L1 blockade in patients.Therefore, we propose to investigate the changes that occur in the anti-tumor T cell responses in patients receiving PD-1/PD-L1 blockade immunotherapy, in conjunction with vaccination with the NY-ESO tumor antigen.
- Does the frequency of NY-ESO specific T cells increase as a result of vaccination in the peripheral blood?Does the anti-PD-L1 augment this further?
- What is the phenotype of the NY-ESO specific T cells in the blood? Does immunotherapy change their phenotype or functional state?
- Does the frequency of NY-ESO specific T cells in the blood correlate with response to therapy?
As part of the Collaborative Project with TR&D#1 we will use the E+E nano-aAPC based system to expand NY-ESO157-165 specific CTL from HLA A2 positive patients and compare that approach to tetramer based analysis. We expect that the E+E expansion based approach will be more sensitive than tetramer based analysis. This will provide the opportunity to explore this system in patients with NSCLC and preliminary data that can be used to develop new collaborative grants with the Schneck lab.
The push-pull relationship will explore how E+E can be used to expand T cells from patients with melanoma who have received vaccination or not. Thus, these patients sample may require different signal 2’s than PBMC from either naïve healthy donors or unvaccinated patients with cancer. This will provide the opportunity to explore this system in patients with NSCLC analyzing NY-ESO1 specific responses which are major interest in TR&D1. We expect that our push pull experiments will help us modify signal 2 and facilitateTR&D 1’s development specific signal 2’s such as a anti-CD28 versus anti-4-1-BB for specific clinical settings. We also expect that based on the push-pull relationship the Kaech lab will have a better understanding of the number and function of the NY-ESO responses in patients with melanoma and the impact vaccination has had on those responses.