# Project 1: Evaluating stem-like T cells and improving efficacy of checkpoint inhibitors in NSCLC

> **NIH NIH P50** · EMORY UNIVERSITY · 2024 · $128,039

## Abstract

Programmed cell death-1 (PD-1) targeted therapies have changed the landscape of lung cancer treatment1.
While some impressive results have been generated, the mechanisms that dictate which patients will, or will
not, respond to this treatment are not well defined. It is important to understand the immunological factors
associated with clinical responses not only to improve current therapies but also to identify predictive
biomarkers. We have recently identified a novel population of PD-1+ TCF-1+ CD28+ CD8 T cells with stem-
cell-like features in a mouse model of T cell exhaustion6-8. The proliferative burst of CD8 T cells after PD-1
blockade comes from this stem-like CD8 T cell population, and is dependent on signals from costimulatory
molecule CD28. Importantly, our preliminary data suggest that stem-like CD8 T cells are present in non-small
cell lung cancer (NSCLC) patients. Based on our observations, we hypothesize that the stem- like CD8 T cells
play a critical role in successful PD-1 targeted therapies in NSCLC patients. One of the major goals of this
proposal is to identify and characterize these stem-like CD8 T cells in NSCLC patients. Another important point
to be addressed in this proposal is if the presence of these stem-like CD8 T cells correlates with proliferative
responses of CD8 T cells as well as clinical efficacy of the immunotherapies. The following Specific Aims are
proposed to achieve our goals:
Aim 1: To identify and characterize the phenotype, location, and function of stem-like CD8 T-cells in
lung cancer patients. Aim 1a. Characterize the transcriptional, epigenetic, and functional characteristics of
tumor infiltrating stem-like CD8 T cells in NSCLC; Aim 1b. Determine the clonal relationship between T-cell
populations in tumor, draining lymph node, and blood using TCR sequencing.
Aim 2: To study the efficacy and immune responses of combined inhibition of PD-1 and mTOR in a
neo-adjuvant therapy trial in NSCLC patients. Aim 2a. To examine the clinical efficacy of the combined
inhibition of PD-1 and mTOR in a neo-adjuvant therapy trial for patients with early stage NSCLC. Aim 2b. To
examine the correlation between immune responses and clinical efficacy of the combination therapy.
Aim 3: To evaluate T cell dynamics in lung cancer patients using in vivo deuterium labeling. Aim 3a. To
measure proliferation in T cell populations in NSCLC patients using in vivo deuterium labeling. Aim 3b. To
determine the CD8 T cell populations that proliferate in response to mTOR and PD1 blockade using in vivo
deuterium labeling.

## Key facts

- **NIH application ID:** 11196449
- **Project number:** 3P50CA217691-05S1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Rafi Ahmed
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $128,039
- **Award type:** 3
- **Project period:** 2019-07-10 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11196449

## Citation

> US National Institutes of Health, RePORTER application 11196449, Project 1: Evaluating stem-like T cells and improving efficacy of checkpoint inhibitors in NSCLC (3P50CA217691-05S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11196449. Licensed CC0.

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