# T-cell intrinsic mechanisms of resistance to PD-1 checkpoint blockade

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $169,500

## Abstract

Abstract
This Urgent Supplement is addressing the possible effects of cancer therapies, and PD-1 blockade in
particular, on immune responses to COVID-19 infection and vaccination. The primary objective of the parent
proposal CA243486 entitled “T cell intrinsic mechanisms of resistance to PD-1 checkpoint blockade” is to
determine the function of T cell receptors in the molecular mechanism of resistance to PD-1 checkpoint
blockade.
The COVID-19 pandemic underscores the urgent need for effective vaccines and treatments, especially in
immunocompromised individuals including majority of cancer patients. Previously reported data on animal
vaccination against coronaviruses (CoV), including SARS-CoV, demonstrated that parenteral or intramuscular
immunization, which predominantly activates systemic immunity, may be inadequate in prevention of these and
other respiratory tract infections. Since respiratory mucosa is a primary target for CoV, it has been
demonstrated that targeted mucosal immunization could be a much more effective strategy as it involves
activation of all types of adaptive immunity: systemic, mucosal and cellular. It has been shown that resistance
to SARS-CoV infection in mice is primarily driven by cellular immunity represented by the resident memory T
cells. In humans, SARS-CoV-specific memory T cells have been detected in the peripheral blood of SARS
patients six or more years post-infection despite the lack of virus-specific memory B cells. We hypothesize that
(1) the long-term protection against CoV including SARS-CoV2 can be achieved by a mucosal vaccine eliciting
long-lasting cellular immunity and (2) checkpoint blockade can elevate the T cell response during COVID-19
vaccination. In this supplement to our parent grant we propose to identify SARS-CoV2 specific T cell epitopes
in cancer patients and healthy individuals (Aim 1) and utilize the most immunogenic epitopes in engineering of
a recombinant vaccine library (Aim 2). Since short peptide epitopes are poor immunogens, we will utilize a
non-toxic cholera toxin B (CTB) protein as a mucosal adjuvant and as a carrier for targeted delivery of
immunogens to the lung dendritic cells (Aim 2). Next, the vaccine library will be tested for immunogenicity
using mouse models with and without PD-1 blockade to evaluate the effect of checkpoint blockade on T cell
activation during vaccination. The most efficient vaccine prototype will be further validated using a SARS-CoV2
mouse model (Aim 3). This project will help to evaluate the role of T cells in immunity to COVID-19 in healthy
individuals and cancer patients, test the efficacy of a novel vaccine using in in vivo mouse model and
determine the role of PD-1 blockade in T cell response to immunization.

## Key facts

- **NIH application ID:** 10171108
- **Project number:** 3R01CA243486-01A1S1
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** MICHELLE KROGSGAARD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $169,500
- **Award type:** 3
- **Project period:** 2020-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10171108

## Citation

> US National Institutes of Health, RePORTER application 10171108, T-cell intrinsic mechanisms of resistance to PD-1 checkpoint blockade (3R01CA243486-01A1S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10171108. Licensed CC0.

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