# Defining the Mechanisms of Immune Escape After Adoptive T cell Therapies

> **NIH NIH P01** · FRED HUTCHINSON CANCER CENTER · 2024 · $846,699

## Abstract

Abstract
Disease relapse, graft-versus-host disease (GVHD)/cytokine release syndrome (CRS) and opportunistic
infection are major limitations of adoptive cell therapy (ACT) that includes hematopoietic cell transplantation
(HCT), chimeric antigen receptor (CAR) and T cell receptor (TCR) transgenic T cell therapies. Cytomegalovirus
(CMV) infection is a frequent and life-threatening infectious complication in these immune suppressed patients
that significantly limits the successful outcome of HCT. We have developed innovative preclinical models of CMV
reactivation and both leukemia and multiple myeloma (MM) relapse after ACT. In the HCT setting, we have
modelled the two most promising platforms to improve transplant outcome that were developed within the current
P01, namely naïve T cell (Tn) depletion and post-transplant cyclophosphamide (PT-Cy). We demonstrate
profound effects on alloantigen driven T cell exhaustion, residual stem-like memory T cell populations and NK
cell expansion in the bone marrow. We plan to utilize our unique, but well-established preclinical models to define
the impact of these new clinical HCT platforms on the cellular and molecular pathways that mediate pathogen
and leukemia specific immune responses, with the aim of using new synthetic cytokines to enhance critical
protective immunity. We will expand these studies to new fully murine CAR T cell models of B cell leukemia and
MM, focussing on identification of pathways of both toxicity and immune escape, again with the aim of generating
new therapeutic approaches to optimize outcomes. These preclinical studies will be leveraged to expand and
optimize those planned in Projects 2 and 3. In this manner we will facilitate the development of a new generation
of cell therapies.

## Key facts

- **NIH application ID:** 10935585
- **Project number:** 2P01CA018029-48A1
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** Geoffrey Roger HILL
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $846,699
- **Award type:** 2
- **Project period:** 1997-08-28 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10935585

## Citation

> US National Institutes of Health, RePORTER application 10935585, Defining the Mechanisms of Immune Escape After Adoptive T cell Therapies (2P01CA018029-48A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10935585. Licensed CC0.

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