# Escape from CAR T surveillance through lineage plasticity

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2022 · $578,670

## Abstract

PROJECT SUMMARY
Cancer cell genomic plasticity can enable resistance to cancer therapy for both solid tumors and
hematologic malignancy. Escape from cytotoxic or molecularly targeted therapy through an
inherent capacity to reprogram differentiation state or lineage has now been described following
adoptive cell therapy or immune checkpoint blockade in adult epithelial tumors. Transfer of T
cells genetically modified to express chimeric antigen receptors (CAR T cells) targeting the B
cell surface antigen CD19 induces remission in 70-90% of patients with relapsed/refractory B
cell acute lymphocytic leukemia (B-ALL) resulting in FDA-approval for this indication. However,
a large fraction of those patients relapse within one year of treatment. This occurs with two main
patterns, 1) early antigen-positive (CD19pos) relapse, attributed to poor CAR T expansion or lack
of persistence, and 2) later antigen-negative relapse. Evasion of CD19-targeted immunotherapy
can result from loss of all B lineage phenotypic markers with acquisition of stable, alternative
phenotypes in MLL-rearranged (MLL-r), BCR-ABL driven, TCF3-ZNF384 and other subtypes of
ALL. Remarkably, emergence of phenotypic switch can occur years after CD19-targeted
immunotherapy. Understanding the mechanisms of immunotherapeutic resistance and
identifying strategies to overcome these will be critical in improving remission depth and
durability of response.
 Our proposal will address two major deficits in cancer models to identify factors
contributing to relapse from immunotherapy: the lack of immune-intact model systems that
recapitulate the lineage switching phenomenon observed using CD19-targeted immunotherapy
and the lack of faithful mouse models recapitulating infant/childhood MLL-r B-ALL. This
collaborative proposal brings together the extensive expertise of the Ernst group in the biology
of MLL-r leukemia and hematopoiesis with the CAR T cell expertise of the Fry/Kohler groups to
develop innovative new models systems to study evasion from CAR T cell therapy through
lineage reprogramming. Our preliminary CAR T cell data employs immune-intact mouse models
to illustrate that CD19neg relapse includes cells that exhibit gain of myeloid antigens and a
myeloid transcriptional profile. On the pediatric B-ALL front, we develop a retroviral system to
produce B-ALL that captures the inherent plasticity of MLL-r leukemias and switches to AML in
vivo. Our proposal assesses the ability for both leukemia-intrinsic as well as extrinsic host-
environmental components to influence escape from CAR T killing through lineage
reprogramming. The findings of our studies, including the discovery of novel strategies to block
lineage reprogramming have the potential to inform the development of similar approaches in
other forms of cancer treated with cellular therapy and, potentially, immune checkpoint
inhibitors. In addition, these studies may lead to a better understanding of lineage plasticity and
the extent to ...

## Key facts

- **NIH application ID:** 10419173
- **Project number:** 1R01CA269269-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Patricia Ernst
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $578,670
- **Award type:** 1
- **Project period:** 2022-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10419173

## Citation

> US National Institutes of Health, RePORTER application 10419173, Escape from CAR T surveillance through lineage plasticity (1R01CA269269-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10419173. Licensed CC0.

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