# Clonal drivers of resistance to immune checkpoint blockade in liver malignancies

> **NIH NIH R21** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2022 · $227,205

## Abstract

PROJECT SUMMARY
Background and relevance to NIH mission. Immune checkpoint blockade based therapy has quickly become the
treatment paradigm for several advanced cancer including liver malignancies providing the clinical oncologist
with a formidable weapon to achieve dramatic and durable tumor response. The widespread clinical use of
modulators of the immune checkpoint, however, has clearly shown that a subset of patients are intrinsically
poorly responsive to such treatments, while others might develop recurrent disease after an initial response.
While this phenomenon is widely recognized the mechanisms underlying intrinsic and acquired resistance to
immune therapy are still poorly understood, posing an urgent need for the development of novel technological
tools to study and predict which clones within a tumor will likely drive recurrence.
Research design. To investigate the cancer cell intrinsic mechanisms of adaptation and the tumor clonal
dynamics in response to immune-checkpoint blockade in an autochthonous experimental model of cancer we
will barcode somatic mosaic GEM models of liver cancer to look into the clonal drivers of resistance to immune-
checkpoint blockade leveraging a CRISPR-Cas9 based clonal recovery method. Methods. We have generated
somatic mosaic cancer models which faithfully recapitulate the biological behavior, the genomic complexity and
functional heterogeneity of human disease. To investigate the clonal response to immune therapy malignant
cells will be transduced with a dual reporter/suicide cassette barcoded lentiviral library that enables the precise
recovery and expansion of any given barcoded clone by using a CRISPR/Cas9 based “fishing” method. These
novel technology will be instrumental in the isolation and characterization of those clones/malignant cell
populations that are intrinsically prone to evade the immune response or that stochastically acquire the ability to
evade the adaptive immune response in the context of immune competent models of cancer. Genetic, molecular
and metabolic characterization of such populations will shed light on the mechanisms driving the evasion from
immune checkpoint blockade. Ultimately, we will gain fundamental information about clonal dynamics during
disease progression in renal malignancies, in addition, by enabling the recovery of single clones and the
generation of clonal avatars, this approach would help understanding the relative contribution of intrinsic cell
plasticity vs. stochastic genetic events in driving disease recurrence. The technology would eventually
demonstrate broader applications in the field of cancer biology and provide novel knowledge and valuable
research tools to tackle different cancer types, particularly those characterized by a poor response to immune
checkpoints modulation.

## Key facts

- **NIH application ID:** 10357211
- **Project number:** 1R21CA259799-01A1
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Giannicola Genovese
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $227,205
- **Award type:** 1
- **Project period:** 2022-01-12 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10357211

## Citation

> US National Institutes of Health, RePORTER application 10357211, Clonal drivers of resistance to immune checkpoint blockade in liver malignancies (1R21CA259799-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10357211. Licensed CC0.

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