# Understanding Immunotype, a Novel Biomarker for Checkpoint Blockade Resistance

> **NIH NIH R01** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2023 · $527,057

## Abstract

ABSTRACT
An estimated 44% of patients with cancer in the United States are eligible to receive immune
checkpoint blockade (ICB). FDA-approved ICB agents include α-PD-1 and α-CTLA-4
antibodies, but the majority of patients do not benefit because their tumors are resistant to
these agents. ICB treatment is expensive and may lead to serious toxicity. Prospective
identification of patients with ICB-resistant cancers would reduce unnecessary risk and cost
and give patients opportunities to seek more appropriate treatment options. To address the
unmet need for a peripheral blood biomarker for ICB effectiveness, we performed immune
profiling of ICB-treated patients with melanoma, using multiparametric flow cytometry to
characterize immune cells in pretreatment peripheral blood. Our analyses revealed a new
peripheral blood immune profile which we called Immunotype-1 (IT-1), defined in part by the
presence LAG-3+CD8+ T cells as a promising biomarker of ICB resistance. This finding was
validated in an independent dataset of metastatic urothelial cancer. Patients with IT-1 have
inferior overall survival, progression free survival, and response rates to α-PD-1 blockade.
Leveraging our leadership in the clinical development of ICBs, we have assembled one of
the largest biobanks of peripheral blood samples from >600 ICB-treated patients across
cancer types. In this proposal, we aim to test the hypothesis that IT-1 is a pan cancer
biomarker for ICB, reflecting an exhausted, tumor-specific LAG-3+CD8+ T cell population
whose function can be recovered for therapeutic benefit using α-LAG-3 blockade. The
Specific Aims are to: 1) Phenotypically and functionally characterize the peripheral blood
LAG-3+CD8+ T cell population and determine if this population is represented in the tumor
microenvironment in patients with the IT-1 phenotype; 2) Determine the association
between IT-1 and clinical outcome in ICB-treated patients across cancer types; and 3)
Assess whether IT-1 identifies patients who will respond to relatlimab (α-LAG-3) +
nivolumab (α-PD-1). Our project is rooted in strong clinical data and thus likely to identify a
biomarker that is mechanism-based, clinically implementable, and most importantly,
therapeutically actionable.

## Key facts

- **NIH application ID:** 11005119
- **Project number:** 7R01CA276286-02
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** Margaret Kathleen Callahan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $527,057
- **Award type:** 7
- **Project period:** 2023-07-10 → 2028-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11005119

## Citation

> US National Institutes of Health, RePORTER application 11005119, Understanding Immunotype, a Novel Biomarker for Checkpoint Blockade Resistance (7R01CA276286-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11005119. Licensed CC0.

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