# Project 1: Evaluating the synergy of LAG3 and PD-1 in melanoma patients

> **NIH NIH P50** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $378,022

## Abstract

PROJECT SUMMARY/ABSTRACT: PROJECT 1
Melanoma is the most aggressive skin cancer and causes over 10,000 deaths per year in the US. While great
strides have been made in the treatment of melanoma, many patients are still non-responsive to immunotherapy.
Understanding the function of PD1 and LAG3 on the immune response in both the tumor and periphery of
patients is critical to the progress of immunotherapy in melanoma. Although LAG3 is the third ‘checkpoint’ to be
targeted with >10 agents in clinical trials, we still know very little about how LAG3 blockade, alone or with anti-
PD1, impacts the immune response to melanoma. We have demonstrated synergistic PD1/LAG3 combinatorial
immunotherapy in mouse models of cancer and clear evidence of clinical benefit from dual inhibitory receptor
(IR) blockade has stimulated anti-PD1 and anti-LAG3 trials in cancer patients failing previous immunotherapies.
Our overarching hypothesis is that LAG3 and PD1 single-agent blockades differentially regulate, and synergize
to promote, CD8+ T cell function in the tumor and peripheral blood of MPs and that a LAG3-dominant IR module
in peripheral CD8+ T cells downregulates patient response to PD1-targeted therapy.
Specific Aim 1. What is the mechanism of anti-PD1 (nivo) and anti-LAG3 (rela), alone and in combination,
on the phenotype and function of CD8+ T cells? We have initiated accrual in a unique biomarker-focused
phase II randomized clinical trial to evaluate the combination of anti-PD1 and/or anti-LAG3 therapy in treatment
naïve melanoma patients. We hypothesize that T cell activation and proliferation pathways are differentially
regulated in CD8+ T cells by anti-PD1 vs. anti-PD1/LAG3 and that unique synergistic molecular programs will be
revealed by this immunotherapeutic combination in treatment-naïve patients with metastatic melanoma. Our
novel trial design will assess the mechanistic impact of anti-PD1 and/or LAG3 immunotherapy in peripheral and
tumor CD8+ T cells.
Specific Aim 2. Does IL6 drive a LAG3-dominant IR module in peripheral CD8+ T cells, and does it predict
responsiveness to immunotherapy? We have recently made a series of novel findings regarding IR
expression in peripheral CD8+ T cells that implies a novel mechanism of immune resistance in melanoma
patients. We hypothesize that IL6-driven systemic immune dysfunction and subsequent resistance to anti-PD1
therapy is driven by a LAG3-dominant IR module and that this dysfunction can be ameliorated by anti-LAG3/PD1
blockade.
This project will [i] define new biomarkers of response and/or resistance to nivo, rela, and the combination;
[ii] potentially identify a patient population that will optimally benefit from LAG3-based therapies; and [iii]
develop novel combinatorial immunotherapies of increased efficacy in melanoma.

## Key facts

- **NIH application ID:** 10469635
- **Project number:** 5P50CA254865-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Dario AA Vignali
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $378,022
- **Award type:** 5
- **Project period:** 2021-08-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10469635

## Citation

> US National Institutes of Health, RePORTER application 10469635, Project 1: Evaluating the synergy of LAG3 and PD-1 in melanoma patients (5P50CA254865-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10469635. Licensed CC0.

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