# Abbreviated targeted therapy to improve anti-PD-1 inhibitor efficacy in melanoma

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $380,517

## Abstract

Project Summary/Abstract
Mitogen activated protein kinase (MAPK)-targeted therapy (MTT) currently is approved for treating metastatic
melanoma patients with tumors harboring an oncogenic mutation in BRAF. Anti-PD-1 antibodies are the
standard front-line approach for patients with metastatic melanoma, regardless of genotype, but responses
only are seen in 40-45% of patients. To improve outcomes with MTT and anti-PD1, more effective approaches
are needed. We recently demonstrated that MTT leads to increased tumor infiltrating lymphocyte (TIL) number,
clonality, and effector function, as well as increased immune exhaustion markers such as PD-1, its ligand PD-
L1, and TIM3. We hypothesize that these MTT-associated tumor microenvironment changes enhance immune
responses in the tumor microenvironment and have the potential to convert an immunologically non-responsive
tumor microenvironment into one more responsive to subsequent anti-PD1 therapy. To test our hypothesis, we
have opened a trial (NCT031429029) that incorporates a lead-in phase of MTT, a brief period of concomitant
MTT and anti-PD-1 therapy with pembrolizumab (pembro), followed by single-agent pembro (Aim 1). We will
investigate the clinical benefit rate (CBR) of abbreviated MTT in combination with pembro and determine if
MTT-associated effects on the tumor-immune microenvironment are associated with improved CBR at 24
weeks. As part of the trial, serial biopsies (pretreatment, post-MTT lead-in, and on-MTT plus pembro) and
peripheral blood will be collected, and our team of clinical, translational, and basic investigators will use these
samples to identify biomarkers associated with response and to develop a mechanistic understanding of the
effects of MTT alone and in combination with anti-PD-1 antibody therapy on the tumor microenvironment. We
also will evaluate the effects of anti-PD-1 and MTT on T cell responses in a GEMM melanoma model and in
patients (Aim 2). We will analyze T cell subsets in the mouse melanoma model, assessing the generation of
memory T cells in mice that control tumors using tumor rechallenge studies. We will characterize T cell
responses in the patients enrolled in the clinical trial in Aim 1, focusing on features of effector, memory, and
exhausted T cell subsets. Lastly, we will examine memory populations in melanoma patients who are long-
term survivors after treatment with immune checkpoint inhibitors or MTT. Finally, we will pair these
translational studies with a complementary mouse melanoma model to determine how this therapy affects the
generation, function and maintenance of T cell subsets, and identify new potential therapeutic strategies using
in vivo CRISPR screens of mouse melanoma cells. (Aim 3)

## Key facts

- **NIH application ID:** 9906872
- **Project number:** 5R01CA229851-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Arlene H. Sharpe
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $380,517
- **Award type:** 5
- **Project period:** 2018-05-17 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9906872

## Citation

> US National Institutes of Health, RePORTER application 9906872, Abbreviated targeted therapy to improve anti-PD-1 inhibitor efficacy in melanoma (5R01CA229851-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9906872. Licensed CC0.

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