# Project 2: Immunotherapy with CMP-001 intratumoral and nivolumab in melanoma

> **NIH NIH P50** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $378,023

## Abstract

PROJECT SUMMARY ABSTRACT: Project 2
Immunotherapy with anti-PD1 monoclonal antibodies (mAbs) is associated with improved response and
survival rates in multiple solid tumors, including melanoma1. Anti-PD1 mAbs (anti-PD1) produces durable
clinical responses in 33-40% of melanoma patients with minimal toxicity. While dual anti-PD1/anti-CTLA4
blockade produces higher response rates (58%) and 5-year PFS (36%), this is associated with 55% grade 3/4
adverse events. Therefore, there is a critical need for novel combinatorial immunotherapy to improve the
efficacy of anti-PD1 while mitigating the rate of serious adverse events in advanced melanoma. One major
barrier limiting the efficacy of anti-PD1 is the lack of spontaneous tumor-infiltrating T cells (TILs) and defective
IFNa production in tumor microenvironment (TME) in so-called “cold” or non-inflamed tumors. One promising
therapeutic approach to overcome this hurdle is via toll-like receptor 9 (TLR9) agonists. TLR9 is predominantly
expressed by plasmacytoid dendritic cells (pDCs) and B cells and binds to agonists including unmethylated
cytosine guanosine oligodinucleotides (CpG). We have recently performed the first-in-human trial of
neoadjuvant intratumoral CMP, a novel type A CpG, and Nivolumab in PD1-naïve high-risk resectable
melanoma (NCT03618641). In 30 evaluable melanoma patients, we have observed 60% major pathologic
responses with increased CD8+ TILs and peritumoral CD303+ pDCs in injected tumors, and higher frequency
circulating PD1+Ki67+CD8+ T cells in responders. Therapy with intratumoral CMP and Nivolumab
(CMP/Nivolumab) has also shown clinical efficacy in PD1 refractory melanoma with responses in non-injected
tumors, supporting the occurrence of systemic antitumor immunity beyond the injected tumors. To further our
understanding of the mechanisms of responses or resistance to CMP/Nivolumab in injected and non-injected
tumors, we will take advantage of a substudy of 60 melanoma patients included in the randomized phase II/III
clinical trial evaluating CMP/nivolumab vs. nivolumab in PD1 naïve metastatic melanoma with accessible
tumors for intratumoral CMP. Based on our preliminary findings, we will investigate whether CMP/Nivolumab
:1) increases pDC activation and recruitment into injected tumors to promote CD8+TIL expansion and functions
in injected and non-injected tumors; 2) induces melanoma cell death, primes potent neoepitope-specific CD8+T
cells in injected tumors, and epitope spreading to melanoma-associated antigens; and 3) fails to induce potent
T cell responses because of melanoma cell-extrinsic or melanoma cell-intrinsic mechanisms. Collectively, the
findings in this application will improve our understanding of the mechanisms of response and resistance to
CMP/Nivolumab in melanoma. They will further support novel combinatorial immunotherapies to further
enhance the immunogenicity and clinical activity of CMP/Nivolumab in injected and non-injected tumors of
advanced melanoma.

## Key facts

- **NIH application ID:** 10469636
- **Project number:** 5P50CA254865-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** HASSANE M ZAROUR
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $378,023
- **Award type:** 5
- **Project period:** 2021-08-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10469636

## Citation

> US National Institutes of Health, RePORTER application 10469636, Project 2: Immunotherapy with CMP-001 intratumoral and nivolumab in melanoma (5P50CA254865-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10469636. Licensed CC0.

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