# Neoadjuvant Immunotherapy with Intratumoral CPG and PD-1 Blockade in Melanoma

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $551,927

## Abstract

PROJECT SUMMARY ABSTRACT
High-risk resectable melanoma patients (MPs) with clinically detectable stage III with or without in-transit
metastases have high-risk relapse1. Neoadjuvant immunotherapy of melanoma with anti-PD1 monoclonal
antibodies alone showed evidence of immunological, pathological and clinical responses in 25-30% MPs with
minimal toxicity. Neoajduvant PD1/CTLA4 blockade further improved pathological and clinical responses while
causing grade 3 adverse events in 73-90% treated melanoma patients. These observations suggest that
Neoadjuvant immunotherapy represents an appealing approach for the early assessment of the efficacy and
toxicity of novel combinatorial immunotherapies of melanoma. In the present application, we propose to
evaluate CMP-001 (CMP), a type A CpG which has several unique properties supporting its potency in
increasing antigen presentation and T cell priming. In contrast to other CpGs tested in the clinic, CMP appears
to potently induce IFNα but no IL10 production by plasmacytoid dendritic cells (pDCs). It is therefore a very
promising therapeutic agent to circumvent the lack of IFNα production observed in “cold” tumors, which are
poorly T cell-infiltrated and fail to response to immune checkpoint blockade. To evaluate the efficacy and
toxicity of CMP in melanoma, we have implemented the first-in-human neoadjuvant clinical trial with CMP
intratumoral and Nivolumab (CMP/Nivolumab) in PD1 naïve high-risk resectable melanoma patients. The
primary end-point of the study is the rate of major pathologic response, comprising pathological complete and
near-complete as assessed using consensus criteria. In this application, we will determine the mechanisms of
responses or resistance to CMP/Nivolumab. Based on our preliminary findings, we investigate whether
CMP/Nivolumab :1) increases pDC activation and maturation in the tumor microenvironment to promote
CD8+TIL expansion and functions; 2) induces melanoma cell death and primes potent neoepitope-specific
CD8+T cells; 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 melanoma.

## Key facts

- **NIH application ID:** 10142580
- **Project number:** 1R01CA257265-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Diwakar Davar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $551,927
- **Award type:** 1
- **Project period:** 2021-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10142580

## Citation

> US National Institutes of Health, RePORTER application 10142580, Neoadjuvant Immunotherapy with Intratumoral CPG and PD-1 Blockade in Melanoma (1R01CA257265-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10142580. Licensed CC0.

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