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University of Pittsburgh Melanoma and Skin Cancer SPORE

University of Pittsburgh

Principal Investigators

Headshot of Hassane Zarour, M.D.

Hassane Zarour, M.D.
Contact Principal Investigator
University of Pittsburgh
5117 Centre Avenue; Suite 1.32a
UPMC Hillman Cancer Center
Pittsburgh, PA 15232
412-623-7707

Headshot of John Kirkwood, M.D.

John Kirkwood, M.D.
Co-Principal Investigator
University of Pittsburgh
5117 Centre Avenue; Suite 1.32c
UPMC Hillman Cancer Center
Pittsburgh, PA 15232
412-623-7707

Overview

The overall goal of the Melanoma and Skin Cancer Program (MSCP) Specialized Program of Research Excellence (SPORE) is to develop novel translational research to overcome the hurdles of current therapies of melanoma and cutaneous squamous cell carcinoma (cSCCs). The MSCP SPORE includes three translational research projects, resulting from seminal and innovative findings made by the investigators of the MSCP SPORE, which are translated into new combinatorial immunotherapy trials for patients with melanoma and skin cancers.

  • Project 1 assesses the clinical and immunological activity of anti-LAG3 alone and in combination with anti-PD1, for the first time, in treatment-naïve melanoma patients (MPs) who have not received prior Immune Checkpoint Blockade (ICB).
  • Project 4 investigates how neoadjuvant PD-1 blockade shapes the tumor microenvironment, spatial biology, and immune contexture in high-risk resectable cutaneous squamous cell carcinoma (cSCC).
  • Project 5 explores the vasculature of the melanoma tumor microenvironment and its effect on the metabolism of immune cells, most notably in the context of a clinical trial utilizing the antiangiogenic axitinib in combination with immune checkpoint blockade.

Shared-facility cores provide state-of-the-art expertise and economies-of-scale in 1) sample collection and processing, translational pathology, data annotation, biospecimen repository, and immunomonitoring (Core 1); and 2) biostatistics and bioinformatics (Core 2), supporting rigor and reproducibility across all research projects.

The Career Enhancement Program (CEP) and Development Research Program (DRP) will attract talented basic, translational, and clinical investigators into melanoma research.

The MSCP SPORE leverages Hillman Cancer Center (HCC) resources and institutional commitment with state-of-the-art research and clinical facilities, clinical regulatory services to support clinical trial coordination, and translational research.

The MSCP SPORE includes outstanding External and Internal Advisory Boards, an Executive Committee and Patient Advocates. The organizational structure of the MSCP SPORE will facilitate thorough following of progress and managing of potential hurdles for each project. The MSCP SPORE will share data with the scientific community and other SPOREs in agreement with the NIH policy. The MSCP SPORE will benefit from and promote multiple horizontal and vertical collaborations with academic institutions, NCI, pharmaceutical companies, and cooperative groups.

Project 1: Evaluating the synergy of LAG3 and PD1 in Melanoma Patients

Project Co-Leaders

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. Project 1 includes a novel biomarker-focused phase II randomized clinical trial to evaluate the combination of anti-PD1 (Nivolumab) and/or anti-LAG3 Relatlimab) therapy in treatment naïve melanoma patients. We hypothesize that different transcriptional and functional pathways are regulated by anti-PD1 and anti-LAG3 in CD8+ T cells, and that unique synergistic molecular programs will be revealed by this immunotherapeutic combination. We will assess the mechanistic impact of anti-PD1 and/or LAG3 immunotherapy in peripheral and tumor CD8+ T cells. Based on novel findings, we also hypothesize that cytokine-driven systemic immune dysfunction and subsequent resistance to anti-PD1 therapy is driven by a LAG3-led inhibitory receptor module, and that this dysfunction can be ameliorated by anti-LAG3 blockade.

Collectively, the findings in this application will define new biomarkers of response and resistance to Nivolimab, Relatlimab, and the combination. They will identify a patient population that will optimally benefit from LAG3-based therapies and support novel combinatorial immunotherapies of increased efficacy in melanoma.

Project 4: Deconvoluting Response to Neoadjuvant anti-PD-1 in cSCC

Project Co-Leaders

Cutaneous squamous cell carcinoma (cSCC) is uniquely sensitive to PD-1 blockade, likely due to its high tumor mutational burden (TMB) resulting from ultraviolet (UV)-induced carcinogenesis. Single-agent α-PD-1 therapy achieves response rates of 35–50%, and in high-risk resectable disease, neoadjuvant PD-1 blockade has produced high rates of pathologic response in non-randomized phase II studies, changing the standard management approach. However, the biological mechanisms driving response and resistance to α-PD-1 in this setting remain poorly understood.

We recently completed a non-randomized phase II trial of neoadjuvant pembrolizumab (200 mg every 3 weeks for two cycles) in patients with high-risk resectable cSCC. Among 26 evaluable patients, we observed a 61% pathologic complete response (pCR) rate and identified pCR-associated immune niches enriched for MHCII⁺CD11c⁺ dendritic cells and CD20⁺ B cells. These findings are consistent with recent reports that antigen-presenting cell (APC)–containing niches promote the differentiation and maintenance of TCF1⁺ stem-like CD8⁺ T cells, which are critical mediators of response to PD-1 blockade.

Building on these data, we will integrate bulk and spatial transcriptomics, multiplex immunofluorescence (mIF), and unbiased computational analyses to define the cellular and molecular determinants of response and resistance to α-PD-1 in cSCC. The proposed studies will elucidate fundamental mechanisms of PD-1–mediated tumor immunity and provide a rational framework for developing combinatorial immunotherapeutic strategies to enhance clinical efficacy in cSCC and related epithelial malignancies.

Project 5: Microenvironment Manipulation using Anti-Angiogenics to Improve Immunotherapy in Melanoma

Project Co-Leaders

While immunotherapy with immune checkpoint blockade has revolutionized the treatment of melanoma, many patients treated fail to respond or acquire resistance. One feature of resistance is a remodeling of the tumor microenvironment, the local milieu of the tumor consisting of cancer, immune, and stromal cells. We've previously shown that progression on immunotherapy can result in a more metabolically active and hostile tumor microenvironment, characterized by altered vasculature.

In this Project, we hypothesize that targeting the vasculature using antiangiogenic compounds like axitinib might normalize the tumor microenvironment and allow for T cell function. Based off of robust preclinical data, we developed a Phase II clinical trial to treat individuals who have progressed on immune checkpoint blockade with axitinib in combination with continued immunotherapy. This trial has shown that in some individuals, antiangiogenic therapy can re-invigorate the immune response driven by immune checkpoint blockade. We are using cutting edge techniques to profile how treatment with anti-angiogenics precisely remodels the tumor microenvironment and supports immunity, identifying features that may be used to predict responses.

Administrative Core

Core Co-Directors

The Administrative Core will provide scientific and fiscal oversight and enhance communication on multiple levels to ensure the success of the SPORE. The Core will oversee day-to-day operations, coordinate periodic administrative and scientific reviews, and work closely with the NCI Program Office. Core personnel will coordinate SPORE activities at the Hillman Cancer Center and the University of Pittsburgh, and with outside collaborating institutions, and advocacy groups. The Core will oversee the Developmental Research Program (DRP) and the Career Enhancement Program (CEP). The Core will provide the administrative framework to evaluate program activities and redirect resources as needed to maximize translational progress. The Core will work to raise melanoma cancer awareness and to increase philanthropic support of melanoma and skin cancer research. The Core will be used equally by the three research projects, the other two Cores, the DRP, and the CEP.

Biospecimen and Translational Pathology

Core Director

The Biospecimen and Translational Pathology (Core 1) has the responsibility for the procurement, flow and delivery to the SPORE investigators of biological specimens (tissues, tumor cells, tumor-infiltrating immune cells and cells in the peripheral circulation) and for providing clinicopathological annotation for all subjects enrolled in the clinical trials. Core 1 will procure and process all body fluids and tissues harvested from melanoma patients enrolled in SPORE studies and provide immunopathological tissue evaluations. Core 1 will also assist the SPORE investigators in implementing assays necessary for evaluation of immunologic responses to immune therapies. Core 1 will ensure that all samples it collects are accompanied by annotations that will permit linking laboratory analyses with clinical results. Data and annotations will be stored in the SPORE research database and will be updated and retrieved for research projects following established HIPAA protocols.

Biostatistics and Bioinformatics

Core Co-Directors

The Biostatistics and Bioinformatics Core (Core 2) provides services for the design of experiments and the analysis of in vitro, in vivo, clinical, translational and -omics data. The investigators and staff of both segments of the Core have significant experience in research in skin cancers, so that data are analyzed in the appropriate scientific context, increasing the Core's efficiency and effectiveness compared to general purpose data analysis services. The Biostatistics and Bioinformatics Core combines classical statistical techniques with contemporary Bayesian, machine learning and genomics methods to ensure that every research project, DRP and CEP awardee in the SPORE has access to the most appropriate analyses. Core 2 will also work closely with Core 1 to ensure that data flows between laboratories, clinics and analysts are efficient and that data and resource sharing can be effective and comprehensive.

Developmental Research Program

Program Co-Directors

The Developmental Research Program (DRP) provides seed funding to explore promising novel research in melanoma and other skin cancers, particularly by investigators not currently engaged in research in this area. The DRP Co-Directors track the progress of the successful applications and assign mentors to funded investigators to ensure that they obtain any needed services from the SPORE Cores, and that they are effectively integrated into the SPORE program. Awardees present their research results to the SPORE membership after one year of funding to become eligible for a second year of support. Progress toward translation as well as impact and innovation will determine whether DRP projects are found to merit promotion to full SPORE projects at the time of formulating a renewal bid. Awardees are also advised as appropriate in the preparation of grant applications for funding outside the SPORE mechanism and given access to all SPORE Core resources to aid in this endeavor.

Career Enhancement Program

Program Co-Directors

The mission of the Career Enhancement Program (CEP) is to stimulate basic, translational, and clinical research by recruiting and supporting new investigators in the area of melanoma and other skin cancers. The CEP provides financial resources for this mission, while the SPORE itself provides a supportive and stimulating research environment. The CEP will track progress of the successful applications and provide advisors to funded investigators to ensure that they obtain any needed services from the SPORE Cores and that they are fully-integrated into the SPORE program. Awardees present their research results to the SPORE investigators after one year of support in order to become eligible for a second year of support. Progress toward translation as well as likely impact and innovation determine whether ongoing CEP projects evolve into future full SPORE projects. Awardees will also be advised as appropriate in the preparation of grant applications for funding outside the SPORE mechanism and given access to Core resources to aid in this endeavor.

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