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Last Updated: 09/13/21

Melanoma and Skin Cancer SPORE

University of Pittsburgh

Principal Investigator(s):

Hassane Zarour, MD
Hassane Zarour, MD

John Kirkwood, MD
John Kirkwood, MD

Principal Investigator(s) Contact Information

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

John Kirkwood, MD
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 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 MPs who have not received prior ICB.

Project 2 evaluates the efficacy, and immunogenicity of CMP-001 (CMP), a type A CpG, in PD1 naïve metastatic melanoma in the context of a phase II/III randomized clinical trial with intratumoral CMP and nivolumab (CMP/nivo) vs. nivolumab.

Project 3 tests a novel microneedle array (MNA) device to deliver both a potent chemotherapeutic agent to induce immunogenic cell death and an innate immune stimulant into accessible cSCCs. This approach will be tested both in immunocompetent and immunosuppressed cancer patients.

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:
Dario A.A. Vignali, PhD (Basic and Translational Co-Leader)
Tullia Bruno, PhD (Basic and Translational Co-Leader)
John M. Kirkwood, MD (Clinical Co-Leader)

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 2: Immunotherapy with CMP intra-tumoral and Nivolumab in melanoma

Project Co-Leaders:
Hassane M. Zarour, MD (Basic Co-Leader)
Diwakar Davar, MD (Clinical Co-Leader)

Immunotherapy with anti-PD1 monoclonal antibodies (mAbs) is associated with improved response and survival rates in multiple solid tumors, including 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 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.

Project 3: Localized microneedle-directed combination immunotherapy for cSCC

Project Co-Leaders:
Louis Falo, MD, PhD (Basic Co-Leader)
Jason Luke, MD (Clinical Co-Leader)
Oleg Akilov, MD, PhD (Clinical Co-Leader)

This project evaluates a novel combination immunotherapy approach applicable to a broad range of accessible skin cancers. Specifically, we will target both a potent chemotherapeutic agent to induce immunogenic cell death and an innate immune stimulant specifically to the 3D space of the tumor microenvironment (TME) of cutaneous squamous cell carcinomas (cSCCs). This strategy is enabled by a dissolvable microneedle array (MNA) device developed and produced in our laboratories. These studies represent the first tumor immunotherapy clinical trials utilizing spatially and kinetically controlled delivery of a synergistically acting combination therapy. This approach uniquely enables individualized patient-specific immunotherapy through low dose localized drug delivery, obviating obstacles related to tumor and antigen heterogeneity and reducing/preventing adverse effects associated with systemic exposure. Thus, the strategy could be applicable to a large patient population, including those who are immunosuppressed or have or are at risk for autoimmune diseases, as well as a broad range of skin cancers through a completely non-specific and generalizable MNA “band-aid”-like delivery platform. Our hypothesis is that in situ MNA-directed immunotherapy (MNA-IT) will kill tumor cells locally and induce a proinflammatory TME, enabling immune elimination of the treated tumor while potentially inducing durable systemic immunity. It is supported by both preclinical studies and results from our own clinical trials.

To evaluate MNA-IT in patients with cSCCs, we will perform an iterative phase Ib/II clinical trial evaluating MNA-IT single and combination therapies utilizing dissolving MNAs to deliver doxorubicin, a STING agonist, or both directly to the TME of cSCCs. This will be evaluated in both immunocompetent patients and in immunosuppressed transplant recipients. We will evaluate safety, clinical, and pathologic responses, and explore therapy-induced changes in the TME and peripheral blood before, during, and after therapy. Through forward reaching pre-clinical studies, we will develop a “next-generation” combination MNA-IT to achieve sustained release of immune checkpoint inhibitors in the TME to support a sustained pro-inflammatory TME favoring the induction of systemic tumor immunity.

Administrative Core

Core Directors:
Hassane M. Zarour, MD (Co-Director)
John M. Kirkwood, MD (Co-Director)

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 Directors:
Theresa L. Whiteside, PhD (Co-Director)
Peter C. Lucas, MD, PhD (Co-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 Directors:
Daniel P. Normolle, PhD (Co-Director)
Riyue Bao, PhD (Co-Director)

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 Directors:
Walter J. Storkus, PhD (Co-Director)
Daniel P. Normolle, PhD (Co-Director)
Katherine M. Aird, PhD (Co-Director)
Hassane M. Zarour, MD (Co-Director)

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 Directors:
Walter J. Storkus, PhD (Co-Director)
Daniel P. Normolle, PhD (Co-Director)
John M. Kirkwood, MD (Co-Director)
Robert Binder, PhD (Co-Director)

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.