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Last Updated: 09/08/21

The University of Texas MD Anderson Cancer Center SPORE in Melanoma

The University of Texas MD Anderson Cancer Center

Principal Investigator(s):

Michael Davies, MD, PhD
Michael Davies, MD, PhD

Principal Investigator(s) Contact Information

Michael Davies, MD, PhD
Professor and Chair
Department of Melanoma Medical Oncology
The University of Texas MD Anderson Cancer Center
1515 Holcombe Blvd. Unit 430
Houston, TX 77030
(713) 792-3454

Overview

Melanoma is the deadliest form of skin cancer. Landmark genomic and immunologic studies have translated into the recently approved targeted and immune therapies for patients with metastatic disease. While targeted therapies achieve high response rates most responses are generally transient. Immunotherapies can achieve long-term responses but only in a subset of patients, and often with serious toxicities. Several key challenges remain to maximize the clinical benefit of immunotherapy: 1) poorly understood markers and mechanisms of resistance to immunotherapy, and a lack of effective strategies to overcome them; 2) limited experience or efficacy in patients with central nervous system involvement, a common metastatic site and cause of death for melanoma and other cancers; and 3) lack of benefit in patients with non-cutaneous melanomas, particularly the uveal melanoma subtype. The central hypothesis of this SPORE proposal is that an integrated analysis of immune and molecular features in patients with advanced melanoma will improve our understanding of response and resistance to immunotherapy, and lead to more effective treatments. To test this hypothesis, we will focus on the most critical unmet needs of melanoma patients, building on current immunotherapeutic strategies and developing our own novel concepts to identify more effective treatment options by:

  • Addressing resistance to the PD-1 immune checkpoint inhibitor through inhibition of the PI3K pathway in PTEN-null metastatic melanoma patients (Project 1).
  • Determining the clinical utility of PD-1 blockade using nivolumab administered intrathecally in metastatic melanoma patients with leptomeningeal disease (LMD) (Project 2).
  • Evaluating a new therapeutic strategy for uveal melanoma that uses adoptive cell therapy to target an immunogenic epitope of the melanosomal transport protein SLC45A2 (Project 3).

Three cores (Administrative Core, Clinical Database, Tissue Resource, and Translational Pathology Core [Core 2] and Biostatistics and Bioinformatics Core [Core 3]) provide specialized services to support our SPORE investigators and their proposed research studies. Together, these three projects and cores, and our Developmental Research and Career Enhancement Programs, will provide a comprehensive attack on critical unmet needs for patients battling these deadly manifestations of melanoma, and pave the way for other cancers with limited therapeutic options.

Project 1: Targeting the PI3K Pathway to Overcome Resistance to Immunotherapy in Melanomas with Loss of PTEN

Project Co-Leaders:
Michael Davies, MD, PhD
Hussein Tawbi, MD, PhD (Clinical/Applied)
Weiyi Peng, MD, PhD (Basic)

PTEN, a tumor suppressor that regulates the oncogenic PI3K-AKT signaling pathway, demonstrates complete loss of expression in up to 30% of these tumors. PTEN loss in melanomas increases the expression of immunosuppressive cytokines, decreases the intratumoral infiltration of critical effector T cells, causes resistance to T-cell mediated immunotherapy in vitro and in vivo, and correlates with worse outcomes with FDA-approved anti-PD-1 antibodies in stage IV patients. Treatment with GSK2636771, an isoform-specific inhibitor of PI3Kβ, decreased AKT activation, increased T cell infiltration, and increased the efficacy of anti-PD-1 in vivo in an immunocompetent model of PTEN-null, PD-1-resistant melanoma, and did not harm the viability or function of immune cells. Based on these studies, we are conducting a phase I/II clinical trial of GSK2636771 in combination with the anti-PD-1 antibody pembrolizumab in metastatic melanoma patients with PTEN loss that failed to respond to anti-PD-1. Blood and tumor samples will be collected prior to and during treatment as well as at progression. In Aim 1 we will determine the effects of this treatment on the activation of the PI3K-AKT pathway, and the relationship between pathway inhibition, GSK2636771 steady-state levels, and treatment outcomes. In Aim 2 we will evaluate the immune effects of the combination treatment by evaluating tumor and blood samples, with results compared to clinical responsiveness. In Aim 3 we will use preclinical models to evaluate intermittent dosing and combinatorial approaches with additional isoform-selective PI3K inhibitors as strategies to further improve the efficacy of GSK2636771 with anti-PD-1. These studies will improve our understanding of the role of the PI3K-AKT pathway in immunotherapy resistance and identify additional strategies for future testing in cancers with PTEN loss.

Project 2: Intrathecal Anti-PD-1 Immunotherapy for Metastatic Melanoma Patients with Leptomeningeal Disease (LMD)

Project Co-Leaders:
Isabella Glitza Oliva, MD, PhD (Clinical/Applied)
Jennifer Wargo, MD, MMSc (Basic)
Amy Heimberger, MD

Antibodies that inhibit PD-1 on the surface of T cells have revolutionized the treatment and outcomes of patients with metastatic melanoma. However, metastasis to the central nervous system (CNS) remains a common and devastating complication of advanced melanoma, and the CNS is a frequent site of treatment failure for current therapies. In particular, there are very poor outcomes and limited treatment options for patients that develop leptomeningeal disease (LMD). LMD can cause significant neurological deficits, and the median survival for melanoma patients with LMD is less than 2 months. Our unique and long-term experience with intrathecal IL2 (IT IL2) has demonstrated that intrathecal immunotherapy can achieve durable disease control and survival in a subset of melanoma patients with LMD. However, long-term survival with IT IL2 is rare, and treatment-related toxicity with IT IL2 is universal. We hypothesize that IT administration of anti-PD-1 will be safe and induce an anti-tumor immune response in the CSF in metastatic melanoma patients with LMD. In Aim 1 we will conduct a novel phase I/Ib study to determine the safety and maximum tolerated dose of combined IT and intravenous (IV) administration of the anti-PD-1 antibody nivolumab in metastatic melanoma patients with LMD. In Aim 2, CSF and blood collected from patients in the trial at multiple timepoints will be analyzed for immune cell subsets and cytokines to characterize the effects of IT + IV nivolumab treatment. In Aim 3, cell-free tumor DNA (ctDNA) isolated CSF and blood will undergo next generation sequencing (NGS) to detect and quantify somatic mutations to evaluate changes in mutation burden and profile over time, and to compare mutations detected in the CSF to those detected in blood and in tumor tissue. Together these studies address an unmet clinical need for new treatment options for melanoma patients with LMD, and to improve our understanding of the molecular and immune features of this aggressive disease.

Project 3: Immunotherapeutic Targeting of SLC45A2 for Treatment of Uveal Melanoma

Project Co-Leaders:
Cassian Yee, MD (Clinical/Applied)
Greg Lizée, PhD (Basic)
Sapna Patel, MD (Clinical/Applied)

The development of effective therapy for advanced uveal melanoma remains an unmet need. Our group has demonstrated that adoptively transferred cytotoxic T lymphocytes (CTL) can induce durable clinical responses in patients with cutaneous melanoma, particular in patients with long-term persistence of the transferred cells. We have accordingly developed an in vitro process using IL-21 to generate long-lived central memory-type T cells. Following our identification of an epitope of the melanoma-associated transporter protein SLC45A2 that is highly expressed in uveal melanoma cells but not in normal melanocytes and capable of eliciting a potent cytotoxic response against uveal melanoma cell lines, we will evaluate this epitope and search for others within the same protein that can mediate adoptively transferred CTL-driven uveal melanoma disease regression. We propose a Phase I study to determine the safety and efficacy of CTL targeting SLC45A2 in patients with metastatic uveal melanoma. This study includes a dose- escalation cohort of SLC45A2-specific CTL primed by IL-21, followed by an expansion cohort of the same CTL in combination with ipilimumab. We will measure in vivo persistence of transferred SLC45A2-specific T cells at weekly intervals and correlate with clinical response, and additionally assess induction of a multivalent T cell response through antigen-spreading. Finally, in an effort to expand the number of melanoma patients eligible for SLC45A2-targeted immunotherapy, we will, 1) identify additional epitopes from this protein that may be presented by other prevalent HLA class allotypes, and 2) search for HLA class II-restricted peptides from SLC45A2 to boost helper T cell-mediated amplification of the anti-tumor immune response. These studies represent a critical new avenue for uveal melanoma treatment using targeted immunotherapy, which holds the potential to improve patient survival for this challenging malignancy.

Administrative Core

Core Directors:
Michael Davies, MD, PhD
Elizabeth A. Grimm, PhD
Jeffrey E. Lee, MD

The Administrative Core (Core 1) will be responsible for the successful execution and management of all SPORE activities related to financial oversight and coordination, organization of all necessary meetings, and publicity and record keeping for all projects and the two other cores. This group will also provide regulatory oversight activities for clinical trials; ensure compliance with all institutional, federal, and NCI-specific regulations; and oversee the peer-review and oversight processes of the Career Enhancement Program and Developmental Research Program.

Melanoma Clinical Database, Tissue Resource, and Translational Pathology Core (MELCORE)

Core Directors:
Jeffrey Gershenwald, MD
Victor Prieto, MD, PhD
Michael Davies, MD, PhD
Alexander Lazar, MD, PhD
Jennifer Wargo, MD, MMSc

The primary goal of the MD Anderson SPORE in Melanoma is to translate our fundamental understanding of melanoma into improved patient care by improving melanoma prevention, detection, and therapy. Building upon this experience and to further this goal, it is essential to continue to conduct high-impact, well-planned, translational research involving well-annotated curated biospecimens and relevant clinical data to identify the pathophysiologic mechanisms of melanoma and the metastatic cascade, identify biomarkers and targets for antitumor therapy, and evaluating the mechanisms of response and resistance in new treatment strategies. The Melanoma Clinical Database, Tissue Resource, and Translational Pathology Core (Core 2) will be a resource for clinicopathologic data, well-annotated biospecimens, and for optimized acquisition, processing, distribution and analyses that facilitate integration of conventional biomarkers, molecular and immunologic data, with clinicopathologic, treatment, recurrence and follow-up. Overall, these approaches will facilitate the discovery of clinically impactful predictive and prognostic biomarkers, as well as enhanced approaches to anti-tumor therapy across several clinically unmet needs for patients with melanoma.

Biostatistics and Bioinformatics Core

Core Directors:
J. Jack Lee, PhD
Han Liang, PhD

The Biostatistics and Bioinformatics Core 3 provides comprehensive service to guide design of experiments, to optimize quantitative data analysis, and to maintain statistical justification and interpretation of results. Specifically, Core 3 will implement sound experimental design principles that are tailored to address specific scientific questions for each project. Core 3 will also carry out data analyses using suitable statistical methods and bioinformatics algorithms, and will contribute to the interpretation of results through written reports and frequent interactions with project investigators. Whenever appropriate, Core 3 will develop new analysis tools to address new challenges in the analysis of various data, especially high-throughput genomic and proteomic data. Members of Core 3 will participate in monthly SPORE meetings with all project investigators, ensuring that statistical and data analysis/management issues are carefully considered during all phases of each SPORE experiment. Thus, from inception to reporting and publication, basic laboratory and translational experiments will benefit from the SPORE program that will be used to augment existing MD Anderson Cancer Center biostatistics resources.

Developmental Research Program

Program Directors:
Elizabeth A. Grimm, PhD
Jeffrey E. Lee, MD
Jennifer Wargo, MD, MMSc

The Developmental Research Program is designed to solicit, evaluate, and award funds to support novel projects focused on melanoma biology, prevention, and patient treatment. This program will span the full duration of the parent grant, aiming to supporting at least three one- to two-year awards per year at a maximum of $50,000/year for each award. Awardees are expected to present their research at our research seminars and be included in all activities as part of our effort to develop additional novel projects and approaches. SPORE leaders will help develop successful projects into full grants or future SPORE projects. Our scope includes both cutaneous and uveal melanoma.

Career Enhancement Program

Program Directors:
Elizabeth A. Grimm, PhD
Jeffrey E. Lee, MD
Jennifer Wargo, MD, MMSc

Based on our experience in developing the careers of melanoma investigators, our Career Enhancement Program will continue aggressively to recruit junior as well as established faculty members for a melanoma career focus with special emphasis on the inclusion of qualified minorities and women, to become leaders in melanoma research. We will provide at least one year of career and research mentorship (clinical- and/or laboratory-based, as appropriate for that person), which will be coordinated by Dr. Grimm for laboratory projects, and Dr. JE Lee for clinical research. Individualized career enhancement plans may include didactic courses, melanoma seminars and rounds, grant-writing and protocol development, attendance at national melanoma and/or cancer meetings, and completing and publishing a translational melanoma cancer research project. We will monitor the success of our awardees and provide long-term mentorship support and advocacy even after the funding for the specific Career Enhancement Program funding ends.