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Last Updated: 08/23/19

MD Anderson SPORE in Melanoma

University of Texas/MD Anderson Cancer Center

Principal Investigator:
Patrick Hwu, MD

PRINCIPAL INVESTIGATOR CONTACT INFORMATION

Patrick Hwu, MD
Professor and Division Head
Division of Cancer Medicine
The University of Texas MD Anderson Cancer Center
1515 Holcombe Blvd.
Unit 430
Houston, TX 77030-4009
Phone: 713-563-1728
Email: phwu@mdanderson.org

OVERVIEW

Melanoma is the deadliest form of skin cancer, with an increasing incidence and mortality, and a 5-year survival rate less than 20% for patients with metastatic disease. Several recent landmark genomic and immunologic studies have generated important new insights into the pathogenesis, drivers, and regulators of this disease, translating into the approval of both targeted and immune therapies for patients with metastatic disease. While targeted therapies have achieved high response rates, they are generally transient; likewise, immunotherapies bring about dramatic, long-term, complete responses but only in a subset of patients and often with serious toxicities. Despite the progress that has been made, several key challenges remain to maximizing 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 any benefit from single-agent immunotherapies 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 pursuing the following specific aims:

  • Address resistance to the PD-1 immune checkpoint inhibitor through inhibition of the PI3K pathway in PTENnull metastatic melanoma patients (Project 1).
  • Determine the clinical utility of PD-1 blockade using nivolumab administered intrathecally in metastatic melanoma patients with leptomeningeal disease (Project 2).
  • Evaluate a new therapeutic strategy for uveal melanoma that uses adoptive cell therapy to target an immunogenic epitope of 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 (Clinical/Applied)
Hussein Tawbi, MD, PhD (Clinical/Applied)
Weiyi Peng, MD, PhD (Basic)

Cutaneous melanomas (CM) have a very high rate of somatic mutations, and oncogenic drivers are identified in the majority of patients. PTEN, a tumor suppressor that regulates the oncogenic PI3K-AKT signaling pathway, demonstrates complete loss of expression in up to 30% of these tumors. Our previous studies showed that loss of PTEN is associated with shorter overall survival in stage III melanoma patients, and with inferior outcomes with targeted therapies in patients with stage IV disease. Building upon these studies, recently we investigated the impact of PTEN loss on the anti-tumor immune response and immunotherapy. Initial preclinical studies demonstrated that loss of PTEN in melanomas increases the expression of immunosuppressive cytokines, decreases the intratumoral infiltration of critical effector T cells, and causes resistance to T-cell mediated immunotherapy in vitro and in vivo. Analyses of cohorts of advanced melanoma patients showed that loss of PTEN was associated with decreased CD8+ T cell infiltration in stage III melanoma patients, and significantly decreased response rates to FDA approved anti-PD-1 antibodies in stage IV disease. Treatment with GSK2636771, an isoform-specific inhibitor of PI3Kβ, decreased AKT activation, increased T cell infiltration, and increased the efficacy of anti-PD-1 checkpoint inhibitor therapy in vivo in an immunocompetent model of PTEN-null, PD-1-resistant melanoma. Notably, GSK2636771 did not harm the viability or function of immune cells, consistent with the selective dependence on PI3Kβ in cells with PTEN loss. Based on these studies, we hypothesize that inhibition of the PI3K-AKT pathway will overcome resistance to anti-PD-1 immunotherapy in melanomas with loss of PTEN. To test this hypothesis, and address the unmet need for effective therapies for PD-1-refractory patients, 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 to improve our understanding of the effects of this regimen and the results of the trial. 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 for the presence and changes in immune cell subsets and immunoregulatory cytokines, which will also be 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 the anti-tumor immune response and immunotherapy resistance and help identify additional rational strategies for future testing in this and other cancers with PTEN loss.

PROJECT 2: INTRATHECAL ANTI-PD-1 IMMUNOTHERAPY FOR METASTATIC MELANOMA PATIENTS WITH LEPTOMENINGEAL DISEASE (LMD)

Project Co-Leaders:
Patrick Hwu, MD (Basic)
Amy Heimberger, MD (Clinical/Applied)
Isabella Glitza Oliva, MD, PhD (Clinical/Applied)

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. There are multiple treatment options for melanoma patients with parenchymal brain metastases. In contrast, there are very few 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. Thus, there is a critical unmet need to develop more effective treatments for patients with LMD from melanoma. Previous experience with trastuzumab and rituximab in breast cancer and lymphoma, respectively, have demonstrated that intrathecal (IT) administration of cancer therapies can increase drug levels in the cerebrospinal fluid (CSF) and clinical benefit in patients with LMD. Our unique and long-term experience with intrathecal IL2 (IT IL2) has similarly 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. Thus, there remains an unmet need for therapies for LMD that are more active and less toxic. We hypothesize that IT administration of anti-PD-1 antibodies will be safe and induce an anti-tumor immune response in the CSF in metastatic melanoma patients with LMD. In order to test this hypothesis, 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. This is trial, which has recently been approved by the FDA, will be the first to assess the safety of IT anti-PD-1, and it represents an important new option for 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. The results will be analyzed to characterize the effects of IT + IV nivolumab treatment, and to improve our understanding of the immune microenvironment of the CSF. In Aim 3, cell-free tumor DNA (ctDNA) isolated CSF and blood will undergo next generation sequencing (NGS) to detect and quantify somatic mutations. Results will be used 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. The results of these studies will also provide important information to prioritize and optimize future trials for patients with LMD from melanoma and other cancer types.

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)

While novel immunotherapy regimens show promise in treating cutaneous melanoma, effective therapies for advanced uveal melanoma remain a clear unmet need in the field for a disease that is highly treatment refractory and leads to dismal patient survival rates. Adoptive cell therapy (ACT) is a form of immunotherapy with strong potential to improve the outcome for uveal melanoma patients. ACT involves the ex vivo isolation and expansion of antigen-specific, tumor-reactive T cells that are infused into the patient with the aim of mediating disease regression and maintaining a durable response. Our group has demonstrated that longer persistence of adoptively transferred cytotoxic T lymphocytes (CTL) in patients with cutaneous melanoma correlates with improved clinical response, and we have accordingly developed an in vitro process using IL-21 to generate long-lived central memory-type T cells whose in vivo survival extends up to years from the time of infusion. Following our crucial 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. Specifically, we propose a Phase I study in which we will determine the safety and clinical efficacy of ACT targeting SLC45A2 in patients with metastatic uveal melanoma. This study will include a dose- escalation cohort of SLC45A2-specific CTL primed by IL-21 to enrich for central-memory-like CD8 T cells, followed by an expansion cohort of the same CTL at a dose without limiting toxicities in combination with CTLA4 blockade (ipilimumab). We have previously demonstrated the ability of this combination to achieve complete, durable responses with strong T cell persistence and antigen-spreading in refractory metastatic melanoma. To evaluate the study, 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.

CORE 1: ADMINISTRATIVE CORE

Core Directors:
Patrick Hwu, MD
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. The core will be led by Drs. Patrick Hwu, Elizabeth Grimm, and Jeffrey Lee.

CORE 2: MELANOMA CLINICAL DATABASE, TISSUE RESOURCE AND TRANSLATIONAL PATHOLOGY CORE (MELCORE)

Core Directors:
Jeffrey Gershenwald, MD
Victor Prieto, MD, PhD

Over the past 15 years, the primary goal of the MD Anderson SPORE in Melanoma has been 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 maintain a comprehensive, prospective, relational database containing detailed clinical, pathologic, and outcome data for patients with melanoma seen and treated at MD Anderson. Core 2 will also procure and process tissue, blood, and cerebrospinal fluid specimens in support of the SPORE Projects, and will facilitate the downstream analysis for histopathologic features, including immunohistochemistry with image analysis and molecular analysis of prospectively collected melanoma specimens as well as archival material. A noteworthy addition for the current SPORE submission is the development and integration of the uveal melanoma database module as well as the addition of an automated request module for sample distribution to facilitate all SPORE-based and other research projects. The current proposal includes expanded efforts and infrastructure to support the optimization of fresh tissue collection and processing of distant metastases from image- guided biopsies, analyte (DNA, RNA, protein) extraction from prospectively collected and archival tissue samples suitable for molecular and immunological interrogation, and the conduct of NanoString gene expression profiling. The samples and/or analytes isolated from biospecimens will be distributed to SPORE projects and other investigators in accordance with our Core operating procedures, and Core 2 will work with each of the SPORE projects, CCSG Cores, collaborator laboratories, and with the Administrative and Biostatistics Cores, to ensure maximum efficiency of tissue/derivatives. Together, 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. This centralized resource will contribute significantly to the success of the multidisciplinary and translational research projects outlined in this proposal.

CORE 3: 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

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

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

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

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.