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Funded Research

Pilot Trial of Tumor Infiltrating Lymphocytes for Melanoma Brain Metastasis

Pilot Trial of Tumor Infiltrating Lymphocytes for Melanoma Brain Metastasis

Pilot Trial of Tumor Infiltrating Lymphocytes for Melanoma Brain Metastasis

Allison Betof Warner, MD, PhD

Mentor Jedd Wolchok, MD, PhD; Mike Postow, MD
Award Type Career Development Award
Institution Memorial Sloan Kettering Cancer Center
Donor Support Silverstein Family Research Grant Challenge Women in Science

 

Melanoma brain metastases (MBM) are a leading cause of morbidity and mortality for patients with advanced disease. Modern systemic therapies do not adequately control brain metastases. For patients whose disease has progressed on standard immunotherapy and targeted therapy (if appropriate), there are no approved treatments that have demonstrated efficacy against MBM. Little is known about the mechanisms of MBM growth or treatment resistance. Few new treatment approaches are on the horizon, as patients with MBM are frequently excluded from clinical trials.

A new type of immunotherapy using tumor infiltrating lymphocytes (TIL) has demonstrated efficacy in advanced melanoma. Lifileucel, an drug made from patients’ own T cells, was recently shown to be safe and effective in patients with melanoma that has progressed on standard immunotherapy and targeted therapy. These promising preliminary results have been met with great enthusiasm for TIL therapy as a potential approach for melanoma that has progressed after immunotherapy treatment. Follow-up studies are ongoing with expectation of FDA approval within the next year. Participants with active MBM were excluded from lifileucel trials to date, so the feasibility and safety of lifileucel are unknown in this population. Only a small number of patients with active MBM have been treated with any type of TIL therapy. To address the critical need for therapeutic options and deeper biological understanding of MBM, we propose a pilot study to rigorously define the feasibility of treating patients with MBM with lifileucel.

This will be the first study to evaluate lifileucel for active MBM. Establishing feasibility and safety of this approach could rapidly lead to larger phase II efficacy and combination trials, which have the potential to change treatment paradigms and improve outcomes from this dreaded complication of melanoma. We have proposed extensive correlative analyses using blood and cerebrospinal fluid (CSF) to enhance our mechanistic understanding of the biology driving the growth and treatment resistance of brain metastases and what changes occur during the course of cell therapy treatment.

Treatment of MBM, particularly after progression on standard immunotherapy treatments, is one of the most urgent unmet needs in the therapy of melanoma. Successful completion of this trial and the correlative studies could improve clinical management of this morbid complication of melanoma and inform decision-making for further cellular therapy approaches in MBM and other cancers that metastasize to the brain.

Melanoma Immunotherapy with GPR182 blockade

Melanoma Immunotherapy with GPR182 blockade

Melanoma Immunotherapy with GPR182 blockade

Yuwen Zhu, PhD

Award Type Mid-Career Bridge Grant
Institution University of Colorado Denver

Description:

Immune checkpoint inhibitor therapy has greatly improved survival of patients with late-stage melanoma. However, about 2/3 of patients do not benefit from this therapy. One of the main hurdles is that many melanoma tissues lack effector CDS+ T cell infiltrates. Chemokines such as CXCL9 and CXCL 10 play an important role in regulating T cell infiltration into the tumors. Atypical Chemokine Receptors are a group of GPCR proteins that are expressed in non-immune cells to actively clear chemokines by endocytosis. Our studies uncovered GPR182 as a novel ACKR receptor selectively upregulated in peritumoral lymphatics. Our preliminary results indicated that ablation of this molecule in mice leads to increased effector T cell infiltration and thereby the retardment of tumor growth in several mouse melanoma models. We further found that GPR182 interacts with chemokines broadly In vitro and blockade of CXCR3 completely abolished improved antitumor immunity in GPR182-deficient mice. Here we hypothesize that GPR182 inhibits anti-tumor immune response by limiting chemokine availability and targeting this pathway will offer a novel approach to converting immunologically cold melanoma to hot ones. We will dissect the molecular interaction between GPR182 and chemokines, and also examine the chemokine endocytosis by GPR182 with tumors. The mechanisms by which GPR182 inhibits antitumor T cell response w II be investigated. Finally, the in vivo antitumor effect of a peptide, which blocks the interaction between GPR182 and chemokines, will be optimized. By the completion of these studies, we will identify a new strategy of inflaming Immunologically cold melanoma and will have a better understanding of the immunomodulatory role of the lymphatics in melanoma.

Exhausted CD8 T cells as an early indicator of lymph node metastasis and the need for adjuvant therapy in Stage II melanoma

Exhausted CD8 T cells as an early indicator of lymph node metastasis and the need for adjuvant therapy in Stage II melanoma

Exhausted CD8 T cells as an early indicator of lymph node metastasis and the need for adjuvant therapy in Stage II melanoma

Alexander C. Huang, MD

Co-PI Ramin Herati, MD; John Muira, MD
Mentor Ravi Amaravadi, MD
Award Type Team Awards
Institution University of Pennsylvania
Donor Support MRF Breakthrough Consortium-Bristol Myers Squibb Young Investigator Research Team Award to Advance the Field of Translational Immuno-Oncology

Description:

Immunotherapy has been shown to be effective in treating melanoma, even at an early stage of disease. Patients with Stage II melanoma are now able to receive a class of medicines known as anti-PD-1 therapy, that boost the immune system’s fight against cancer following surgical removal of the tumor. Because most patients are cured after surgery alone, the challenge is to determine who really needs immunotherapy versus those who might get medicine they do not need and risk complications from the medicine. We seek to study the immune cells in the sentinel lymph node and in the blood to test whether these immune cells can serve as cellular “beacons” to indicate the presence of otherwise undetected residual tumor, which would help us identify who would benefit the most from immunotherapy. We will also determine if we can link immune cells in the blood to the cellular “beacons” in the sentinel lymph node and thus be able to monitor the effectiveness of immunotherapy. Together, these data will help us determine who is best served by immunotherapy, potentially opening the door to opportunities for better survival and fewer complications.

Identification of angiopoietin-2/Tie signaling molecules as a predictive biomarkers for ICI resistance in melanoma

Identification of angiopoietin-2/Tie signaling molecules as a predictive biomarkers for ICI resistance in melanoma

Identification of angiopoietin-2/Tie signaling molecules as a predictive biomarkers for ICI resistance in melanoma

Minah Kim, PhD

Award Type Pilot Proposal
Institution Columbia University
Donor Support MRF Breakthrough Consortium Pilot Translational Award

Description:

Although immune checkpoint inhibitors (ICI) such as programmed death-1 (PD-1) blockade have made meaningful advances in the treatment of melanoma, drug resistance has limited their therapeutic efficacy as approximately 70% of patients still experience disease progression within 5 years. Therefore, understanding mechanisms of ICI therapy resistance and identification of biomarkers for predicting response to ICI treatment are unmet needs. Along with new blood vessel formation in the tumor by angiogenic factors, vascular destabilization is recognized as a hallmark of tumor growth and metastasis. Emerging evidence suggests a fundamental link between tumor vascular abnormalities and ICI therapy resistance whereby vascular destabilization impairs the immune cell infiltration to the tumor and promotes and immune evasion. Consistently, recent clinical and preclinical evidence has highlighted the importance of targeting proangiogenic factors to improve immunotherapy efficacy in cancer. Angiopoietin-2 (Ang2), which binds to the receptor tyrosine kinase Tie2, is a potent vessel-destabilizing factor and its upregulation correlates with poor prognosis and disease progression in many types of tumors. Building on our previous work on Ang2/Tie signaling in the tumor microenvironment, in this project we propose to identify Ang2/Tie signaling molecules as predictive biomarkers for immune evasion and ICI therapy resistance in melanoma. Successful completion of this project could significantly enhance the clinical management in patients with melanoma receiving ICI therapy.

Racial, Sex, and Socioeconomic Inequities in Melanoma Surgical Interventions & Outcomes: A Multivariate Analysis

Racial, Sex, and Socioeconomic Inequities in Melanoma Surgical Interventions & Outcomes: A Multivariate Analysis

Racial, Sex, and Socioeconomic Inequities in Melanoma Surgical Interventions & Outcomes: A Multivariate Analysis

Rewan Abdelwahab

Mentor Addison Demer, MD
Award Type Medical Student Award
Institution Mayo Foundation for Medical Education and Research
Donor Support Honoring Richard Arthur Draeger from his Family

Description:

Background: Racial inequities in melanoma survival have been documented in the literature. The largest Black-white difference in overall cancer survival is for melanoma and has been worsening in recent years. Surgery remains the standard of care for localized, primary cutaneous invasive melanoma.

Objective: To determine if differences in the time to intervention, surgical approaches, and surgical outcomes may contribute to the current, stark disparities in melanoma survival outcomes between non-Hispanic white and Black individuals.

Methods: Analysis of melanoma data from the National Cancer database from 2008 to 2017. The national cancer database is part of an ongoing collaboration between the Commission on Cancer of the American College of Surgeons and the American Cancer Society and is the largest clinical registry world, capturing
most of the cancer diagnosis in the United States.

Results: Controlling for other confounding factors such as type of melanoma, thickness of tumor, type of medical institutions among others, we seek to determine if differences exist in time to intervention, post-operative complications, and use of surgical techniques between non-Hispanic white and Black individuals.

Limitations: Database study, limited data on racial minority patients in database. Observational studies and retrospective analyses cannot prove causation but rather reveal correlations that may ultimately highlight areas of future study.

Conclusions: By identifying differences in melanoma surgical treatment among patients of varying racial/ethnic backgrounds, we ultimately hope to promote improved patient outcomes and reduce melanoma mortality through research-based interventions.