Resident/Fellow Award – Melanoma Research Foundation

OPRM1 AND CD8+ T-CELL SPATIAL DISTRIBUTION IN ADVANCED CUTANEOUS MELANOMA

kaleandflax — Wed, 27 May 2026 19:32:16 +0000

Immunotherapy has greatly improved treatment for people with advanced cutaneous melanoma, but many patients either do not respond or stop responding over time. One important reason for this failure is that the body’s immune cells are unable to reach and attack the cancer. In some melanomas, cancer-fighting CD8 T cells are present near the tumor but remain stuck outside the cancer cell clusters instead of entering them. This pattern, known as immune exclusion, is linked to poor responses to immunotherapy, yet the reasons it occurs are not well understood.

This project focuses on a gene called OPRM1, which produces the mu-opioid receptor. While this receptor is best known for its role in pain control, recent research suggests it may also influence how the immune system behaves in cancer. Laboratory studies show that opioid signaling can weaken immune responses against tumors, and blocking this pathway may help immune cells function more effectively. However, in human melanoma, it is not known whether OPRM1 plays a role in keeping immune cells away from cancer cells.

Using stored tumor samples from patients with advanced melanoma, this study will examine where immune cells are located in relation to melanoma cells and measure OPRM1 levels within the tumor. Advanced imaging methods will allow us to determine whether tumors with higher OPRM1 expression are more likely to keep immune cells at a distance from the cancer.

By identifying a possible biological reason why immune cells fail to reach melanoma tumors, this research aims to improve understanding of immunotherapy resistance and support the future development of treatment strategies that help the immune system more effectively target melanoma, particularly for patients with limited remaining options.

Non-invasive Assessment of Response to Neoadjuvant Therapy in cN+ Melanoma

kaleandflax — Wed, 27 May 2026 19:32:01 +0000

Why This Research Matters
Recent advances in melanoma treatment use drugs called checkpoint inhibitors before surgery to help the immune system attack cancer. This approach, known as neoadjuvant therapy, works better than surgery followed by treatment afterward. About 60% of patients have an excellent response, meaning little to no cancer remains. Currently, doctors must surgically remove lymph nodes to determine how well treatment worked, which can lead to complications such as fluid buildup, infection, and nerve injury. If treatment response could be assessed without major surgery, many patients could avoid these risks.

What We Are Studying
This study will test less invasive ways to measure treatment response. A core needle biopsy uses a small needle to collect tiny tissue samples and is a minor procedure. We will compare biopsy results to full lymph node analysis, the current standard. We will also evaluate whether imaging scans and blood tests can help predict response.

How the Study Works
Patients with melanoma involving lymph nodes will receive standard checkpoint inhibitor therapy for six weeks, followed by planned surgery to remove the lymph nodes. Before the lymph node is sent to the pathology lab, small tissue samples will be collected using a needle. Pathologists will assess both the needle samples and the entire lymph node to measure remaining cancer. Blood samples and imaging scans will be collected before and after treatment to determine whether response can be predicted without tissue sampling.

Expected Impact
If needle biopsies are accurate, many patients could avoid extensive lymph node surgery. Patients who respond well may skip additional surgery or treatment, reducing complications and improving quality of life, while non-responders could transition quickly to more intensive therapies. This study will provide key data to support larger trials that could make melanoma care safer and more personalized.

Complete response in patients with advanced melanoma treated with ICIs

kaleandflax — Wed, 27 May 2026 19:31:49 +0000

Immunotherapy, a novel form of cancer treatment that boosts a person’s own immune system to fight cancer cells, has revolutionized care for patients with melanoma and has helped them live significantly longer. People who respond well to immunotherapy tend to have long lasting responses; however, there are people who still end up having their disease come back. In addition, there are also side effects associated with immunotherapy that can be permanent and life-threatening. There are single drug immunotherapies and there are combination immunotherapies given for melanoma, each with a different risk profile for chances of side effects and a different likelihood of response.

Our goal is to characterize the patients here at our cancer center who have received immunotherapy as their first treatment for advanced stage melanoma. Our hypothesis is that patients who respond very well to immunotherapy will have long lasting responses regardless of the amount of immunotherapy they get after they have a good response. We aim to capture information regarding the type of immunotherapy they have gotten, how long they have been receiving the therapy for, any side effects they may have developed from the treatment, and whether their disease came back, either after discontinuing treatment or while they were on treatment. We will compare patients who have had their disease come back after treatment to those patients who did not to see if there are any differences in characteristics of their melanoma. We are also interested in exploring whether these patient’s original tumors contain any information about their immune cells that may help guide likelihood of having side effects to immunotherapy. This information will help us better understand how long we should be continuing these treatments for and balancing the risks of developing serious side effects in order to improve care for patients with melanoma.

Optimizing circadian rhythms and immunotherapy outcomes via light therapy

kaleandflax — Wed, 27 May 2026 19:31:38 +0000

Cancer can evolve to hide from the immune system by putting “brakes” on how the body searches for abnormal cells. Immunotherapy (IO) is a treatment that releases these brakes to activate the immune system to destroy cancer cells. Melanoma, an aggressive skin cancer, and the most common type of lung cancer (non-small cell lung cancer) are particularly sensitive to IO and survival has improved since IO came into use. Since not all patients respond and responses don’t always last, we are exploring ways to increase IO effectiveness.

Recent studies show IO can be more effective when given in the morning instead of later in the day and that immune system activity is controlled by a person’s circadian rhythm (CR), or the internal clock that controls body functions like sleep. Cancer patients can have dysregulated CR, which has been associated with poorer survival. We are studying how modifying the CR of patients might improve responses to IO.

The external factor that most influences CR is light. There is evidence for the beneficial effects of bright light therapy (BLT) in cancer patients for improving symptoms like fatigue. We do not yet know how BLT can affect IO outcomes, so our study aims to show that BLT is feasible and safe in patients starting IO. We will deliver BLT via an easy-to-use iPad app called Circadian OS, which emits light while patients use the iPad as they normally would (browsing the Internet, checking email, streaming content, etc.). Patients will be asked to use BLT for 60 minutes daily for at least 7 days before their first IO treatment. We will also collect blood and urine to inform us on how BLT might affect patients’ CR and immune systems. Once we demonstrate BLT is feasible and safe, we will be able to design a larger study that compares IO outcomes in patients who receive BLT and patients who do not to see if BLT helps. Our ultimate goal is to improve the effectiveness of IO with a simple tool that patients can use at home.

Sex-Specific Mechanisms of Immune Evasion in Cutaneous Melanoma

kaleandflax — Wed, 27 May 2026 19:31:25 +0000

Melanoma remains a critical health challenge where a significant disparity exists: men experience worse survival rates than women. Even when diagnosed at the same stage and treated with identical immunotherapies, male patients are less likely to respond. This suggests that current “one-size-fits-all” treatments fail to account for fundamental biological differences in the male immune system. A central paradox is that male tumors often carry more mutations. Biologically, high mutation rates usually make cancer easier for the immune system to detect because the cells look more “foreign.” Yet, the male immune response is frequently suppressed. My research proposes that this is due to “alternative brakes”—distinct molecular checkpoints (like VISTA or LAG3) that male tumors activate to shut down immune cells. Because standard therapies (like anti-PD1) do not target these specific male-biased brakes, the immune system remains paralyzed. To solve this, I will use advanced computational analysis of Single-Cell RNA Sequencing data. Historically, cancer research treated tumors like a “smoothie,” blending all cells together to get an average measurement that obscures critical details. My project treats the tumor like a “fruit salad,” analyzing thousands of individual cells to uncover the rare, specific defects in the male immune environment that are invisible to standard bulk sequencing. This high-resolution approach allows me to: 1. Identify the specific immune cells in men that are “exhausted” or inactive. 2. Map the chemical signals the tumor uses to suppress them. 3. Develop a “Male Resistance Score” to predict which patients are at high risk of treatment failure. By understanding these sex-specific mechanisms, we can move toward true personalized medicine. This research could eventually save patients from wasting months on ineffective therapy, guiding them instead toward drug combinations tailored to their specific biological sex.

Vision Loss After Plaque Radiotherapy for Posterior Uveal Melanoma

kaleandflax — Wed, 27 May 2026 19:31:09 +0000

Uveal melanoma is the most common cancer that arises inside the eye. Today, most patients are treated with plaque radiotherapy, a highly effective form of targeted radiation that saves the eye and controls the tumor. While this treatment is life-saving, many patients experience gradual and sometimes severe vision loss in the treated eye, which can affect daily activities, independence, and overall quality of life.

A loss of 15 or more letters on a standard eye chart represents a meaningful decline in vision that patients can notice in everyday tasks such as reading, driving, or recognizing faces. Although this level of vision loss is widely used in clinical trials and by regulatory agencies, little is known about when it typically occurs and which patients are at highest risk after treatment for ocular melanoma.

This project studies vision outcomes in a large group of 4,000 patients who were treated with plaque radiotherapy for uveal melanoma before the routine use of modern vision-protecting injections. By carefully analyzing long-term vision changes, we aim to understand how often significant vision loss occurs, how soon after treatment it develops, and how tumor size and treatment factors influence this risk.

The results of this study will help doctors provide clearer and more personalized information to patients at the time of diagnosis. It will also provide a critical comparison point for newer treatments designed to reduce vision loss after radiation therapy. Ultimately, this work supports the goal of not only saving patients’ lives but also preserving their vision and quality of life.

Targeting developmental lineage programs in melanoma

kaleandflax — Wed, 27 May 2026 19:30:46 +0000

Melanoma is a cancer derived from melanocytes, the pigment cells of the skin and other tissues. In addition to mutations, melanoma formation requires the expression of genes reminiscent of early melanocyte development. Previous work has shown that blocking these genes can prevent melanomas from forming. However, it remains unclear what the impact of blocking these genes would be once the melanoma is already established. This proposal aims to ask questions that are both fundamental and clinically relevant: What happens to melanoma cells when they suddenly lose the genes that make them a melanoma? Would the loss of melanoma-defining genes force the melanoma cells to stop proliferating and die or does it push the melanoma cells to become an entirely different kind of cancer? So far research into these questions has been limited by the lack of systems to simulate treating a patient who presents with advanced melanoma. To do this, we propose using a combination of cell lines made from patient tumors and also stem cell-based approaches that would allow us to suddenly shut off the genes specific to melanocyte development that are needed for melanoma formation. By creating these models, we hope to evaluate the therapeutic potential of targeting these genes. The patient derived cell lines help take advantage of the unique diversity of each patient to ensure our studies are reproducible and applicable to a wide variety of melanoma phenotypes. The stem cell system would allow us to mimic early melanocyte development and by extension more precisely understand the way melanoma cell identity is regulated. Together, we expect these approaches will be complementary and help comprehensively define a new way to treat melanoma – one that aims to block the genes that constitutes cancer cell identity.

Reprogramming Melanoma Tumor Microenvironment by Intratumoral Flu Vaccine a

James Merrick — Wed, 27 May 2026 19:30:33 +0000

Melanoma is the fifth most common cancer and is the deadliest form of skin cancer. While new immunotherapies called “checkpoint inhibitors” have revolutionized treatment, only about 30% of patients experience long-lasting benefit. Many tumors create a hostile environment that shields cancer cells from the immune system by recruiting suppressive cells and exhausting the T cells that would otherwise attack the tumor.

We propose a novel combination approach using two existing treatments: an influenza (flu) vaccine injected directly into tumors and a drug that blocks a protein called BRD4. When flu vaccine is injected into tumors, it activates the immune system to go to the site of cancer cells. The BRD4-blocking drug removes the suppressive cells that normally protect the tumor and keeps T cells from becoming exhausted, allowing them to continue fighting.

Our research will test whether giving flu vaccine first, followed by the BRD4 drug, can reprogram the tumor environment to be allow the immune system to be more active and effectively clear cancer cells. We will measure tumor shrinkage, analyze the immune cells inside tumors, and determine whether this combination helps checkpoint inhibitors, a current class of medications used to treat melanoma, work better.

This approach is particularly promising because flu vaccines are already FDA-approved and widely available, and BRD4 inhibitors are being tested in cancer clinical trials. If successful, this combination could offer additional treatment options for melanoma patients who don’t respond to current immunotherapies, potentially providing a safe, accessible treatment strategy that could be rapidly translated to the clinic.

Cutaneous Genital and Acral Melanoma Treatment Trends and Outcomes

Virginia Snider — Wed, 27 May 2026 19:30:19 +0000

Wide local excision (WLE) removes clinical tumor and adjacent skin (‘tumor margin’). After defect repair, tissue is evaluated microscopically. Re-excision occurs if tumor remain. Mohs Micrographic Surgery (MMS) removes clinical and microscopic tumor before defect repair. While recurrence, positive margin, and upstaging (increase in tumor’s stage after diagnostic biopsy) rates for trunk and proximal extremity melanoma WLE are 2%, for ‘specialty site’ (acral and genital) cutaneous melanomas these rates each increase to 10%. Before 2020, the National Comprehensive Cancer Network guidelines recommended WLE for melanoma. In 2020 they included the option of MMS for early-stage specialty site cutaneous melanomas due to their cosmetic, functional, and anatomically-constrained nature. Single-center studies demonstrate 0.5%-1% and 10% recurrence rates for MMS and WLE-treated specialty site cutaneous melanomas, respectively. However, multicentered, larger studies on specialty site, especially genital and acral (palm, sole, and nail) melanomas, are lacking.
Objectives: Utilize Surveillance, Epidemiology, and End Results (SEER)-Medicare to evaluate national rates and outcomes of WLE and MMS for specialty site cutaneous melanomas over the last 20 years. Outcomes include mortality, melanoma specific survival, and recurrence rates. Associations between immune-status, race, income, gender, education and surgical treatment (WLE and MMS) will be studied to determine if disparities exist.

Methods: Kaplan Meier statistics and Joinpoint analysis will analyze recurrence and trends over time, respectively. Multivariable logistic regression will evaluate associations between demographic factors and surgical management (MMS vs WLE).

Significance: This nationwide evaluation of specialty site cutaneous melanoma surgical trends and outcomes can impact melanoma guidelines, optimize patient care, and identify treatment disparities.

Uncovering longitudinal microbiome changes in ICI resistance and toxicity

kaleandflax — Wed, 27 May 2026 19:30:09 +0000

In the last decade, rapid advances have been made in melanoma treatment, most notably the introduction of immune checkpoint inhibitors (ICIs), which stimulate the body’s immune system to kill melanoma cells. However, many patients do not respond to ICIs (termed ICI resistance), and others develop autoimmune-like side effects (termed immune-related adverse events, or irAEs). Discovery of easily-measurable markers that identify melanoma patients who may not respond to ICIs or that may be developing irAEs will help clinicians maximize the benefit from ICIs and minimize side effects.

The gut microbiome (GMB) is a community of bacteria that resides in the body’s intestines that can influence how effective the body’s cancer-fighting immune cells are against melanoma and how well they respond to stimulation by ICIs. The GMB can also produce small molecules, or “metabolites”, that can similarly influence the behavior of the immune system against melanoma. The makeup of the GMB and its metabolites can change while patients are receiving ICIs, but it is not known whether these changes correlate with development of ICI resistance or irAEs. Thus, further study of how the GMB evolves while on ICI therapy may enable use of the GMB or its byproducts as clinical markers of ICI resistance and irAEs, allowing for rapid intervention for patients that may not be responding to ICIs or developing potentially dangerous side effects.

In this study, we propose to compare GMB evolution patterns in melanoma patients that respond to ICIs in different ways to learn more about whether GMB evolution patterns could eventually be used to predict ICI resistance or irAEs. We also propose to compare levels of short-chain fatty acids (SCFAs), which are GMB metabolites that can shape ICI response, in patients with different types of ICI resistance and in patients with vs without irAEs. This will allow us to assess the potential of using SCFA levels to predict ICI resistance or irAEs.