Prognosticators of Treatment Response to Immunotherapy in Veteran Mucosal Melanoma Patients: A Real-World Outcomes Study
Prognosticators of Treatment Response to Immunotherapy in Veteran Mucosal Melanoma Patients: A Real-World Outcomes Study
Nicole Trepanowski
| Mentor | Rebecca Hartman, MD, MPH; Mary Brophy, MD |
|---|---|
| Award Type | Medical Student Award |
| Institution | Brigham and Women’s Hospital |
| Donor Support | In memory of Hope E. Troman |
Description:
Mucosal melanoma (MM) is a rare form of melanoma with poor survival outcomes. Data on treatment for MM is limited to results from studies on cutaneous melanoma or from small cohorts of MM patients. The Veterans Affairs population is one of the largest U.S. healthcare networks and includes individuals traditionally under-represented in clinical trials (older age and diverse ethnic and racial backgrounds). Using data from the Veterans Affairs will allow us to examine one of the largest cohorts of MM patients.
Immune checkpoint inhibitors (ICIs), specifically anti-programmed death-1 (PD-1) therapies (nivolumab and pembrolizumab) and anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) (ipilimumab), have emerged as promising therapeutic candidates for treatment of MM, but studies have thus far yielded mixed results. A large-scale outcomes study in patients treated with immunotherapy may provide us with additional information to guide therapy choice based on real-world data.
Survival among MM patients varies by anatomical location, possibly due to anatomical surgical constraints, different lymphovascular supplies, different stages at diagnosis, different tumor mutational burdens, and different immune system characteristics by site. We will examine whether site of primary tumor predicts improved survival with ICI treatment.
Melanoma Risks and Risk Prediction in Patients with Actinic Keratosis
Melanoma Risks and Risk Prediction in Patients with Actinic Keratosis
Mackenzie Wehner, MD, MPhil
| Mentor | Sharon Giordano, MD, MPH & David Margolis, MD, PhD |
|---|---|
| Award Type | Career Development Award |
| Institution | The University of Texas MD Anderson Cancer Center |
Description:
Actinic keratoses are common pre-cancerous skin lesions that can transform into cutaneous squamous cell carcinoma and whose presence may also be associated with increased risk for melanoma.
Objectives: This project aims to examine the absolute risks of melanoma in patients with actinic keratoses, which are unknown, and to create a melanoma risk prediction model for patients with actinic keratoses, which has not previously been done.
Rationale: Actinic keratoses arise in the setting of chronic UV exposure and affect tens of millions of people in the United States each year. The majority of actinic keratosis clinical care and research focuses on the individual actinic keratosis and its risk of malignant transformation to cutaneous squamous cell carcinoma. However, there is some evidence that the presence of actinic keratoses may be associated with increased risk of melanoma for the patient as a whole. Though they are not currently used this way, actinic keratoses may be an important clinical biomarker of melanoma risk. Unfortunately, there are no current guidelines or recommendations for clinicians to follow for melanoma surveillance or early detection in patients with actinic keratoses. The overarching goal is of this project to provide evidence to guide clinical care and form the foundation for future recommendations on melanoma surveillance and early detection in patients with actinic keratoses, a large and high-risk group.
Methods: In Aim 1, we will determine the absolute risks and timing of melanoma in patients with actinic keratoses using a retrospective cohort design in a dataset of 5 million Medicare beneficiaries. We will use Kaplan Meier and parametric accelerated failure time models to calculate unadjusted and adjusted absolute risk estimates, respectively. Aim 2, we will create and validate a risk prediction model for melanoma in patients with actinic keratoses using a Medicare claims dataset, a commercial claims dataset (Optum, 69 million patients), and UK Biobank (500,000 patients). We will create the risk prediction model in Medicare using routinely collected data available in claims and validate it in Optum. Then we will test the performance of our model using only routinely collected data against that of a model that also includes phenotypic, UV exposure, and genetic information in UK Biobank.
Expected Results: The completion of these aims will build the evidence-base for needed recommendations for tens of millions of patients with actinic keratoses each year in the US who are at increased risk for melanoma. The methodology, results, and research skills developed as part of this application will be utilized in future studies in skin cancer risk prediction. Completion of the proposed research and career development plan will serve as a platform upon which Dr. Wehner can successfully transition to scientific independence in patient-oriented skin cancer research.
Harnessing Epigenetic therapies to License Melanoma Vaccine
Harnessing Epigenetic therapies to License Melanoma Vaccine
Nicolas Vabret, PhD
| Mentor | Nina Bhardwaj, MD, PhD |
|---|---|
| Award Type | Career Development Award |
| Institution | Icahn School of Medicine at Mount Sinai |
Description:
Therapies that inhibit epigenetic modulators can induce a state of “virus mimicry” in cancer cells by activating long-overlooked “junk DNA” of the human genome. This state of viral mimicry triggers immune responses and induces the expression of immunogenic antigens that are specific to the cancer cells. In this project, we will evaluate the efficacy of cancer vaccines that target these antigens when they are administered in combination with epigenetic therapy that induce their expression in cancer cells.
Targeting metabolic vulnerabilities of melanoma metastasis in lymph
Targeting metabolic vulnerabilities of melanoma metastasis in lymph
Jessalyn Ubellacker, PhD
| Mentor | Brendan Manning, PhD |
|---|---|
| Award Type | Career Development Award |
| Institution | Harvard University |
Description:
The major reason melanoma causes illness and death in patients is because the melanoma cells from the skin can travel to lymph nodes or into the blood which allows them to spread and grow in other organs in the body, such as the lung or liver. We do not yet fully know how melanoma cells are able to travel into the lymph or blood. However, the harsh environment of the blood kills most of the melanoma cells before they make it to other organs. Only melanoma cells that have specific changes to small molecules inside the cell that help protect the melanoma cells against stress survive in the blood and then grow at organs distant from where the initial melanoma was located on the skin.
My previous work discovered that melanoma cells that travel to the lymph acquire changes to lipids inside of the cell that then shield them from stress in the blood. Specifically, I found that melanoma cells that acquired a fatty acid called oleic acid from the lymph were protected from stress and by blocking this oleic acid the cells were not able to travel to distant organs as efficiently. In addition to these recent changes, I anticipate that melanoma cells undergo many more changes to the fatty acids and other lipids inside of the cell that will shield them from the stress the cells experience when they travel through the bloodstream. I believe these changes remain to be discovered.
The goal of my proposal is to investigate these additional lipid changes in the melanoma cells that are allow them to survive better in the blood. Then, my lab group will work to block those changes from occurring to prevent the cells from traveling to and growing in other organs in the body, such as the lung or liver. This project has the potential to help block early-stage melanoma from spreading to distant organs and causing illness and death in patients. If we can identify the lipid changes that help protect melanoma cells and discover ways to prevent those changes from occurring we will be able to develop new treatments to help patients diagnosed with early-stage melanoma.
Immunotherapy using personalized T cell receptor engineered T cells
Immunotherapy using personalized T cell receptor engineered T cells
Colt Egelston, PhD
| Mentor | Peter Lee, MD |
|---|---|
| Award Type | Career Development Award |
| Institution | Beckman Research Institute of the City of Hope |
| Donor Support | Funded by the Cavan Family Foundation |
Description:
Immunotherapy has fundamentally changed the way we treat melanoma patients. Checkpoint blockade specifically, which unleashes T cell killing of cancer cells, has extended patient survival and significantly increased the percentage of patients that are deemed disease-free after therapy. Despite these successes, many melanoma patients still do not respond to immunotherapy; and even among those that respond initially, a significant percentage develop resistance or relapse after therapy. Barriers to the ultimate success of immunotherapy include tumor specific T cell dysfunction or the inability to generate sufficient numbers of tumor specific T cells due to immunosuppressive features of tumors. Recent research has demonstrated how these barriers emerge, showing that many melanoma tumors contain tumor specific T cells, but they lack the ability to kill cancer cells due to a state of dysfunction termed ‘T cell exhaustion’. Here we propose to use a combination of cutting-edge single cell RNA sequencing and T cell engineering methodology to generate large numbers of anti-tumor T cells. To do so, we will use single cell RNA sequencing on melanoma patient tumor infiltrating T cells to identify their T cell receptor (TCR), which allows tumor-specific T cells to recognize and kill cancer cells. We will use these TCR RNA sequences to then engineer large numbers of tumor- specific T cells (TCR-T cells) and test them for their ability to kill melanoma cancer cells from the same patient the T cell receptors were identified in. Next, we will test if any of the TCR-T cells we construct are capable of killing cancer cells from other melanoma patients. If so, we will begin to build a library of TCR-T that can be rapidly employed in the clinic for subsets of melanoma patients. This innovative strategy offers both a personalized engineering approach and the ability to rapidly generate high numbers of tumor-specific immune cells for clinical administration to patients. Thus, we believe that these studies will lead to a novel immunotherapy treatment option for melanoma patients that will offer durable, long-lasting survival.
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