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Dena Guo

Physics, '17


Longitudinal assessment of tumor heterogeneity during immunotherapy for metastatic melanoma

Mentor: Annick Van den Abbeele, MD (DFCI)

Melanoma is an aggressive form of skin cancer that develops from genetic changes in melanocytes, the pigment producing cells in the epidermal layers of skin. Traditional treatments for melanoma include surgery, radiation therapy, and systemic therapy. Patients with early stages of melanoma have a 90% survival rate over 5 years in the United States. However, patients with advanced melanoma, where the tumor has metastasized to other parts of the body, only have a 10% survival rate over 5 years and less than 25% of patients survive for longer than 1 year. Thus, novel targeted treatment approaches like immunotherapy are being investigated in medical research and clinical trials to improve the survival rates of patients with metastatic melanoma. In this investigation, patients with metastatic melanoma were treated with a novel immunotherapeutic agent and the metabolic activity of their tumors was measured using Positron Emission Tomography Computed Tomography (PET/CT) imaging, before, during and after the induction dose of the immunotherapy. PET/CT was used to measure changes in tumor characteristics (e.g. size and metabolic activity) during the course of the therapy. These patients were also monitored after the end of therapy to evaluate their clinical outcome (e.g. remission, progression, or recurrence of their disease) and survival rates. The PET/CT images of these patients will be analyzed to assess how the tumor characteristics changed in response to the immunotherapy, and to observe variations or heterogeneity. The heterogeneity of metabolic activity within and between the tumors in the same patient, and in the cohort of patients will be measured during this analysis. The immunotherapeutic agent was a monoclonal antibody that targets cytotoxic T-lymphocyte antigen-4 (CTLA-4), a protein receptor found on the surface of activated T cells. CTLA-4 acts as a brake for the immune system. When CTLA-4 binds to ligands on the surface of melanoma cells, it downregulates the activation of T cells and prevents the immune system from destroying the tumors. The monoclonal antibody specifically binds to CTLA-4 and inhibits the function of the bound protein molecule, thus boosting the immune system’s response to the tumors. Oncologists routinely use imaging throughout traditional treatment to observe the effects of treatment and determine the next course of action. When melanoma cells are killed by the immune system during immunotherapy, changes in the characteristics of the metastatic tumors may be observed with PET/CT imaging, which provides two complementary components of tumor characterization that are important for monitoring the cytotoxic effect of immunotherapy. PET measures metabolic activity within tumor cells with high sensitivity but has limited spatial resolution, while CT provides high resolution anatomical imaging but cannot differentiate between active and dead tumor tissue. Therefore, combined PET/CT imaging measures location and metabolic activity within tumors in one setting. For PET/CT imaging, patients were injected with the glucose analog 18F-fluorodeoxyglucose (18F-FDG) to measure metabolic activity of their tumors. As a glucose analog, 18F-FDG is transported into cells that require glucose as an energy source. Cancer cells tend to use more glucose than cells in the surrounding tissue (the Warburg effect), so tumors uptake more 18F-FDG and appear as hyperintense regions in PET/CT images. When the 18F undergoes nuclear decay, it emits a positron, a positively-charged particle with the mass of an electron. Emitted positrons travel a very short distance before interacting with an electron and annihilating, releasing two gamma rays that travel in opposite directions. PET detects these pairs of annihilation gamma rays and pinpoints the location and quantity of 18F-FDG within the tumor and surrounding tissues, while CT provides the anatomical reference for the location of the detected 18F-FDG signals.

A patient with a tumor in the left inguinal lymph node, near the spine. After being imaged via PET/CT, the separate PET and CT images are combined to generate a single PET/CT (bottom) image, which measures the location and metabolic activity within tumors in one setting. Source: