This research considers the treatment of malignant melanoma. Data were collected from patient records for 78 individuals treated within the Yale Cancer Center Melanoma Unit. The patients were diagnosed with malignant melanoma prior to 1994 and progressed to stage I11 or N disease before their deaths.Due to the rapid progression of malignant melanoma, treatments are initiated at the time of diagnosis. Results of experimental Extreme Drug Resistance (EDR) tests subsequently become available. Physicians are warned the test results are not intended to guide therapy; however, assay directed therapies arguably result in better outcomes with other cancers. Thus, the question arises of whether the use of these tests might benefit patients in this context.This study evaluates the treatment decisions made using a multi-disciplinary approach within the Yale Cancer Center Melanoma Unit regarding patients with malignant melanoma relative to information contained in EDR tests conducted by Oncotech Inc. Within this comparison, three specific outcomes consistent with hypotheses of the study were assessed: the utilization of test results, drug toxicity and cost effectiveness and survival.Results were found to suggest that the initial treatment decisions of the Yale Cancer Center Melanoma Unit were in accord with tests results that were received henceforth for 74 of 78 patients. Two of those patients were in terminal stages of the disease thus treatments were unchanged; however two patients received a change in therapy.It is suggested that physicians made use of the tests as they became available. However, only two patients with therapies altered by the test results were shown to face reduced costs, drug toxicity, or have the benefit of improved survival. From the patient data collected, four patients receiving drugs to which their tumors exhibited EDR were found to exhibit shorter survival times. Literature review studies conducted to evaluate physician treatment approach and patient preference rate favorably the consideration of quality of life issues. The principle finding of this observational study which focuses upon the development of the Yale Cancer Center Melanoma Unit, suggest that a multidisciplinary approach to the treatment of malignant melanoma may offer quality of life benefits to the patient.

Immune checkpoint blockade (ICB) therapies have transformed the treatment landscape for advanced melanoma, extending patient survival and improving quality of life for numerous patients with a disease that was once considered to be universally fatal. However, despite the success of ICB for many patients, over half are either resistant to initial therapy, or develop resistance over time after an initial response. The mechanisms underlying this therapy resistance remain unclear for the majority of patients. We have recently identified loss of the co-stimulatory and adhesion molecule CD58 on melanoma cells as a driver for cancer immune evasion and ICB resistance. In this thesis, we use in vitro co-culture models of patient-derived melanoma cells and tumor infiltrating lymphocytes as well as in vivo patient-derived xenograft models to demonstrate the necessity of CD58 interactions with its ligand CD2 on T cells for T cell activation, tumor infiltration, and effector cytotoxicity. Furthermore, using genome-wide genetic and protein screening approaches, we identify CMTM6 as a positive regulator of CD58, and uncover its role in mediating CD58’s regulation of inhibitory PD-L1 signaling by binding to both proteins and preventing their lysosomal degradation. Thus, CMTM6 co-regulates these co- inhibitory and co-stimulatory signals such that, in the absence of CD58, CMTM6 becomes available to bind and stabilize additional PD-L1, enhancing its inhibitory signals to T cells. Finally, we identify a potential role for CD58 on T cells as a marker of effector memory T cells with enhanced effector and progenitor function. The CD58-CD2 axis therefore serves a multi-faceted, underappreciated role in melanoma cancer immunity, and may serve as a therapeutic target for enhancing anti-tumor T cell responses.

\ / Doctorat en Sciences biomédicales et pharmaceutiques / info:eu-repo/semantics/nonPublished