Personalising Immunotherapy in Early and Advanced Stage Melanoma

Abstract

Introduction: Melanoma is a paradigm of how the treatment landscape can be revolutionised over a decade. The advent of immune checkpoint blockade (ICB) has dramatically improved the outcomes of patients with both early and advanced stage disease. Nevertheless, patients are still dying of their disease, highlighting the urgent need to identify which patients will respond to therapy, in order to improve patient stratification and avoid unnecessary toxicity risk. Thus, precision immuno-oncology approaches are required to improve cancer care. Therapy decisions need to be made based on patient-specific immunological signatures, but clinically validated biomarkers for this purpose are currently lacking. The primary aim of this work was to explore liquid biopsy as a minimally invasive approach to investigate peripheral T cell evolution early on treatment as a potential predictive biomarker of response to immunotherapy in melanoma. Additionally, the impact of patient clinical variables on peripheral T cell and T cell receptor (TCR) repertoire evolution under the selective pressure of ICB in advanced melanoma was investigated. Methods: To assess the peripheral T cell compartment of metastatic melanoma patients undergoing first line anti-PD1 based ICB treatment, peripheral blood samples were taken prior to and early on treatment then analysed by flow cytometry. Phenotypic assessment of peripheral T cells and TCR sequencing data were used to correlate changes in peripheral T cell subset dynamics and TCR repertoire to patient clinical variables before treatment (T0) and after the first cycle of ICB at week 3 (W3). A prospective study was set up to investigate whether changes in peripheral T cells early on adjuvant ICB therapy can predict patient response in stage III melanoma. Results: Flow cytometry revealed expansion of a subset of CD8+ memory immune effector cytotoxic T cells in peripheral blood. At W3 after therapy initiation, expansion of these cells was significantly greater in patients that responded to ICB. An increase of 0.8% in the ratio of this subset of T cells relative to all CD8+ memory cells at W3 was associated with improved survival and separated 6-month responders from non-responders; this was confirmed in a separate validation cohort. Analysis from later W9 treatment time point revealed the presence of the T cell subset, however there was no longer a correlation with response, highlighting the dynamic nature of the immune signature and indicating that these changes occur early and are transient. Evaluation of whether changes in W3 T cell subset expansion were associated with immune related adverse events revealed no correlation between T cell subset expansion and grade of toxicity, suggesting that these cells are not a predictive marker of immunotherapy toxicity in this setting. Notably, expansion of a separate regulatory T cell subset did correlate with grade of toxicity. Investigation of clinical variables associated with the immune signature demonstrated a correlation between the immune effector T cell subset abundance and age at T0 (r=0.40), which reduced following treatment at W3 (r=0.07). However, at W3 two significantly opposing patterns (p=0.03) of TCR repertoire rearrangement were observed in patients who responded to treatment, with patients ≥70 years of age showing an increase in TCR clonality and patients

Date of Award	22 Jun 2022
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Sara Valpione (Supervisor), Elaine Kilgour (Supervisor), Paul Lorigan (Supervisor), Richard Marais (Supervisor) & Nathalie Dhomen (Supervisor)