Anti-Programmed Death 1(Anti-PD1) induced cutaneous toxicities in patients with metastatic melanoma

This thesis addresses a wide range of cutaneous toxicities associated with anti-PD1 antibodies. These immunotherapies are now commonly utilised for the patients with American Joint Committee on Cancer (AJCC) stage III and IV melanoma. Due to increasing usage of anti-PD1 antibodies, it is paramount for clinicians to be familiar with a range of different side effects. This research project was aimed at identifying and diagnosing the cutaneous toxicities associated with the drug use. Then attempts were made to identify the mechanisms behind the associated cutaneous toxicities, any association to the disease progression, specific immunohistochemistry and histology findings within the cutaneous toxicities, and lastly to explore appropriate treatment options for these affected patients. Chapter 1 consists of a literature review. As a part of invited review, the concepts of anti-PD1 antibodies and their roles in melanoma treatment, and varying cutaneous toxicities associated with anti-PD1 antibody use in comparison to BRAFi and MEKi, which were precedent therapies for melanoma are discussed. Chapter 2 discusses the clinical aspects of the cutaneous toxicities of the anti-PD1 antibodies in patients with metastatic melanoma and compares them against patients with genitourinary/solid organ malignancies. Chapter 3 addresses mechanisms of anti-PD1 antibody induced immune mediated cutaneous disorders. Both B and T cell mediated conditions. Chapter 4 addresses mechanisms of anti-PD1 antibody induced nonimmune mediated cutaneous disorders such as melanocyte and keratinocyte related changes. Chapter 5 focuses on the differences of skin toxicities in anti-PD1 antibody and combined therapies of anti-CTLA4 and anti-PD1 antibodies. Chapter 6 discusses the correlations between the development of anti-PD1 induced cutaneous toxicities and survival. Chapter 7 forms the discussion on management of the common cutaneous toxicities and future directions