Immunotherapy for ALK-Rearranged Non-Small Cell Lung Cancer: Challenges Inform Promising Approaches

SIMPLE SUMMARY: Non-small cell lung cancer is the most common type of lung cancer. Anaplastic Lymphoma Kinase (ALK) rearrangements have been found in 5–6% of non-small cell lung cancers. While ALK rearranged non-small cell lung cancer is exquisitely sensitive to ALK directed targeted therapies, it is generally resistant to immune-based therapies. We aim to describe the mechanisms by which ALK-rearranged non-small cell lung cancers escape host immunity and are thereby unresponsive to immunotherapies. Furthermore, we describe new immunotherapy strategies and the promises and challenges in incorporating these into clinical practice. ABSTRACT: Rearrangements in the Anaplastic Lymphoma Kinase (ALK) gene have been implicated in 5–6% of all non-small cell lung cancers. ALK-rearranged non-small cell lung cancers are sensitive to ALK-directed tyrosine kinase inhibitors, but generally resistant to single-agent immune checkpoint inhibitors. Here, we aim to describe the mechanisms of ALK aberrations in non-small cell lung cancer by which an immunosuppressed tumor microenvironment is created, leading to host immune evasion. We report pre-clinical and clinical studies evaluating novel immunotherapeutic approaches and describe the promises and challenges of incorporating immune-based treatments for ALK-rearranged non-small cell lung cancer.