Narrative review: immunotherapy in anaplastic lymphoma kinase (ALK)+ lung cancer-current status and future directions

Abstract

Background and objective: Patients with metastatic anaplastic lymphoma kinase (ALK)+ non-small cell lung cancer (NSCLC) often experience years of disease control on targeted therapies but the disease eventually develops resistance and progresses. Multiple clinical trial efforts to incorporate PD-1/PD-L1 immunotherapy into the treatment paradigm for ALK+ NSCLC have resulted in significant toxicities without clear improvement in patient outcomes. Observations from clinical trials, translational studies, and preclinical models suggest the immune system interacts with ALK+ NSCLC and this interaction is heightened with the initiation of targeted therapy. The objective of this review is to summarize knowledge to date about current and potential immunotherapy approaches for patients with ALK+ NSCLC.

Methods: To identify the relevant literature and clinical trials the databases PubMed.gov and ClinicalTrials.gov were queried with keywords "ALK" and "lung cancer". PubMed search was further refined with terms such as "immunotherapy", "tumor microenvironment or TME", "PD-1", and "T cells". The search for clinical trials was limited to interventional studies.

Key content and findings: In this review, the current status of PD-1/PD-L1 immunotherapy for ALK+ NSCLC is updated and alternative immunotherapy approaches are highlighted in the context of available patient level and translational data on the ALK+ NSCLC tumor microenvironment (TME). An increase in CD8⁺ T cells within the ALK+ NSCLC TME has been observed with targeted therapy initiation across multiple studies. Therapies to augment this including tumor infiltrating lymphocyte (TIL) therapy, modified cytokines, and oncolytic viruses are reviewed. Furthermore, the contribution of innate immune cells in TKI mediated tumor cell clearance is discussed as a future target for novel immunotherapy approaches that promote cancer cell phagocytosis.

Conclusions: Immune modulating strategies derived from current and evolving knowledge of the ALK+ NSCLC TME may have a role in ALK+ NSCLC beyond PD-1/PD-L1 based immunotherapy.

Keywords: Anaplastic lymphoma kinase (ALK); immunotherapy; non-small cell lung cancer (NSCLC); tumor microenvironment (TME).

Figure 1

Future immune based approaches to augment the tyrosine kinase inhibitor response in ALK+ NSCLC. Schematic diagram of tyrosine kinase inhibitor mediated ALK+ NSCLC cell death and changes to the T cell content of the tumor microenvironment. Potential strategies to amplify the immune response to ALK+ NSCLC cell death include adoptive cell therapy with NK cells or tumor infiltrating lymphocyte therapy, modified cytokines that preferentially target effector cells, oncolytic virus therapy to increase tumor cell death and inflammatory milieu within the tumor microenvironment, and novel immune checkpoints that enhance innate immune cell recognition of ALK+ NSCLC cells. ALK, anaplastic lymphoma kinase; NSCLC, non-small cell lung cancer; NK, natural killer; TILs, tumor infiltrating lymphocytes.