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.

Superparamagnetic Iron Oxide Nanoparticles Reprogram the Tumor Microenvironment and Reduce Lung Cancer Regrowth after Crizotinib Treatment

“…The development of resistance to targeted therapies in ALK-positive patients remains a major challenge, and combining TKI with immunotherapy has not shown significant clinical benefits. 9 Considering the immune modulatory effect of SPION-CCPMs we assessed whether macrophage priming with SPION-CCPM instillation in tumor-bearing mice shows promise as an adjuvant therapy. Eml4-Alk tumors were monitored by μCT, grown to 30 mm 3 volume, and then treated with crizotinib (TKI targeting ALK) 46 until tumors regressed or mice became noncompliant.…”

“…However, acquired TKI resistance is inevitable and remains a critical issue. The use of immune-checkpoint inhibitors (ICI) as a monotherapy in ALK-positive tumors show modest efficacy and severe toxicities upon combination of ICI and TKI treatment . Therefore, ALK-positive patients require novel approaches to completely eradicate tumors or delay relapse.…”

“…The use of immune-checkpoint inhibitors (ICI) as a monotherapy in ALK-positive tumors show modest efficacy and severe toxicities upon combination of ICI and TKI treatment. 9 Therefore, ALK-positive patients require novel approaches to completely eradicate tumors or delay relapse. Considering that the lung harbors significant basal levels of macrophage populations, therapeutic strategies that intervene by reprogramming or depleting M2 TAMs have been proposed to enhance responsiveness to current “standard-of-care” options.…”

Current opportunities and challenges in ALK-positive lung cancer

“…Through the lens of ALK-positive lung cancer, we also take a deep dive into topics broadly relevant to oncogene-addicted tumors, including: (I) the biology and targeting of brain metastases ( 24 ); (II) lineage plasticity (e.g., epithelial mesenchymal transition and histologic transformation) ( 25 ); and (III) the barriers in harnessing immune responses [i.e., lack of benefit from anti-PD(L)1 immune checkpoint inhibition] and future directions for leveraging immunotherapy (e.g., ALK-directed vaccine approaches, adoptive cell therapy, oncolytic viruses) ( 26 ). Each of these topics currently represents a major scientific and therapeutic bottleneck, relevant across oncogene-addicted lung cancers, and we anticipate that breakthroughs therein will move the needle on patient outcomes.…”