Emerging Roles of ALK in Immunity and Insights for Immunotherapy

Wang, Lan; Lui, Vivian Wai Yan

doi:10.3390/cancers12020426

Cited by 15 publications

(12 citation statements)

References 65 publications

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“…ALK expression was mainly restricted in immune-privilege location during normal development, fused and overexpressed ALK would activate humoral and cellular immune reaction against the tumor. 48 And in our cohort, we also found ALK mutational frequency was higher in inflamed phenotype. This consequence seemed to be contradictory with the poor clinical efficacy of ICBs in ALK rearranged patients.…”

Section: Discussionsupporting

confidence: 65%

“…On the other hand, fused ALK could induce expression of immunosuppressive factors and suppressed cell surface expression of HLA I molecule. 48 Different fusion patterns of ALK were also found having different impacts on tumor immune microenvironment. 50 Further studies are indispensable to detailed analyzing various influence on tumor immunity of different mutant or fused ALK .…”

Section: Discussionmentioning

confidence: 99%

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Tumor Mutation Burden and Differentially Mutated Genes Among Immune Phenotypes in Patients with Lung Adenocarcinoma

Wang¹,

Chen²,

Meng³

et al. 2021

OTT

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Introduction Nowadays, immune checkpoint blockades (ICBs) have been extensively applied in non-small cell lung cancer (NSCLC) treatment. However, the outcome of anti-program death-1/program death ligand-1 (anti-PD-1/PD-L1) therapy is not satisfying in EGFR -mutant lung adenocarcinoma (LUAD) patients and its exact mechanisms have not been fully understood. Since tumor mutation burden (TMB) and tumor immune phenotype had been thought as potential predictors for efficacy of ICBs, we further studied the TMB and immune phenotype in LUAD patients to explore potential mechanisms for poor efficacy of ICBs in EGFR positive mutated patients and to find possible factors that could impact the tumor immune phenotype which might uncover some new therapeutic strategies or combination therapies. Methods We enrolled 223 LUAD patients who underwent surgery in our hospital. We evaluated TMB through targeted panel sequencing. The tumor immune phenotype, which could be divided into non-inflamed, intermediate and inflamed, was determined through immunohistochemistry using formalin-fixed paraffin-embedded samples. Enumeration data were analyzed by Chi-square test or Fisher exact test and shown as number (proportion). Logistic regression model was employed for univariate and multivariate analysis of the association between TMB levels and clinical characteristics. Results The median TMB level was 4.0445 mutations/Mb. Multivariate analysis showed the TMB level was significantly associated with age ( P =0.026), gender ( P =0.041) and EGFR mutation status ( P =0.015), and in EGFR -mutant patients we found a lower proportion of patients with mutated KRAS and BRCA2 . Furthermore, we found patients with or without metastatic lesions would have different immune phenotype ( P =0.007). And the mutational frequencies of ALK, CDKN2A, MAP2K1, IDH2 and PTEN were significantly different among three immune phenotypes. Conclusion Low TMB level could be the reason for the poor efficacy of ICBs in patients having EGFR mutation. And mutational frequencies of KRAS and BRCA2 were lower in EGFR -mutant patients. Furthermore, ALK, CDKN2A, MAP2K1, IDH2 and PTEN might involve in the formation of immune phenotypes.

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Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Tumor Mutation Burden and Differentially Mutated Genes Among Immune Phenotypes in Patients with Lung Adenocarcinoma

Wang¹,

Chen²,

Meng³

et al. 2021

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“…In ALK -rearranged NSCLC, one strategy to convert the immunosuppressed TME to an immune-responsive TME is by use of an ALK -directed vaccine, in order to stimulate TILs into the TME [ 10 ]. ALK has been shown to be antigenic in human lymphomas, with demonstration of spontaneous B and T cell responses against the ALK protein by measurable antibodies, CD8 + cytotoxic T cells and CD4 + helper T cells directed against ALK epitopes [ 69 , 70 ].…”

Section: Immunotherapy Approaches In Treatment Of Alk-rearranged Nmentioning

confidence: 99%

“…These are considered to be “immune-privileged sites”, i.e., sites with sufficient immune tolerance to self-antigens [ 9 ]. Thus, the ALK protein may represent a potential antigen for the human immune system [ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

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

Sankar

Nagrath

Ramnath

2021

Cancers

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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.

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“…However, efficacy is modest and median survival does not exceed 12–15 months according to retrospective studies [ 116 , 117 ]. An exciting prospect is the ability to target ALK-derived neopeptides using autologous or allogeneic T-cell receptor (TCR)-transgenic T-cells, based on the fact that anti-ALK T-cell responses are readily detectable in normal donors and many ALK + NSCLC patients [ 118 , 119 ]. The TCR-therapy field has been revolutionized by several technological breakthroughs during the last few years [ 120 ], so that these concepts are expected to enter early clinical testing soon.…”

Section: State-of-the-art After the First Linementioning

confidence: 99%

Therapeutic Sequencing in ALK+ NSCLC

Elsayed

Christopoulos

2021

Pharmaceuticals

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Anaplastic lymphoma kinase-rearranged non-small-cell lung cancer (ALK+ NSCLC) is a model disease for the use of targeted pharmaceuticals in thoracic oncology. Due to higher systemic and intracranial efficacy, the second-generation ALK tyrosine kinase inhibitors (TKI) alectinib and brigatinib have irrevocably displaced crizotinib as standard first-line treatment, based on the results of the ALEX and ALTA-1L trials. Besides, lorlatinib and brigatinib are the preferred second-line therapies for progression under second-generation TKI and crizotinib, respectively, based on the results of several phase II studies. Tissue or liquid rebiopsies at the time of disease progression, even though not mandated by the approval status of any ALK inhibitor, are gaining importance for individualization and optimization of patient management. Of particular interest are cases with off-target resistance, for example MET, HER2 or KRAS alterations, which require special therapeutic maneuvers, e.g., inclusion in early clinical trials or off-label administration of respectively targeted drugs. On the other hand, up to approximately half of the patients failing TKI, develop anatomically restricted progression, which can be initially tackled with local ablative measures without switch of systemic therapy. Among the overall biologically favorable ALK+ tumors, with a mean tumor mutational burden uniquely below 3 mutations per Mb and the longest survival among NSCLC currently, presence of the EML4-ALK fusion variant 3 and/or TP53 mutations identify high-risk cases with earlier treatment failure and a need for more aggressive surveillance and treatment strategies. The potential clinical utility of longitudinal ctDNA assays for earlier detection of disease progression and improved guidance of therapy in these patients is a currently a matter of intense investigation. Major pharmaceutical challenges for the field are the development of more potent, fourth-generation TKI and effective immuno-oncological interventions, especially ALK-directed cell therapies, which will be essential for further improving survival and achieving cure of ALK+ tumors.

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Emerging Roles of ALK in Immunity and Insights for Immunotherapy

Cited by 15 publications

References 65 publications

Tumor Mutation Burden and Differentially Mutated Genes Among Immune Phenotypes in Patients with Lung Adenocarcinoma

Tumor Mutation Burden and Differentially Mutated Genes Among Immune Phenotypes in Patients with Lung Adenocarcinoma

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

Therapeutic Sequencing in ALK+ NSCLC

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