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. 2024 Jul 30:6:100164.
doi: 10.1016/j.jlb.2024.100164. eCollection 2024 Dec.

Anti-ALK autoantibodies in patients with ALK-positive Non-Small Cell Lung Cancer (NSCLC): A monocentric experience

Claudia Parisi  1   2 , José Carlos Benitez  3 , Hélène Lecourt  4 , Filippo Gustavo dall'Olio  1 , Mihaela Aldea  1 , Felix Blanc-Durand  1 , Véronique Vergé  5 , Cyril Quivoron  4 , Charles Naltet  1 , Pamela Abdayem  1 , Pernelle Lavaud  1 , Maria Rosa Ghigna  6 , Luc Friboulet  7 , Yohann Loriot  8 , Stéphane De Botton  9 , Vincent Ribrag  9 , Andrea Ardizzoni  10 , David Planchard  1 , Jean-Charles Soria  1 , Fabrice Barlesi  1 , Benjamin Besse  1
Affiliations

Anti-ALK autoantibodies in patients with ALK-positive Non-Small Cell Lung Cancer (NSCLC): A monocentric experience

Claudia Parisi et al. J Liq Biopsy. .

Abstract

Importance: Deregulation of anaplastic lymphoma kinase (ALK) occurs in 3-7% of advanced NSCLC mainly because of chromosomic rearrangements at the ALK locus. Next to its oncogenic function, ALK chimeric oncoprotein is a possible antigen for human immune system. The prognostic value of natural anti-ALK immunogenicity remains poorly explored in ALK ​+ ​NSCLC. We hereby report preliminary results of a plasmatic anti-ALK a-abs titration assessment in a cohort of ALK ​+ ​NSCLC pts.

Objective: To evaluate the prevalence of pre-existing circulating anti-ALK a-abs in ALK ​+ ​NSCLC pts. Key secondary objectives are the assessment of anti-ALK a-abs prognostic value and association with brain metastases (BM).

Design: This monocentric case series included 60 ALK ​+ ​NSCLC pts progressing on any anti-ALK TKIs between October 2015 and February 2021 ​at Gustave Roussy Cancer Campus. Fifty-six plasma samples were analyzed through a semiquantitative immunocytochemical technique. Plasma samples were obtained from two prospective studies approved by our Institutional Review Board: the MATCH-R trial (NCT02517892) and the MSN trial (RECF1256).

Participants: We included pts diagnosed with unresectable stage III or IV NSCLC, either by contemporaneous or historical biopsy. ALK-rearrangement was identified by FISH, IHC or NGS. Pts were aged more than 18-year-old and had previously signed informed consent for one of the studies. Pts had received at least one anti-ALK-TKI during the disease history. Pts were not eligible if they had been diagnosed with a second cancer.

Main outcomes and measures: The prevalence of plasmatic anti-ALK a-abs titer was reported as percentage. Progression-free survival, overall survival, and time to BM were analyzed using Kaplan-Meier methods.

Results: We found an anti-ALK a-abs titer in 5 (9 ​%) pts. anti-ALK a-abs did not contribute to prolongation of survival. Although not significant, there was a trend towards protection against BM in the presence of anti-ALK a-abs.

Conclusions and relevance: Because ALK fusion proteins are exclusively produced intracellularly, not all ALK autoantibodies may have direct anti-tumor impact with favorable prognostic value. This is the first investigation to explore the impact of circulating anti-ALK a-abs on BM. Prospective studies with longer follow-up are warranted to further explore the impact of anti-ALK a-abs on BM.

Keywords: ALK; Anaplastic lymphoma kinase; Brain metastases; Circulating antibodies; Humoral response; Immunogenicity; Lung cancer; NSCLC.

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Conflict of interest statement

JCS: received consultancy fees from Relay Therapeutics; was an employee of AstraZeneca 2017–2019; has shares in AstraZeneca, Daiichi Sankyo, Gritstone; he is a full-time employee of Amgen since August 2021. Personal fees outside of this work: Astex, AstraZeneca, Bayer, Blend Therapeutics, Boehringer-Ingelheim, Clovis, Eli Lilly, Gammamabs, Merus, Mission Therapeutics, Pfizer, Pharmamar, Pierre Fabre, Roche, Sanofi, Servier, Symphogen, Tarveda; Gritstone; AstraZeneca. BB: Contracted/supported research grants: Abbvie, Amgen, AstraZeneca, BeiGene, Blueprint Medicines, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Cristal Therapeutics, Daiichi-Sankyo, Eli Lilly, GSK, Ignyta, IPSEN, Inivata, Janssen, Merck KGaA, MSD, Nektar, Onxeo, OSE immunotherapeutics, Pfizer, Pharma Mar, Roche-Genentech, Sanofi, Servier, Spectrum Pharmaceuticals, Takeda, Tiziana Pharma, Tolero Pharmaceuticals. The other authors declare no potential conflicts of interest related to this study.

Figures

Fig. 1
Fig. 1
ALK chimeric protein and its signaling network.
Fig. 2
Fig. 2
Kaplan-Meier (KM) curves of time to brain metastases (ttBM) in anti ALK ab ​+ group (antibodies) and anti ALK ab-group (no antibodies).
See this image and copyright information in PMC

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