Profiling Preexisting Antibodies in Patients Treated With Anti–PD-1 Therapy for Advanced Non–Small Cell Lung Cancer
Open accessAbstract
Importance: Administration of anti-programmed cell death protein 1 (anti-PD-1) is now standard therapy in advanced non-small cell lung cancer (NSCLC). However, immune checkpoint inhibitors, including anti-PD-1, have not been assessed in patients with subclinical disease with advanced NSCLC, and no useful clinical biomarkers have been associated with immune-related adverse events (irAEs) among these patients treated with anti-PD-1. Objective: To assess the safety and efficacy of anti-PD-1 treatment in patients with subclinical disease with advanced NSCLC and with or without preexisting autoimmune markers, including rheumatoid factor, antinuclear antibody, antithyroglobulin, and antithyroid peroxidase; and to assess potential clinical biomarkers that may be meaningfully and conveniently associated with clinical benefit or with irAEs following anti-PD-1 treatment. Design, Setting, and Participants: This medical records analysis retrospectively evaluated 137 patients who received nivolumab or pembrolizumab monotherapy at Sendai Kousei Hospital in Japan between January 2016 and January 2018. Treatment efficacy and irAEs were evaluated along with candidate factors that may be associated with irAEs. Exposures: Absence or presence of specific autoimmune markers and antibodies before treatment. Main Outcomes and Measures: Preexisting antibodies and autoimmune markers, progression-free survival (PFS), and irAEs. Results: Of 137 patients with advanced NSCLC, 105 were men, the median age was 68 (range, 36-88) years, 99 underwent nivolumab monotherapy, 38 underwent pembrolizumab monotherapy, and 134 had an Eastern Cooperative Oncology Group performance status of 0 or 1. The median PFS was 6.5 (95% CI, 4.4-12.9) months among patients with examined preexisting antibodies and 3.5 (95% CI, 2.4-4.1) months among patients without, suggesting significantly better prognosis in the former. The hazard ratio for disease progression or death in the presence of the examined preexisting antibodies was 0.53 (95% CI, 0.36-0.79; P = .002). The PFS was significantly longer among patients with any preexisting antibodies than among those without. The examined preexisting antibodies (48 patients [73%]) and rheumatoid factor (26 patients [39%]) were more common among patients who developed irAEs. Multivariate analysis indicated that the presence of the examined preexisting antibodies was independently associated with irAEs (odds ratio, 3.25; 95% CI, 1.59-6.65; P = .001). Skin reactions were more frequent among patients with preexisting rheumatoid factor (47% vs 24%, P = .02), whereas thyroid dysfunction was more frequent among patients with preexisting antithyroid antibodies (20% vs 1%, P < .001). Conclusions and Relevance: The presence of the examined preexisting antibodies was associated with clinical benefit and with the development of irAEs in patients with NSCLC treated with nivolumab or pembrolizumab. Thus, the presence of these autoimmune markers may help determine the risk-benefit ratio for individual patients with NSCLC, maximizing therapeutic benefits while minimizing irAEs.
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Pituitary glands expressed CTLA-4 in a subset of cells, which were targets for CTLA-4 antibody binding and resulted in complement deposition.
“pituitary glands expressed CTLA-4 in a subset of these cells, which were targets for CTLA-4 antibody binding, and resulted in complement deposition.”
From Endocrine toxicities of immune checkpoint inhibitors (2021) · cites this paper as [59]
A mouse model of hypophysitis induced by repeated anti-CTLA-4 injections resulted in lymphocytic infiltration into the pituitary gland and circulating anti-pituitary autoantibodies specific to thyrotropin-, gonadotropin-, and corticotropin-secreting cells.
“A mouse model of hypophysitis (induced by repeated injections of anti-CTLA-4 into C57BL/6 mice) resulted in lymphocytic infiltration into the pituitary gland and circulating anti-pituitary autoantibodies specific to thyrotropin-, gonadotropin-, and corticocotropin secreting cells.59”
From Endocrine toxicities of immune checkpoint inhibitors (2021) · cites this paper as [59]
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- Authors
- Toi, Y., Sugawara, S., Sugisaka, J., Ono, H., Kawashima, Y., Aiba, T., Kawana, S., Saito, R., Aso, M., Tsurumi, K., Suzuki, K., Shimizu, H., Domeki, Y., Terayama, K., Nakamura, A., Yamanda, S., Kimura, Y., & Honda, Y.
- Affiliations
- Sendai Kousei Hospital (JP)
- Department of Pulmonary Medicine, Sendai Kousei Hospital, Aoba-ku, Sendai, Miyagi, Japan
- Corresponding author
- Sugawara, Shunichi
- ORCID
- Venue
- JAMA Oncology
- Publisher
- American Medical Association (AMA)
- Published
- 2019-03-01
- Volume
- 5
- Issue
- 3
- Pages
- 376
- ISSN
- 2374-2437 (ISSN-L)
- PMC
- PMC6439838
- OpenAlex
- W2908431216
- Cited by
- 352
- References
- 46
- Citations by year
- 2026: 18 · 2025: 35 · 2024: 57 · 2023: 54 · 2022: 65 · 2021: 60 · 2020: 39 · 2019: 24
- FWCI
- 11.54
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Oncology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Keywords
- pre-existing antibodies, anti-PD-1 therapy, immune checkpoint inhibitors, advanced non-small cell lung cancer, immune-related adverse events, nivolumab, pembrolizumab, autoimmune markers, rheumatoid factor, antinuclear antibodies, progression-free survival, biomarkers, subclinical disease, treatment safety
- MeSH terms
- Antineoplastic Agents, Immunological, Nivolumab, Progression-Free Survival, Adult, Aged, Aged, 80 and over, Autoantibodies, Carcinoma, Non-Small-Cell Lung, Female, Humans, Lung Neoplasms, Male, Middle Aged, Retrospective Studies, Time Factors, Autoimmunity, Programmed Cell Death 1 Receptor, Antibodies, Monoclonal, Humanized
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