Evaluation of autoantibodies as predictors of treatment response and immune‐related adverse events during the treatment with immune checkpoint inhibitors: A prospective longitudinal pan‐cancer study

Abstract

Background The presence of autoantibodies in the serum of cancer patients has been associated with immune‐checkpoint inhibitor (ICI) therapy response and immune‐related adverse events (irAEs). A prospective evaluation of different autoantibodies in different cancer entities is missing. Materials and Methods In this prospective cohort study, we included a pan‐cancer cohort of patients undergoing ICI treatment and measured a comprehensive panel of autoantibodies at treatment start and at the time point of first response evaluation. The presence and induction of autoantibodies (ANA, ENA, myositis, hepatopathy, rheumatoid arthritis) in different cancer entities were assessed and the association between autoantibodies and disease control rate (DCR), objective response rate (ORR), and progression‐free survival (PFS), as well as the development of grade 3 or higher irAEs were evaluated by logistic regression models, cox proportional hazard models, and Kaplan–Meier estimators. Results Of 44 patients with various cancer entities, neither the presence of any positive autoantibody measurement nor the presence of positive antinuclear antibodies (ANA) [≥1:80] at baseline was associated with the examined clinical endpoints (DCR, ORR, PFS) in univariable and multivariable analyses. After 8–12 weeks of ICI treatment, DCR, ORR, and PFS did not significantly differ between patients with and without any positive autoantibody measurement or positive ANA titers. The frequency of irAEs did not differ depending on autoantibody status of the patients. Conclusion Autoantibodies at treatment initiation or induction after 8–12 weeks of ICI treatment are not associated with treatment efficacy as indicated by DCR, ORR, and PFS or higher grade irAEs.

Association between Changes in the Patterns of Antinuclear Autoantibodies during Immune Checkpoint Inhibition Therapy and the Development of Severe Immune Related Adverse Events

“…Considering that the development of irAEs is associated with immune checkpoint blockade response [ 38 ], this is not unexpected since checkpoint blockade can enhance anti-tumoral T cell response at different grades and severe irAEs could reflect stronger immunological T cell responses. In contrast with our results, another study did not find any association between autoantibody induction and a higher grade of irAEs [ 27 ]. This discordance may be due to the heterogeneity in the antibodies tested and the patient cohorts.…”

“…We did not find differences in irAE prevalence between patients with and without pre-existing ANAs nor between patients with and without ANAs in serial samples after ICI initiation. These results are consistent with other studies [ 25 , 26 , 27 , 29 ]. Considering the clinical similarity between autoimmune diseases and irAEs, the lack of association between the presence of ANA and the risk of irAE could be explained by two main reasons.…”

“…Other authors associated seroconversion to positive ANAs, extractable nuclear autoantibodies (ENA) or anti-smooth muscle autoantibodies (ASMA) in the first 30 days after ICI initiation with better treatment outcomes and a higher risk of irAEs [ 28 ]. Similar to our results, other studies did not find a significant association between ANA development and irAE rates [ 27 , 30 , 39 ].…”

“…The presence of ANAs in patients who receive ICI therapies and develop irAEs has been reported. Most published studies have focused on analyzing the predictor role of pre-existing ANAs prior to ICI therapy and their association with the risk of irAEs [ 25 , 26 , 27 ]. Seroconversion to ANA positive after ICI initiation has been also reported [ 28 , 29 ].…”

Checkpoint inhibitor immune-related adverse events: A focused review on autoantibodies and B cells as biomarkers, advancements and future possibilities

“…Similarly, although De Moel et al ( 106) also recorded an increase in rheumatologic AAbs from baseline in late-stage melanoma patients (who were antibody negative pre-treatment), no association with any irAEs was observed. Several reports have also found no significant association between pre-existing ANAs in various cancer patients prior to ICI therapy, with the occurrence of irAEs (97,99,103,104). Despite the temporal resemblance of classic autoimmune diseases with irAEs, it appears that their mechanisms might be different and whether an increase or decrease in classic rheumatological AAbs is beneficial for the prediction of irAEs remains controversial and requires further investigation.…”