Background/Purpose: PD-1 immune checkpoint inhibitors are able to re-activate restrained anti-tumor T-cell responses in melanoma patients. However, PD-1 inhibition may also activate auto-reactive T-cells leading to immune-related adverse events (irAEs). Autoantibodies might also play a role in anti-PD-1 induced irAEs and could potentially be used to identify patients at risk of developing these irAEs. Therefore, we investigated the association between autoantibody-positivity and treatment toxicity and response in melanoma patients treated with anti-PD-1.

Methods: This multicenter, retrospective study included 143 advanced melanoma patients treated with anti-PD-1. Until six months after treatment initiation, toxicities grade ≥2 and recurrences/responses were captured. Autoantibody measurements, comprising IgM rheumatoid factor (RF), antinuclear antibodies (ANA), anti-cyclic citrullinated peptide antibodies (anti-CCP2), anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-Tg) were performed in an ISO15189 accredited laboratory at baseline and after three months of treatment.

Results: A total of 169 irAEs were experienced by 86 patients, the most common being thyroiditis (n=25), dermatitis (n=24), and sicca complaints (n=19). More irAE (30/37 [81%]) were observed in patients with pre-existing detectable autoantibodies than in patients without these autoantibodies (55/106 [52%], p = 0.003) (table 1). This was mainly due to the strong association of anti-thyroid antibodies and thyroid dysfunction (69% in anti-TPO and/or anti-Tg positive patients versus 12% in anti-TPO and/or anti-Tg negative patients, p < 0.001). No association between anti-CCP2, RF or ANA and arthritis, dermatitis, sicca or colitis was observed. The association with thyroid antibodies was strongest in female patients: of seropositive female patients 7/7 (100%) developed thyroiditis, compared to only 10/48 (21%) of anti-TPO and anti-Tg negative patients.

Seroconversion during anti-PD-1-treatment was only seen for thyroid antibodies. Here the combined positivity for anti-TPO and/or anti-Tg increased from 13/143 (9.1%) at baseline to 24/143 (17%) on treatment (p = 0.003). For the other autoantibodies the total number of seropositive patients stayed stable or decreased on treatment (table 2). Seroconversion of anti-Tg and/or anti-TPO was associated with thyroid dysfunction in female patients: 6/10 [60%] of seroconverted patients developed thyroid dysfunction compared to 3/38 [8%] patients that remained seronegative (p = 0.001). Autoantibody-positivity was not associated with disease recurrence (p = 0.45) or response (p = 0.69).

Conclusion: Autoantibody-positivity prior to anti-PD-1 therapy is associated with the development of irAEs in melanoma patients, indicating that anti-PD-1 therapy not only leads to loss of tolerance to tumor antigens but also to nontumor autoantigens. Baseline positivity and seroconversion of anti-thyroid antibodies were associated with the development of thyroiditis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/autoantibody-positivity-before-treatment-is-associated-with-immune-related-adverse-events-in-melanoma-patients-treated-with-anti-pd-1/