Baseline Serum Autoantibody Signatures Predict Recurrence and Toxicity in Melanoma Patients Receiving Adjuvant Immune Checkpoint Blockade

Abstract

Purpose: Adjuvant immunotherapy produces durable benefit for patients with resected melanoma, but many develop recurrence and/or immune-related adverse events (irAE). We investigated whether baseline serum autoantibody (autoAb) signatures predicted recurrence and severe toxicity in patients treated with adjuvant nivolumab, ipilimumab, or ipilimumab plus nivolumab. Experimental Design: This study included 950 patients: 565 from CheckMate 238 (408 ipilimumab versus 157 nivolumab) and 385 from CheckMate 915 (190 nivolumab versus 195 ipilimumab plus nivolumab). Serum autoAbs were profiled using the HuProt Human Proteome Microarray v4.0 (CDI Laboratories, Mayaguez, PR). Analysis of baseline differentially expressed autoAbs was followed by recurrence and severe toxicity signature building for each regimen, testing of the signatures, and additional independent validation for nivolumab using patients from CheckMate 915. Results: In the nivolumab independent validation cohort, high recurrence score predicted significantly worse recurrence-free survival [RFS; adjusted HR (aHR), 3.60; 95% confidence interval (CI), 1.98–6.55], and outperformed a model composed of clinical variables including PD-L1 expression (P < 0.001). Severe toxicity score was a significant predictor of severe irAEs (aHR, 13.53; 95% CI, 2.59–86.65). In the ipilimumab test cohort, high recurrence score was associated with significantly worse RFS (aHR, 3.21; 95% CI, 1.38–7.45) and severe toxicity score significantly predicted severe irAEs (aHR, 11.04; 95% CI, 3.84–37.25). In the ipilimumab plus nivolumab test cohort, high autoAb recurrence score was associated with significantly worse RFS (aHR, 6.45; 95% CI, 1.48–28.02), and high severe toxicity score was significantly associated with severe irAEs (aHR, 23.44; 95% CI, 4.10–212.50). Conclusions: Baseline serum autoAb signatures predicted recurrence and severe toxicity in patients treated with adjuvant immunotherapy. Prospective testing of the signatures that include datasets with longer follow-up and rare but more severe toxicities will help determine their generalizability and potential clinical utility. See related commentary by Hassel and Luke, p. 3914

Predicting response and toxicity to immune checkpoint inhibitors in lung cancer using antibodies to frameshift neoantigens

“…This ampli cation facilitates their measurement. In general support of the utility of antibodies as biomarkers, a very recent study showed that antibodies against self-antigens can serve as biomarkers of melanoma recurrence following adjuvant therapy (52). The antibody biomarkers against non-self antigens described here are additionally unique measurements of patient status.…”

Toxicity-specific peripheral blood T and B cell dynamics in anti-PD-1 and combined immune checkpoint inhibition

“…This underscores that autoantibodies are likely at stake in some irAEs, including those affecting the thyroid gland [45]. Recent work by Johannet et al showed that baseline serum autoantibody signatures are predictive of severe irAEs (not limited to thyroiditis) with adjuvant anti-PD-1 and/or anti-CTLA-4 [46], which presents further evidence that preexistent subclinical autoimmunity may be at the root of various irAEs. Importantly, CXCL13 increase does not per se indicate TLS formation, as tumor-reactive T cells identified through CXCL13 expression can also be a source that expands upon treatment in ICI-responders [47].…”

Evaluation of tumor antigen-specific antibody responses in patients with metastatic triple negative breast cancer treated with cyclophosphamide and pembrolizumab

“…No association was found between median baseline autoantibody levels and disease recurrence in a prospective study of melanoma patients treated with ICB in the adjuvant setting, although an autoantibody signature that predicted recurrence-free survival and irAE development with high accuracy was reported. 37 The authors posited that the immunogenicity of specific autoantigens, such as those included in their recurrence signature, may possess superior predictive power relative to total autoantibody levels. 37 Lack of relationship between pretreatment and post-ICB autoantibody levels and clinical endpoints has also been described in a pan-cancer study, 38 although the authors assayed presence of a prescribed and limited panel of autoantigens and they did not examine autoantibody boostability relative to response.…”

“…37 The authors posited that the immunogenicity of specific autoantigens, such as those included in their recurrence signature, may possess superior predictive power relative to total autoantibody levels. 37 Lack of relationship between pretreatment and post-ICB autoantibody levels and clinical endpoints has also been described in a pan-cancer study, 38 although the authors assayed presence of a prescribed and limited panel of autoantigens and they did not examine autoantibody boostability relative to response. With regard to chemotherapy associations with autoantibodies, a reduction of autoantibody levels was observed in a breast cancer study after treatment with different combinations of chemotherapy, radiation, and hormonal therapy.…”