Autoantibodies May Predict Immune-Related Toxicity: Results from a Phase I Study of Intralesional Bacillus Calmette–Guérin followed by Ipilimumab in Patients with Advanced Metastatic Melanoma

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced melanoma. The first ICI to demonstrate clinical benefit, ipilimumab, targets cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4); however, the long-term overall survival is just 22%. More than 40 years ago intralesional (IL) bacillus Calmette–Guérin (BCG), a living attenuated strain of Mycobacterium bovis, was found to induce tumor regression by stimulating cell-mediated immunity following a localized and self-limiting infection. We evaluated these two immune stimulants in combination with melanoma with the aim of developing a more effective immunotherapy and to assess toxicity. In this phase I study, patients with histologically confirmed stage III/IV metastatic melanoma received IL BCG injection followed by up to four cycles of intravenous ipilimumab (anti-CTLA-4) ( number NCT01838200). The trial was discontinued following treatment of the first five patients as the two patients receiving the escalation dose of BCG developed high-grade immune-related adverse events (irAEs) typical of ipilimumab monotherapy. These irAEs were characterized in both patients by profound increases in the repertoire of autoantibodies directed against both self- and cancer antigens. Interestingly, the induced autoantibodies were detected at time points that preceded the development of symptomatic toxicity. There was no overlap in the antigen specificity between patients and no evidence of clinical responses. Efforts to increase response rates through the use of novel immunotherapeutic combinations may be associated with higher rates of irAEs, thus the imperative to identify biomarkers of toxicity remains strong. While the small patient numbers in this trial do not allow for any conclusive evidence of predictive biomarkers, the observed changes warrant further examination of autoantibody repertoires in larger patient cohorts at risk of developing irAEs during their course of treatment. In summary, dose escalation of IL BCG followed by ipilimumab therapy was not well tolerated in advanced melanoma patients and showed no evidence of clinical benefit. Measuring autoantibody responses may provide early means for identifying patients at risk from developing severe irAEs during cancer immunotherapy.

Autoimmune antibodies correlate with immune checkpoint therapy-induced toxicities

“…Tremendous efforts have been made to identify potential predictive biomarkers for IC-therapy-induced irAEs. These efforts include evaluation of immune cell phenotyping (16), cytokine assays (17), immune repertoire analysis (18), genetic variability of immune regulation (19), gastrointestinal microbiome diversity (20), and autoantibodies (21), etc. Among these potential biomarkers, autoantibodies have garnered particular interest as they can be easily detected from minimally invasive blood collection.…”

“…Among these potential biomarkers, autoantibodies have garnered particular interest as they can be easily detected from minimally invasive blood collection. A recent study investigating the autoantibody repertoire of a small number of patients with advanced metastatic melanoma treated with ipilimumab demonstrated that patients who developed irAEs were characterized by increases in the repertoire of autoantibodies directed against both self and cancer antigens at time points that preceded the development of the toxicity (21). Another recent study identified increased levels of specific B cell populations, including antibody-producing plasmablasts, in patients receiving combination IC therapy treatment.…”

Perspective: cancer vaccines in the era of immune checkpoint blockade

“…For example, BCG has been used since the 1970s to stimulate regression in melanoma and in more recent years and is widely applied as standard therapy for early stage bladder cancer (Alexandroff et al 1999 ). In an attempt to exploit this approach, we recently undertook an early phase clinical trial with intraregional BCG combined with the CTLA4 inhibitor Ipilimumab (Da Gama Duarte et al 2018 ). This trial was discontinued prematurely because of severe auto-immune toxicity in some patients, demonstrating that the approach has the potential to be highly immuno-stimulatory but that some selectivity for cancer may be important in order to constrain toxicity.…”

Progress in Neoantigen Targeted Cancer Immunotherapies

“…High mutation burden is associated with survival benefits from ICB therapy, but autoantibodies may also predict the efficacy of immune checkpoint inhibitors (ICIs) (De Moel et al, 2019). However, recent studies have demonstrated that autoantibodies correlate with immune checkpoint therapy-induced toxicities (Da Gama et al, 2018;De Moel et al, 2019;Tahir et al, 2019). Since the mechanism of ICB therapy is to mediate non-specific suppression of T cells by negative costimulatory signals, it may break the balance of autoimmunity and lead to the activation of autoreactive B cells that produce autoantibodies (Pardoll, 2012;Oh et al, 2017).…”