Immune checkpoint inhibitors have changed the treatment landscape of advanced melanomas. Namely, inhibition of cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4, ipilimumab) was the first immune checkpoint to show a survival benefit in advanced melanoma. Nonetheless, a subset of patients failed to benefit clinically from this immunotherapeutic. In addition, this treatment was often accompanied by the onset of immune-related adverse events (irAEs). As such, strategies aimed at enhancing clinical benefit and reducing adverse events are currently being investigated by means of combination therapies. Bacillus Calmette-Guerin (BCG) is a living attenuated strain of Mycobacterium bovis that stimulates cell-mediated immunity by producing a localized and self-limiting infection. This immunostimulatory agent has shown evidence of anti-tumour activity in several clinical studies with suggested induction of non-specific immune responses, thereby warranting further investigation.
This phase I study determined the safety, clinical efficacy and immunogenicity of the administration of intralesional BCG injection followed by intravenous ipilimumab (NCT01838200). A total of 5 patients with metastatic melanoma were enrolled, with 2 displaying high grade irAEs in accordance with ipilimumab-related toxicities. Furthermore, all patients displayed evidence of clinically progressive disease, with no evident therapeutic benefit. The approval of checkpoint inhibitors targeting programmed death 1 (anti-PD1) as first line therapy resulted in slow patient enrollment and early termination of the trial. Patients displaying irAEs were characterized by drastic increases in their autoantibody repertoire towards tumour and self-antigens, when compared to those with no reported irAEs. This high order of de novo and induced autoantibodies was detected in time points preceding clinical detection of these high-grade toxicities. However, they did not overlap, with unique antigen targets detected in each patient, suggesting evidence of a systemic B-cell deregulation and no organotypic specificity.
Intralesional BCG followed by ipilimumab therapy was not well tolerated in advanced melanoma patients, and showed no evidence of clinical benefit. Investigating humoral immunity may offer a means to detect the early onset of irAEs in a clinical trial setting.