Publications

Orvacabtagene autoleucel (orva-cel) is a fully human B cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T cell therapy evaluated in a phase 1/2 study in patients with relapsed or refractory multiple myeloma (RRMM). To assess treatment-related immunogenicity, anti-CAR therapeutic domain-specific antibodies (ATAs) were monitored in 157 treated patients. The ATAs were detected in 44.6% of patients over the course of study, with titers and incidence increasing over time. The goal of this study was to further characterize the observed immune response. The ATA status did not affect CAR T cell expansion or patient survival outcomes, though reduced persistence was observed in ATA-positive patients. Comprehensive immune profiling—including isotype analysis and B cell epitope mapping—identified five immunodominant consensus peptide sequences within the CAR domain. These epitopes were targeted by both Immunoglobulin G (IgG) and Immunoglobulin M (IgM) isotypes, with a persistent IgM response detected in most ATA-positive individuals. Despite the presence of ATAs, no adverse impact on cellular expansion was observed, potentially due to lymphodepletion and baseline immune suppression characteristic of B cell malignancies. These data suggest that the limited functional T- and B-cell capacity in RRMM may attenuate the clinical consequences of ATA development. The in vitro immunogenicity risk assessment and epitope mapping identified immunogenic hotspots within the CAR structure, which could have led to the high incidence of immune response observed in the patients. However, the analysis from this study points to a weak clinically non-relevant nature of the response that could be attributed to the patient’s immune status and diseased state.

In October 2019, Novartis launched brolucizumab, a single-chain variable fragment molecule targeting vascular endothelial growth factor A, for the treatment of neovascular age-related macular degeneration. In 2020, rare cases of retinal vasculitis and/or retinal vascular occlusion (RV/RO) were reported, often during the first few months after treatment initiation, consistent with a possible immunologic pathobiology. This finding was inconsistent with preclinical studies in cynomolgus monkeys that demonstrated no drug-related intraocular inflammation, or RV/RO, despite the presence of preexisting and treatment-emergent antidrug antibodies (ADAs) in some animals. In this study, the immune response against brolucizumab in humans was assessed using samples from clinical trials and clinical practice. In the brolucizumab-naïve population, anti-brolucizumab ADA responses were detected before any treatment, which was supported by the finding that healthy donors can harbor brolucizumab-specific B cells. This suggested prior exposure of the immune system to proteins with structural similarity. Experiments on samples showed that naïve and brolucizumab-treated ADA-positive patients developed a class-switched, high-affinity immune response, with several linear epitopes being recognized by ADAs. Only patients with RV/RO showed a meaningful T cell response upon recall with brolucizumab. Further studies in cynomolgus monkeys preimmunized against brolucizumab with adjuvant followed by intravitreal brolucizumab challenge demonstrated that high ADA titers were required to generate ocular inflammation and vasculitis/vascular thrombosis, comparable to RV/RO in humans. Immunogenicity therefore seems to be a prerequisite to develop RV/RO. However, because only 2.1% of patients with ADA develop RV/RO, additional factors must play a role in the development of RV/RO.