MB-CART2019.1

Despite advances in the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and other common autoimmune neuropathies (AN), still-many patients with these diseases do not respond satisfactorily to the available treatments. Repurposing of disease-modifying therapies (DMTs) from other autoimmune conditions, particularly multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD), is a promising strategy that may accelerate the establishment of novel treatment choices for AN. This approach appears attractive due to homologies in the pathogenesis of these diseases and the extensive post-marketing experience that has been gathered from treating MS and NMOSD patients. The idea is also strengthened by a number of studies that explored the efficacy of DMTs in animal models of AN but also in some CIDP patients. We here review the available preclinical and clinical data of approved MS therapeutics in terms of their applicability to AN, especially CIDP. Promising therapeutic approaches appear to be B cell–directed and complement-targeting strategies, such as anti-CD20/anti-CD19 agents, Bruton’s tyrosine kinase inhibitors and anti-C5 agents, as they exert their effects in the periphery. This is a major advantage because, in contrast to MS, their action in the periphery is sufficient to exert significant immunomodulation.

This article illustrates the sequential loss of B-cell target antigens in multiply relapsed high-grade B-cell lymphoma treated with targeted therapies.A 58-yr-old woman was diagnosed with high-grade B-cell lymphoma based on lymph node biopsy after experiencing fatigue, night sweats, low-grade fever, and generalized lymphadenopathy.The initial diagnostic lymph node biopsy showed diffuse infiltration of large mature B-cells (CD19+, CD20+, CD79b+) with germinal center immunophenotype.Fluorescent in-situ hybridization (FISH) studies revealed both MYC and BCL2 translocations.The patient received first-line treatment with six cycles of dose-adjusted EPOCH-R and three doses of intrathecal methotrexate, and she achieved complete metabolic response.Ten months later she presented with biopsy-proven relapse and was treated with two cycles of R-ICE (rituximab, ifosfamide, carboplatin and etoposide) followed by ASCT.The patient relapsed 30 mo after transplant, presenting with spinal cord compression and malignant pleural effusion.Flow cytometry of the pleural fluid showed abnormal, transformed lymphoma cells with a B-cell immunophenotype, pos. for CD19, CD10, CD20 (dim) and monotypic lambda surface Ig.She received third-line treatment with gemcitabine and oxaliplatin followed by leukapheresis for manufacture of autologous anti-CD19 chimaeric antigen receptor (CAR) T-cells.She successfully received axi-cel after three days of lymphodepleting chemotherapy and achieved a complete metabolic remission at her first disease response assessment one month after CAR T-cell infusion.One year after CAR T-cell therapy, she had a third relapse.Immunophenotyping of an axillary lymph node biopsy by flow cytometry identified a lambda monotypic B-cell population pos. for CD10, but neg. for CD20.Targeted next-generation sequencing performed on the post-CAR T-cell therapy relapse biopsy showed multiple potentially relevant somatic variants including FOXO1, CDKN2A, KMT2D, MYC, CD79b and MS4A1.CD20 expression by flow cytometry was preserved until the relapse after ASCT and remained absent thereafter, including after axi-cel treatment.In addition, CD79b expression was also lost after exposure to polatuzumab vedotin.Author concluded that B-cell lineage antigen losses after targeted therapy as a mechanism for treatment failure in aggressive DLBCL.