MB-CART2019.1

Autoimmune disorders can affect various organs and if refractory, can be life threatening. Recently, CD19-targeting-chimeric antigen receptor (CAR) T cells were efficacious as an immune suppressive agent in 6 patients with refractory systemic lupus erythematosus and in 1 patient with antisynthetase syndrome.

To test the safety and efficacy of CD19-targeting CAR T cells in a patient with severe antisynthetase syndrome, a complex autoimmune disorder with evidence for B- and T-cell involvement.

This case report describes a patient with antisynthetase syndrome with progressive myositis and interstitial lung disease refractory to available therapies (including rituximab and azathioprine), who was treated with CD19-targeting CAR T cells in June 2022 at University Hospital Tübingen in Tübingen, Germany, with the last follow-up in February 2023. Mycophenolate mofetil was added to the treatment to cotarget CD8+ T cells, hypothesized to contribute to disease activity.

Prior to treatment with CD19-targeting CAR T cells, the patient received conditioning therapy with fludarabine (25 mg/m2 [5 days before until 3 days before]) and cyclophosphamide (1000 mg/m2 [3 days before]) followed by infusion of CAR T cells (1.23×106/kg [manufactured by transduction of autologous T cells with a CD19 lentiviral vector and amplification in the CliniMACS Prodigy system]) and mycophenolate mofetil (2 g/d) 35 days after CD19-targeting CAR T-cell infusion.

The patient's response to therapy was followed by magnetic resonance imaging of the thigh muscle, Physician Global Assessment, functional muscle and pulmonary tests, and peripheral blood quantification of anti-Jo-1 antibody levels, lymphocyte subsets, immunoglobulins, and serological muscle enzymes.

Rapid clinical improvement was observed after CD19-targeting CAR T-cell infusion. Eight months after treatment, the patient's scores on the Physician Global Assessment and muscle and pulmonary function tests improved, and there were no detectable signs of myositis on magnetic resonance imaging. Serological muscle enzymes (alanine aminotransferase, aspartate aminotransferase, creatinine kinase, and lactate dehydrogenase), CD8+ T-cell subsets, and inflammatory cytokine secretion in the peripheral blood mononuclear cells (interferon gamma, interleukin 1 [IL-1], IL-6, and IL-13) were all normalized. Further, there was a reduction in anti-Jo-1 antibody levels and a partial recovery of IgA (to 67% of normal value), IgG (to 87%), and IgM (to 58%).

CD19-targeting CAR T cells directed against B cells and plasmablasts deeply reset B-cell immunity. Together with mycophenolate mofetil, CD19-targeting CAR T cells may break pathologic B-cell, as well as T-cell responses, inducing remission in refractory antisynthetase syndrome.

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.