Treatment of a patient with severe systemic sclerosis (SSc) using CD19-targeted CAR T cells

Bergmann, Christina; Müller, Fabian; Distler, Jörg H W; Györfi, Andrea-Hermina; Völkl, Simon; Aigner, Michael; Kretschmann, Sascha; Reimann, Hannah; Harrer, Thomas; Bayerl, Nadine; Boeltz, Sebastian; Wirsching, Andreas; Taubmann, Jule; Rösler, Wolf; Spriewald, Bernd M.; Wacker, Jochen; Atzinger, Armin; Uder, Michael; Kuwert, Torsten; Mackensen, Andréas; Schett, Georg

doi:10.1136/ard-2023-223952

Cited by 91 publications

(30 citation statements)

References 8 publications

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“…In case reports or small case series, CD19 CAR T cell therapy has been successfully used to treat SLE, idiopathic inflammatory myopathy, and systemic sclerosis. 1,2,[31][32][33][34] The rapid and sustained clearance of symptoms of SLE after CD19 CAR T cell therapy in the aforementioned case description is remarkable and reinforces the essential role of the B cell lineage in the pathogenesis of SLE. In contrast to monoclonal antibodies, CAR T cells combine antigen recognition and effector function in one "drug" and therefore do not depend on the presence of sufficient effector cells or complement to exert their B cell-depleting function (Figure 3).…”

Section: Lessons From Deep B Cell Depletion Via Cd19 Car T Cells In Slementioning

confidence: 78%

“…Because autoimmune B cells also express CD19, they are susceptible to being killed by specific CAR T cells. In case reports or small case series, CD19 CAR T cell therapy has been successfully used to treat SLE, idiopathic inflammatory myopathy, and systemic sclerosis 1,2,31–34 . The rapid and sustained clearance of symptoms of SLE after CD19 CAR T cell therapy in the aforementioned case description is remarkable and reinforces the essential role of the B cell lineage in the pathogenesis of SLE.…”

Section: Introductionmentioning

confidence: 91%

“…Plasmablasts as a source for autoantibodies may also pertain to other autoantibody entities such those against the Smith antigen and, outside the SLE field, antisynthetase antibodies (such as anti-Jo-1) or RNA polymerase III antibodies, all of which can disappear after CD19 CAR T cell treatment. 31,34 However, plasmablasts may not be the main source of all autoantibody species (Figure 3). Circumstantial evidence suggests for instance that anti-Ro antibodies remain intact after CD19 CAR T cell therapy, 30 indicating that these autoantibodies may derive from CD19-negative cells, most likely plasma cells, supporting previously published concepts.…”

Section: Disentangling Cellular Sources Of Antibody Production By Car...mentioning

confidence: 99%

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CD19 Chimeric Antigen Receptor T Cell Treatment: Unraveling the Role of B Cells in Systemic Lupus Erythematosus

Taubmann,

Müller,

Yalcin Mutlu

et al. 2024

Arthritis & Rheumatology

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B cell generation of autoantibodies is a crucial step in the pathogenesis of systemic lupus erythematosus (SLE). After their differentiation in the bone marrow, B cells populate the secondary lymphatic organs, where they undergo further maturation leading to the development of memory B cells as well as antibody‐producing plasmablasts and plasma cells. Targeting B cells is an important strategy to treat autoimmune diseases like SLE, in which B cell tolerance is disturbed and autoimmune B cells and autoantibodies emerge. This review discusses the functional aspects of antibody‐ and cell‐based B cell depleting therapy in SLE. It thereby particularly focuses on lessons learned from chimeric antigen receptor (CAR) T cell treatment on the role of B cells in SLE for understanding B cell pathology in SLE. CAR T cells model a deep B cell depletion and thereby allow understanding the role of aberrant B cell activation in the pathogenesis of SLE. Furthermore, the effects of B cell depletion on autoantibody production can be better described, i.e. explaining the concept of different cellular sources of (auto‐) antibodies in the form of short‐lived plasmablasts and long‐lived plasma cells, which differ in their susceptibility to B cell depletion and require different targeted therapeutic approaches. Finally, the safety of deep B cell depletion in autoimmune disease is discussed.This article is protected by copyright. All rights reserved.

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Section: Lessons From Deep B Cell Depletion Via Cd19 Car T Cells In Slementioning

confidence: 78%

Section: Introductionmentioning

confidence: 91%

Section: Disentangling Cellular Sources Of Antibody Production By Car...mentioning

confidence: 99%

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CD19 Chimeric Antigen Receptor T Cell Treatment: Unraveling the Role of B Cells in Systemic Lupus Erythematosus

Taubmann,

Müller,

Yalcin Mutlu

et al. 2024

Arthritis & Rheumatology

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“…This treatment was well tolerated with only mild cytokine-releasing syndrome. For SSc, the same group recently demonstrated a case report in which an SSc patient was treated with CD-19 targeted CAR-T therapy [40 ▪▪ ]. In this case report, CD-19 targeted CAR-T cell therapy improved the symptoms of skin, heart, and joints, although the research group also mentioned that they could not deny the contribution of conditioning therapy (fludarabine and cyclophosphamide) to the short-term effect.…”

Section: B Cell-targeted Therapymentioning

confidence: 98%

Targeting B cells for treatment of systemic sclerosis

Terui

Segawa

Asano

2023

Current Opinion in Rheumatology

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Purpose of review The pathogenesis of systemic sclerosis (SSc) has been linked to dysfunctional B cells as demonstrated in previous research. This review aims to show the evidence and ongoing clinical trials of B cell-targeted therapy and overview the various aspects of B cell involvement in SSc. Recent findings We provide an overview of the current understanding and therapeutic strategies targeting B cells in SSc patients. Several molecular targets of B cells have been identified for treating SSc, including CD20, CD19, B-cell activating factor (BAFF), and proteasome. Summary Many clinical trials have demonstrated that B cells play a critical role in the pathogenesis of SSc and may be a potential therapeutic target to improve disease symptoms. Although large-scale clinical studies are needed, various B cell-targeted therapies have the potential to address the unmet needs of SSc patients.

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“…[15][16][17] Beyond the approved products, more than 300 ongoing trials are investigating novel constructs, targets, and indications, 18 and CAR-T-cell use is rapidly expanding in various hematologic malignancies, solid tumors, and non-oncological indications such as autoimmune diseases and infections. [19][20][21][22][23][24] The widespread use of these potent therapies is in part limited by frequent toxicities, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), early immune effector cell-associated hematoxicity (ICAHT), 25 and hemophagocytic lymphohistiocytosis (HLH), in the acute setting. Definitions and grading of acute post-CAR-T-cell toxicities are available by the American Society for Transplantation and Cellular Therapy.…”

Section: Introductionmentioning

confidence: 99%

Infections after chimeric antigen receptor (CAR)‐T‐cell therapy for hematologic malignancies

Kampouri,

Little,

Rejeski

et al. 2023

Transplant Infectious Dis

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BackgroundChimeric antigen receptor (CAR)‐T‐cell therapies have revolutionized the management of acute lymphoblastic leukemia, non‐Hodgkin lymphoma, and multiple myeloma but come at the price of unique toxicities, including cytokine release syndrome, immune effector cell‐associated neurotoxicity syndrome, and long‐term “on‐target off‐tumor” effects.MethodsAll of these factors increase infection risk in an already highly immunocompromised patient population. Indeed, infectious complications represent the key determinant of non‐relapse mortality after CAR‐T cells. The temporal distribution of these risk factors shapes different infection patterns early versus late post‐CAR‐T‐cell infusion. Furthermore, due to the expression of their targets on B lineage cells at different stages of differentiation, CD19, and B‐cell maturation antigen (BCMA) CAR‐T cells induce distinct immune deficits that could require different prevention strategies. Infection incidence is the highest during the first month post‐infusion and subsequently decreases thereafter. However, infections remain relatively common even a year after infusion.ResultsBacterial infections predominate early after CD19, while a more equal distribution between bacterial and viral causes is seen after BCMA CAR‐T‐cell therapy, and fungal infections are universally rare. Cytomegalovirus (CMV) and other herpesviruses are increasingly breported, but whether routine monitoring is warranted for all, or a subgroup of patients, remains to be determined. Clinical practices vary substantially between centers, and many areas of uncertainty remain, including CMV monitoring, antibacterial and antifungal prophylaxis and duration, use of immunoglobulin replacement therapy, and timing of vaccination.ConclusionRisk stratification tools are available and may help distinguish between infectious and non‐infectious causes of fever post‐infusion and predict severe infections. These tools need prospective validation, and their integration in clinical practice needs to be systematically studied. image

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Treatment of a patient with severe systemic sclerosis (SSc) using CD19-targeted CAR T cells

Cited by 91 publications

References 8 publications

CD19 Chimeric Antigen Receptor T Cell Treatment: Unraveling the Role of B Cells in Systemic Lupus Erythematosus

CD19 Chimeric Antigen Receptor T Cell Treatment: Unraveling the Role of B Cells in Systemic Lupus Erythematosus

Targeting B cells for treatment of systemic sclerosis

Infections after chimeric antigen receptor (CAR)‐T‐cell therapy for hematologic malignancies

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