Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus

Mackensen, Andréas; Müller, Fabian; Mougiakakos, Dimitrios; Boeltz, Sebastian; Wilhelm, Artur; Aigner, Michael; Völkl, Simon; Simón, David; Kleyer, Arnd; Muñoz, Luis; Kretschmann, Sascha; Kharboutli, Soraya; Gary, Regina; Reimann, Hannah; Rösler, Wolf; Uderhardt, Stefan; Bang, Holger; Herrmann, Martin; Ekici, Arif B.; Buettner, Christian; Habenicht, Katharina Maria; Winkler, Thomas; Krönke, Gerhard; Schett, Georg

doi:10.1038/s41591-022-02017-5

Cited by 463 publications

(318 citation statements)

References 45 publications

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“…Furthermore, promising target antigens, such as CD30 in Hodgkin´s lymphoma and colon cancer [ 33 , 39 ], or CD5 on T-cell lymphoma [ 40 ], are co-expressed by healthy T cells creating the risk of durable damage to endogenous healthy T-cells upon targeting by conventional CAR T-cells. Finally, CAR T-cells have gained attraction beyond the realm of oncology and are currently being evaluated as a promising therapy for autoimmune diseases, such as systemic lupus erythematosus [ 41 ]. Here, CAR T-cells with self-limiting activities could lead to depletion of auto-reactive B-cells in a short-term CAR T-cell therapy without the need for potentially life-long persistence of genetic cell products in non-tumor patients.…”

Section: Discussionmentioning

confidence: 99%

CAR Triggered Release of Type-1 Interferon Limits CAR T-Cell Activities by an Artificial Negative Autocrine Loop

Harrer

Schenkel

Bezler³

et al. 2022

Cells

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The advent of chimeric antigen receptor (CAR) T cells expedited the field of cancer immunotherapy enabling durable remissions in patients with refractory hematological malignancies. T cells redirected for universal cytokine-mediated killing (TRUCKs), commonly referred to as “fourth generation” CAR T-cells, are designed to release engineered payloads upon CAR-induced T-cell activation. Building on the TRUCK technology, we aimed to generate CAR T-cells with a CAR-inducible artificial, self-limiting autocrine loop. To this end, we engineered CAR T-cells with CAR triggered secretion of type-1 interferons (IFNs). At baseline, IFNα and IFNβ CAR T-cells showed similar capacities in cytotoxicity and cytokine secretion compared to conventional CAR T-cells. However, under “stress” conditions of repetitive rounds of antigen stimulation using BxPC-3 pancreas carcinoma cells as targets, anti-tumor activity faded in later rounds while being fully active in destructing carcinoma cells during first rounds of stimulation. Mechanistically, the decline in activity was primarily based on type-1 IFN augmented CAR T-cell apoptosis, which was far less the case for CAR T-cells without IFN release. Such autocrine self-limiting loops can be used for applications where transient CAR T-cell activity and persistence upon target recognition is desired to avoid lasting toxicities.

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Section: Discussionmentioning

confidence: 99%

CAR Triggered Release of Type-1 Interferon Limits CAR T-Cell Activities by an Artificial Negative Autocrine Loop

Harrer

Schenkel

Bezler³

et al. 2022

Cells

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“…Importantly, drug-free remission was maintained during longer follow-up since reappearing B cells were naïve and showed non-class-switched B cell receptors. 84,85 This study highlights the role of adaptive immune responses in the development of SLE and is an example of a tolerable and highly effective new therapeutic approach.…”

Section: Targeting B-lymphocytesmentioning

confidence: 96%

Lupus Nephritis: Current Perspectives and Moving Forward

Lichtnekert¹,

Anders²,

Lech³

2022

JIR

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Lupus nephritis is a severe organ manifestation of systemic lupus erythematosus, and its pathogenesis involves complex etiology and mechanisms. Despite significant knowledge gains and extensive efforts put into understanding the development and relapsing disease activity, lupus nephritis remains a substantial cause of morbidity and mortality in lupus patients. Current therapies retain a significant unmet medical need regarding rates of complete response, preventing relapse of lupus nephritis, progression of chronic kidney disease to kidney failure, drug toxicity, and pill burden-related drug non-adherence. Connected to progression of chronic kidney disease are the associated risks for disabling or even lethal cardiovascular events, as well as chronic kidney disease-related secondary immunodeficiency and serious infections. In this regard, biomarkers are needed that can predict treatment response to specific drugs to enable personalized precision medicine. A series of clinical trials with innovative immunomodulatory drugs are ongoing and raise expectations for improvements in the management of lupus nephritis. Here, we review how new developments in pathogenesis connect with current and future perspectives for the management of lupus nephritis.

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“…Ofatumumab and obinutuzumab are humanized anti-CD20 monoclonal antibodies, which have successfully treated patients with PMN who developed serum sickness to rituximab or anti-rituximab antibodies ( 157 , 158 ), and demonstrated superior B-cell depletion compared to rituximab respectively ( 159 ). The efficacy of binutuzumab and belimumab [humanized monoclonal antibody against B-cell activating factor (BAFF)] in lupus nephritis, another disease mediated in part by autoreactive B cells, and CD19 CAR T cells in treatment-refractory SLE are also promising alternative B cell-depleting therapies, which require further evaluation in PMN ( 160 – 163 ).…”

Section: Novel Therapeutics: Potential Targets and Challengesmentioning

confidence: 99%

Membranous nephropathy: Clearer pathology and mechanisms identify potential strategies for treatment

et al. 2022

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Primary membranous nephropathy (PMN) is one of the common causes of adult-onset nephrotic syndrome and is characterized by autoantibodies against podocyte antigens causing in situ immune complex deposition. Much of our understanding of the disease mechanisms underpinning this kidney-limited autoimmune disease originally came from studies of Heymann nephritis, a rat model of PMN, where autoantibodies against megalin produced a similar disease phenotype though megalin is not implicated in human disease. In PMN, the major target antigen was identified to be M-type phospholipase A2 receptor 1 (PLA2R) in 2009. Further utilization of mass spectrometry on immunoprecipitated glomerular extracts and laser micro dissected glomeruli has allowed the rapid discovery of other antigens (thrombospondin type-1 domain-containing protein 7A, neural epidermal growth factor-like 1 protein, semaphorin 3B, protocadherin 7, high temperature requirement A serine peptidase 1, netrin G1) targeted by autoantibodies in PMN. Despite these major advances in our understanding of the pathophysiology of PMN, treatments remain non-specific, often ineffective, or toxic. In this review, we summarize our current understanding of the immune mechanisms driving PMN from animal models and clinical studies, and the implications on the development of future targeted therapeutic strategies.

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Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus

Cited by 463 publications

References 45 publications

CAR Triggered Release of Type-1 Interferon Limits CAR T-Cell Activities by an Artificial Negative Autocrine Loop

CAR Triggered Release of Type-1 Interferon Limits CAR T-Cell Activities by an Artificial Negative Autocrine Loop

Lupus Nephritis: Current Perspectives and Moving Forward

Membranous nephropathy: Clearer pathology and mechanisms identify potential strategies for treatment

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