Severe anti-PD1-related meningoencephalomyelitis successfully treated with anti-integrin alpha4 therapy

Basin, Sarah; Perrin, J.; Michot, Jean‐Marie; Lambotte, Olivier; Cauquil, Cécile

doi:10.1016/j.ejca.2020.12.014

Cited by 11 publications

(8 citation statements)

References 9 publications

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“… 468 Severe anti-programmed death-1 (PD-1)-related meningoencephalomyelitis can be treated with anti-integrin α4 therapy. 469 Studies of murine and human cells expressing RGD-binding integrins proved that αvβ6 and αvβ8 heterodimers were involved in M1 and M3 infections. 470 These targets are of great significance for the mechanistic exploration and treatment of HIT and other infectious diseases, and more research data are needed in the future.…”

Section: Integrin Roles In Physiology and Pathologymentioning

confidence: 99%

Targeting integrin pathways: mechanisms and advances in therapy

Pang

Qiu

et al. 2023

Sig Transduct Target Ther

225

111

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Integrins are considered the main cell-adhesion transmembrane receptors that play multifaceted roles as extracellular matrix (ECM)-cytoskeletal linkers and transducers in biochemical and mechanical signals between cells and their environment in a wide range of states in health and diseases. Integrin functions are dependable on a delicate balance between active and inactive status via multiple mechanisms, including protein-protein interactions, conformational changes, and trafficking. Due to their exposure on the cell surface and sensitivity to the molecular blockade, integrins have been investigated as pharmacological targets for nearly 40 years, but given the complexity of integrins and sometimes opposite characteristics, targeting integrin therapeutics has been a challenge. To date, only seven drugs targeting integrins have been successfully marketed, including abciximab, eptifibatide, tirofiban, natalizumab, vedolizumab, lifitegrast, and carotegrast. Currently, there are approximately 90 kinds of integrin-based therapeutic drugs or imaging agents in clinical studies, including small molecules, antibodies, synthetic mimic peptides, antibody–drug conjugates (ADCs), chimeric antigen receptor (CAR) T-cell therapy, imaging agents, etc. A serious lesson from past integrin drug discovery and research efforts is that successes rely on both a deep understanding of integrin-regulatory mechanisms and unmet clinical needs. Herein, we provide a systematic and complete review of all integrin family members and integrin-mediated downstream signal transduction to highlight ongoing efforts to develop new therapies/diagnoses from bench to clinic. In addition, we further discuss the trend of drug development, how to improve the success rate of clinical trials targeting integrin therapies, and the key points for clinical research, basic research, and translational research.

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Section: Integrin Roles In Physiology and Pathologymentioning

confidence: 99%

Targeting integrin pathways: mechanisms and advances in therapy

Pang

Qiu

et al. 2023

Sig Transduct Target Ther

225

111

View full text Add to dashboard Cite

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“…These medications should be considered only after tocilizumab and/or bortezomib failure as (a) some patients did not improve after tocilizumab/bortezomib, but improved after daratumumab [56][57][58] or tofacitinib [32], (b) the evidence of efficacy of these drugs is mostly anecdotal and, on the contrary, the effects of bortezomib and tocilizumab rely only on case reports/series lacking a control group, and (c) these drugs may be associated with relevant side effects that should not be overlooked. Among the analyzed treatments, natalizumab may represent a safe and effective treatment for refractory T-cell-mediated encephalitides, such as those associated with cancer immunotherapy or intracellular antibodies [67][68][69].…”

Section: Discussionmentioning

confidence: 99%

“…Natalizumab acts by blocking central nervous system immune cell trafficking through alpha4beta1 integrin, and it is commonly used in multiple sclerosis [66]. The efficacy of natalizumab has been reported in one case with Hu-associated limbic encephalitis [67] and in one case with anti-glial fibrillary acid protein antibody meningoencephalitis [68] occurring after exposure to cancer immunotherapy (nivolumab and ipilimumab and pembrolizumab, respectively).…”

Section: Natalizumabmentioning

confidence: 99%

Treatment Options in Refractory Autoimmune Encephalitis

2022

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Autoimmune encephalitis represents a potentially treatable immune-mediated condition that is being more frequently recognized. Prompt immunotherapy is a key factor for the management of autoimmune encephalitis. First-line treatments include intravenous steroids, plasma exchange, and intravenous immunoglobulins, which can be combined in most severe cases. Rituximab and cyclophosphamide are administered as second-line agents in unresponsive cases. A minority of patients may still remain refractory, thus representing a major clinical challenge. In these cases, treatment strategies are controversial, and no guidelines exist. Treatments proposed for refractory autoimmune encephalitis include (1) cytokine-based drugs (such as tocilizumab, interleukin-2/basiliximab, anakinra, and tofacitinib); (2) plasma cell-depleting agents (such as bortezomib and daratumumab); and (3) treatments targeting intrathecal immune cells or their trafficking through the blood-brain barrier (such as intrathecal methotrexate and natalizumab). The efficacy evidence of these drugs is mostly based on case reports or small case series, with few reported controlled studies or systematic reviews. The aim of the present review is to summarize the current evidence and related methodological issues in the use of these drugs for the treatment of refractory autoimmune encephalitis.

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“…One avenue for more selective immune suppression could be based on homing molecules such as integrins, such as ITGA4 which has been seen to be upregulated in multiple irAE studies. In one case report an antibody targeting ITGA4 (natalizumab) was successfully utilized for irAE-meningoencephalomyelitis 10 . An antibody targeting ITGA4 and ITGB7 called vedolizumab has been used successfully for steroid-refractory irAE colitis 9 , which spared effects on anti-tumor immunity during checkpoint blockade.…”

Section: Treatment Challenges With Iraesmentioning

confidence: 99%

Tissue-resident memory T cells in immune-related adverse events: friend or foe?

Reschke

Gajewski

2023

OncoImmunology

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Many cancer patients experience toxicity during checkpoint blockade immunotherapy, which often leads to treatment discontinuation. To this end, understanding the mechanisms mediating immune-related adverse events (irAE) should ultimately enable improvement in clinical outcomes. Recent work has revealed that tissue-resident memory T (T RM ) cells are locally expanded in irAE-dermatitis and -colitis.

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Severe anti-PD1-related meningoencephalomyelitis successfully treated with anti-integrin alpha4 therapy

Cited by 11 publications

References 9 publications

Targeting integrin pathways: mechanisms and advances in therapy

Targeting integrin pathways: mechanisms and advances in therapy

Treatment Options in Refractory Autoimmune Encephalitis

Tissue-resident memory T cells in immune-related adverse events: friend or foe?

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