Local delivery of CAR T cells targeting fibroblast activation protein is safe in patients with pleural mesothelioma: first report of FAPME, a phase I clinical trial

Hiltbrunner, Stefanie; Britschgi, Christian; Schuberth, Petra; Bankel, Lorenz; Nguyen-Kim, Thi Dan Linh; Gulati, Pratiksha; Weder, Walter; Opitz, Isabelle; Lauk, Olivia; Caviezel, Claudio; Bachmann, Helga; Tabor, Annett; Schröder, Petra; Knuth, Alexander; Münz, Christian; Stahel, Rolf A.; Boyman, Onur; Renner, Christoph; Petrausch, Ulf; Curioni-Fontecedro, Alessandra

doi:10.1016/j.annonc.2020.10.474

Cited by 53 publications

(34 citation statements)

References 5 publications

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“…One possible approach to target FAPa+ synovial fibroblasts is the use of chimeric antigen receptor (CAR)-T cells. Local delivery of FAPa targeting CAR T cells in patients with pleural mesothelioma has been shown to be safe in a phase I clinical trial (157). Targeting FAPa expressing fibroblasts with CAR T cells following cardiac injury in mice has been shown to reduce cardiac fibrosis and restore cardiac function (158).…”

Section: Targeting Pathogenic Fibroblasts In Refractory Ramentioning

confidence: 99%

Critical Role of Synovial Tissue–Resident Macrophage and Fibroblast Subsets in the Persistence of Joint Inflammation

Kemble

Croft

2021

Front. Immunol.

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Rheumatoid arthritis (RA) is a chronic prototypic immune-mediated inflammatory disease which is characterized by persistent synovial inflammation, leading to progressive joint destruction. Whilst the introduction of targeted biological drugs has led to a step change in the management of RA, 30-40% of patients do not respond adequately to these treatments, regardless of the mechanism of action of the drug used (ceiling of therapeutic response). In addition, many patients who acheive clinical remission, quickly relapse following the withdrawal of treatment. These observations suggest the existence of additional pathways of disease persistence that remain to be identified and targeted therapeutically. A major barrier for the identification of therapeutic targets and successful clinical translation is the limited understanding of the cellular mechanisms that operate within the synovial microenvironment to sustain joint inflammation. Recent insights into the heterogeneity of tissue resident synovial cells, including macropahges and fibroblasts has revealed distinct subsets of these cells that differentially regulate specific aspects of inflammatory joint pathology, paving the way for targeted interventions to specifically modulate the behaviour of these cells. In this review, we will discuss the phenotypic and functional heterogeneity of tissue resident synovial cells and how this cellular diversity contributes to joint inflammation. We discuss how critical interactions between tissue resident cell types regulate the disease state by establishing critical cellular checkpoints within the synovium designed to suppress inflammation and restore joint homeostasis. We propose that failure of these cellular checkpoints leads to the emergence of imprinted pathogenic fibroblast cell states that drive the persistence of joint inflammation. Finally, we discuss therapeutic strategies that could be employed to specifically target pathogenic subsets of fibroblasts in RA.

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Section: Targeting Pathogenic Fibroblasts In Refractory Ramentioning

confidence: 99%

Critical Role of Synovial Tissue–Resident Macrophage and Fibroblast Subsets in the Persistence of Joint Inflammation

Kemble

Croft

2021

Front. Immunol.

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“…Targeting FAPα‐expressing fibroblasts with chimeric antigen receptor (CAR)–specific T cells has proven to be efficacious in reducing cardiac fibrosis, as well as restoring function and improving recovery following cardiac injury in mice 190 . Furthermore, a phase I clinical trial has proven that local delivery of FAPα CAR T cells is safe in patients with pleural mesothelioma 191 . These findings are promising, prompting development of such therapeutic approaches in RA and other autoimmune diseases 192 …”

Section: Therapeutic Targeting Of Fibroblastsmentioning

confidence: 99%

Fibroblast pathology in inflammatory joint disease

Marsh

Kemble

Nisa

et al. 2021

Immunological Reviews

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In this review, we highlight new approaches and applications of single-cell profiling techniques 1,2 and how these data are leading to unique insights into the phenotypic and functional heterogeneity of fibroblasts in the joint. 3 Finally, we will discuss how defining this previously underappreciated fibroblast heterogeneity in rheumatoid arthritis (RA) is leading to the identification of pathological fibroblast cell states that could be therapeutically targeted in inflammatory joint disease. 4 | Rheumatoid arthritisRA is a prototypic immune-mediated inflammatory disease characterized by persistent synovial joint inflammation that, if untreated, leads to progressive joint damage. [5][6][7] While the

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“…Based on encouraging preclinical studies [ 113 ], a phase I clinical trial was designed to investigate the safety of a fixed single dose of FAP-targeted CAR-T cells administered into the pleura of MPM patients (NCT01722149). Preliminary results showed a good tolerance of the treatment and the persistence of CAR-T cells following inoculation; however, due to the trial design and the small number of patients involved, it was not possible to evaluate the impact of this treatment on patient outcome [ 114 ].…”

Section: Car-t Cell Therapymentioning

confidence: 99%

Immunotherapeutic Approaches in Malignant Pleural Mesothelioma

Terenziani

Zoppi

Fumarola

et al. 2021

Cancers

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Malignant pleural mesothelioma (MPM) is a rare and aggressive malignant disease affecting the mesothelium, commonly associated to asbestos exposure. The current therapeutic actions, based on cisplatin/pemetrexed treatment, are limited due to the late stage at which most patients are diagnosed and to the intrinsic chemo-resistance of the tumor. Another relevant point is the absence of approved therapies in the second line setting following progression of MPM after chemotherapy. Considering the poor prognosis of the disease and the fact that the incidence of this tumor is expected to increase in the next decade, novel therapeutic approaches are urgently needed. In the last few years, several studies have investigated the efficacy and safety of immune-checkpoint inhibitors (ICIs) in the treatment of unresectable advanced MPM, and a number of trials with immunotherapeutic agents are ongoing in both first line and second line settings. In this review, we describe the most promising emerging immunotherapy treatments for MPM (ICIs, engineered T cells to express chimeric antigen receptors (CARs), dendritic cells (DCs) vaccines), focusing on the biological and immunological features of this tumor as well as on the issues surrounding clinical trial design.

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Local delivery of CAR T cells targeting fibroblast activation protein is safe in patients with pleural mesothelioma: first report of FAPME, a phase I clinical trial

Cited by 53 publications

References 5 publications

Critical Role of Synovial Tissue–Resident Macrophage and Fibroblast Subsets in the Persistence of Joint Inflammation

Critical Role of Synovial Tissue–Resident Macrophage and Fibroblast Subsets in the Persistence of Joint Inflammation

Fibroblast pathology in inflammatory joint disease

Immunotherapeutic Approaches in Malignant Pleural Mesothelioma

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