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1.
J Immunother Cancer ; 10(1)2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-35064010

RESUMO

BACKGROUND: T cell engaging therapies, like chimeric antigen receptor T cells and T cell bispecific antibodies (TCBs), efficiently redirect T cells towards tumor cells, facilitating the formation of a cytotoxic synapse and resulting in subsequent tumor cell killing, a process that is accompanied by the release of cytokines. Despite their promising efficacy in the clinic, treatment with TCBs is associated with a risk of cytokine release syndrome (CRS). The aim of this study was to identify small molecules able to mitigate cytokine release while retaining T cell-mediated tumor killing. METHODS: By screening a library of 52 Food and Drug Administration approved kinase inhibitors for their impact on T cell proliferation and cytokine release after CD3 stimulation, we identified mTOR, JAK and Src kinases inhibitors as potential candidates to modulate TCB-mediated cytokine release at pharmacologically active doses. Using an in vitro model of target cell killing by human peripheral blood mononuclear cells, we assessed the effects of mTOR, JAK and Src kinase inhibitors combined with 2+1 T cell bispecific antibodies (TCBs) including CEA-TCB and CD19-TCB on T cell activation, proliferation and target cell killing measured by flow cytometry and cytokine release measured by Luminex. The combination of mTOR, JAK and Src kinase inhibitors together with CD19-TCB was evaluated in vivo in non-tumor bearing stem cell humanized NSG mice in terms of B cell depletion and in a lymphoma patient-derived xenograft (PDX) model in humanized NSG mice in terms of antitumor efficacy. RESULTS: The effect of Src inhibitors differed from those of mTOR and JAK inhibitors with the suppression of CD19-TCB-induced tumor cell lysis in vitro, whereas mTOR and JAK inhibitors primarily affected TCB-mediated cytokine release. Importantly, we confirmed in vivo that Src, JAK and mTOR inhibitors strongly reduced CD19-TCB-induced cytokine release. In humanized NSG mice, continuous treatment with a Src inhibitor prevented CD19-TCB-mediated B cell depletion in contrast to mTOR and JAK inhibitors, which retained CD19-TCB efficacy. Ultimately, transient treatment with Src, mTOR and JAK inhibitors minimally interfered with antitumor efficacy in a lymphoma PDX model. CONCLUSIONS: Taken together, these data support further evaluation of the use of Src, JAK and mTOR inhibitors as prophylactic treatment to prevent occurrence of CRS.


Assuntos
Anticorpos Biespecíficos/efeitos dos fármacos , Citocinas/efeitos dos fármacos , Imunoterapia/métodos , Inibidores de Janus Quinases/uso terapêutico , Inibidores de MTOR/uso terapêutico , Animais , Humanos , Inibidores de Janus Quinases/farmacologia , Inibidores de MTOR/farmacologia , Camundongos
2.
Commun Biol ; 5(1): 52, 2022 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-35027657

RESUMO

Disorders of the eye leading to visual impairment are a major issue that affects millions of people. On the other side ocular toxicities were described for e.g. molecularly targeted therapies in oncology and may hamper their development. Current ocular model systems feature a number of limitations affecting human-relevance and availability. To find new options for pharmacological treatment and assess mechanisms of toxicity, hence, novel complex model systems that are human-relevant and readily available are urgently required. Here, we report the development of a human immunocompetent Choroid-on-Chip (CoC), a human cell-based in vitro model of the choroid layer of the eye integrating melanocytes and microvascular endothelial cells, covered by a layer of retinal pigmented epithelial cells. Immunocompetence is achieved by perfusion of peripheral immune cells. We demonstrate controlled immune cell recruitment into the stromal compartments through a vascular monolayer and in vivo-like cytokine release profiles. To investigate applicability for both efficacy testing of immunosuppressive compounds as well as safety profiling of immunoactivating antibodies, we exposed the CoCs to cyclosporine and tested CD3 bispecific antibodies.


Assuntos
Produtos Biológicos/farmacologia , Corioide/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Procedimentos Analíticos em Microchip , Anticorpos Biespecíficos/efeitos dos fármacos , Anticorpos Biespecíficos/metabolismo , Humanos , Melanócitos/efeitos dos fármacos , Melanócitos/metabolismo
4.
5.
Breast Cancer Res Treat ; 117(3): 471-81, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18819003

RESUMO

In the present study, the efficacy of a new drug, i.e. the bispecific single-chain antibody MT110 targeting the epithelial antigen EpCAM and the T-cell antigen CD3 was tested ex vivo in malignant pleural effusions (MPEs). EpCAM+ epithelial cells were found in 78% of the MPEs (n = 18). Ex vivo treatment of seven MPEs resulted in a dose-dependent specific lysis of 37 +/- 27% (+/- SD) EpCAM+ cells with 10 ng/ml (P = 0.03) and 57 +/- 29.5% EpCAM+ cells with 1,000 ng/ml MT110 (P = 0.016) after 72 h. As a prerequisite for redirected lysis, stimulation of the autologous CD4+ and CD8+ cells in MPE by 1,000 ng/ml MT110 resulted in 21 +/- 17% CD4+/CD25+ and 29.4 +/- 22% CD8+/CD25+ cells (P = 0.016, respectively) after 72 h. This was confirmed by a 22-fold release of TNF-alpha and 230-fold release of IFN-gamma (1,000 ng/ml, 48 h, P = 0.03, respectively). Thus, relapsed breast cancer patients resistant to standard treatment might benefit from targeted therapy using MT110.


Assuntos
Anticorpos Monoclonais/farmacologia , Antígenos de Neoplasias/imunologia , Neoplasias da Mama/imunologia , Moléculas de Adesão Celular/imunologia , Ativação Linfocitária/efeitos dos fármacos , Derrame Pleural Maligno/imunologia , Linfócitos T/efeitos dos fármacos , Anticorpos Biespecíficos/efeitos dos fármacos , Anticorpos Biespecíficos/imunologia , Complexo CD3/imunologia , Citocinas/biossíntese , Molécula de Adesão da Célula Epitelial , Feminino , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Ativação Linfocitária/imunologia , Anticorpos de Cadeia Única , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Linfócitos T/imunologia
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