Toxicity Induced by a Bispecific T Cell–Redirecting Protein Is Mediated by Both T Cells and Myeloid Cells in Immunocompetent Mice

Godbersen-Palmer, Claire; Coupet, Tiffany A.; Grada, Zakaria; Zhang, Samuel C; Sentman, Charles L.

doi:10.4049/jimmunol.1901401

Cited by 14 publications

(16 citation statements)

References 45 publications

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“…18 The main driver of CRS is a strong release of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α and interferon (IFN)-γ (produced by T cells) 19 and TNF-α, interleukin (IL)-1β and IL-6 (produced by myeloid cells). [20][21][22][23] The symptoms of CRS can vary from mild to severe, and are classified in different grades. 24 CRS can be managed with glucocorticoids and/or anti-IL-6/R treatment such as tocilizumab or Open access siltuximab.…”

Section: Introductionmentioning

confidence: 99%

JAK and mTOR inhibitors prevent cytokine release while retaining T cell bispecific antibody in vivo efficacy

Leclercq-Cohen

Haegel

Zimmermann

et al. 2022

J Immunother Cancer

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BackgroundT 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.MethodsBy 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.ResultsThe 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.ConclusionsTaken together, these data support further evaluation of the use of Src, JAK and mTOR inhibitors as prophylactic treatment to prevent occurrence of CRS.

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Section: Introductionmentioning

confidence: 99%

JAK and mTOR inhibitors prevent cytokine release while retaining T cell bispecific antibody in vivo efficacy

Leclercq-Cohen

Haegel

Zimmermann

et al. 2022

J Immunother Cancer

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“…In addition, the release of IFN-γ, IL-2 and GM-CSF (known to be produced by T cells) and of TNF-α, IL-6 and IL-8 (produced by T cells and monocytes) was fully inhibited on re-stimulation in the presence of 100 nM dasatinib ( figure 3D, E ). 18 19 This result emphasizes that dasatinib can switch off activated T cells, rapidly blocking TCB-mediated cytokine release as well as T cell cytotoxicity.…”

Section: Resultsmentioning

confidence: 82%

“…15 CRS is linked to a strong release of pro-inflammatory cytokines by T cells producing TNF-α, IFN-γ and GM-CSF 16 17 and by myeloid cells producing TNF-α, IL-1β and IL-6. [18][19][20][21] Open access Several problems of toxicity grading of CRS were addressed as summarized in a recent publication of a consensus grading scale, 22 mainly driven by treatment interventions, with severe cases easily classified if managed with pressors and/or high-flow oxygen devices. Management of severe CRS also requires appropriate supportive care, high-dose glucocorticoids and benefit from anti-IL-6R/IL-6 treatment such as tocilizumab or silixumab.…”

Section: Introductionmentioning

confidence: 99%

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Src/lck inhibitor dasatinib reversibly switches off cytokine release and T cell cytotoxicity following stimulation with T cell bispecific antibodies

Leclercq-Cohen

Haegel

Schneider

et al. 2021

J Immunother Cancer

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BackgroundT cell engagers are bispecific antibodies recognizing, with one moiety, the CD3ε chain of the T cell receptor and, with the other moiety, specific tumor surface antigens. Crosslinking of CD3 upon simultaneous binding to tumor antigens triggers T cell activation, proliferation and cytokine release, leading to tumor cell killing. Treatment with T cell engagers can be associated with safety liabilities due to on-target on-tumor, on-target off-tumor cytotoxic activity and cytokine release syndrome (CRS). Tyrosine kinases such as SRC, LCK or ZAP70 are involved in downstream signaling pathways after engagement of the T cell receptor and blocking these kinases might serve to abrogate T cell activation when required (online supplemental material 1). Dasatinib was previously identified as a potent kinase inhibitor that switches off CAR T cell functionality.MethodsUsing an in vitro model of target cell killing by human peripheral blood mononuclear cells, we assessed the effects of dasatinib combined with 2+1 T cell bispecific antibodies (TCBs) including CEA-TCB, CD19-TCB or HLA-A2 WT1-TCB on T cell activation, proliferation and target cell killing measured by flow cytometry and cytokine release measured by Luminex. To determine the effective dose of dasatinib, the Incucyte system was used to monitor the kinetics of TCB-mediated target cell killing in the presence of escalating concentrations of dasatinib. Last, the effects of dasatinib were evaluated in vivo in humanized NSG mice co-treated with CD19-TCB. The count of CD20+ blood B cells was used as a readout of efficacy of TCB-mediated killing and cytokine levels were measured in the serum.ResultsDasatinib concentrations above 50 nM prevented cytokine release and switched off-target cell killing, which were subsequently restored on removal of dasatinib. In addition, dasatinib prevented CD19-TCB-mediated B cell depletion in humanized NSG mice. These data confirm that dasatinib can act as a rapid and reversible on/off switch for activated T cells at pharmacologically relevant doses as they are applied in patients according to the label.ConclusionTaken together, we provide evidence for the use of dasatinib as a pharmacological on/off switch to mitigate off-tumor toxicities or CRS by T cell bispecific antibodies.

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“…In this humanised mouse model, the target expression is restricted to the subcutaneous tumour, with no other tissues expressing CEA. Furthermore, this mouse model does not include the human innate, myeloid immune compartment, which is a contributor to the cytokine response [37,38]. Thus, using a different mouse model with respect to immune cell engraftment or target expression can have an impact on cytokine release.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of T-Cell Bispecifics in the Tumour Interstitial Fluid

et al. 2021

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The goal of this study is to investigate the pharmacokinetics in plasma and tumour interstitial fluid of two T-cell bispecifics (TCBs) with different binding affinities to the tumour target and to assess the subsequent cytokine release in a tumour-bearing humanised mouse model. Pharmacokinetics (PK) as well as cytokine data were collected in humanised mice after iv injection of cibisatamab and CEACAM5-TCB which are binding with different binding affinities to the tumour antigen carcinoembryonic antigen (CEA). The PK data were modelled and coupled to a previously published physiologically based PK model. Corresponding cytokine release profiles were compared to in vitro data. The PK model provided a good fit to the data and precise estimation of key PK parameters. High tumour interstitial concentrations were observed for both TCBs, influenced by their respective target binding affinities. In conclusion, we developed a tailored experimental method to measure PK and cytokine release in plasma and at the site of drug action, namely in the tumour. Integrating those data into a mathematical model enabled to investigate the impact of target affinity on tumour accumulation and can have implications for the PKPD assessment of the therapeutic antibodies.

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Toxicity Induced by a Bispecific T Cell–Redirecting Protein Is Mediated by Both T Cells and Myeloid Cells in Immunocompetent Mice

Cited by 14 publications

References 45 publications

JAK and mTOR inhibitors prevent cytokine release while retaining T cell bispecific antibody in vivo efficacy

JAK and mTOR inhibitors prevent cytokine release while retaining T cell bispecific antibody in vivo efficacy

Src/lck inhibitor dasatinib reversibly switches off cytokine release and T cell cytotoxicity following stimulation with T cell bispecific antibodies

Pharmacokinetics and Pharmacodynamics of T-Cell Bispecifics in the Tumour Interstitial Fluid

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