T cell‐dependent bispecific antibodies alter organ‐specific endothelial cell–T cell interaction

Himmels, Patricia; Nguyen, Thi Thu Thao; Mitzner, Maresa Caunt; Arrazate, Alfonso; Yeung, Stacey; Burton, Jeremy; Clark, Robyn; Tótpál, Klára; Jesudason, Raj; Yang, Angela; Solon, Margaret; Eastham, Jeffrey; Modrušan, Zora; Webster, Joshua D.; Lo, Amy A.; Piskol, Robert; Ye, Weilan

doi:10.15252/embr.202255532

Cited by 6 publications

(1 citation statement)

References 84 publications

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“…At the same time, they also upregulated cytokine genes, including IL6 and IL1B , and chemokine genes, including CXCL9, CXCL10, CXCL11, CCL2, CCL5 , and CCL8 , suggestive of their role in further amplifying the cytokine release cascade and recruiting surrounding immune cells. In line with our findings, Himmels and colleagues recently reported that cytokine and chemokines induced by T-cell–dependent bispecific antibodies can mediate the activation of endothelial cells, which results in adhesion and infiltration of peripheral T cells in tumor and/or healthy tissues ( 41 ). Altogether, these data highlight the importance of vasculature in the safety and efficacy of T-cell–engaging therapies.…”

Section: Discussionsupporting

confidence: 92%

Dissecting the Mechanisms Underlying the Cytokine Release Syndrome (CRS) Mediated by T-Cell Bispecific Antibodies

Leclercq-Cohen

Steinhoff

Servera

et al. 2023

Clinical Cancer Research

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Purpose: Target-dependent TCB activity can result in strong and systemic release of cytokines that may develop into Cytokine Release Syndrome (CRS), highlighting the need to understand and prevent this complex clinical syndrome. Experimental design: We explored the cellular and molecular players involved in TCB-mediated cytokine release by single cell RNA sequencing of whole blood treated with CD20-TCB together with bulk RNA sequencing of endothelial cells exposed to TCB-induced cytokine release. We used the in vitro whole blood assay and an in vivo DLBCL model in immunocompetent humanized mice to assess the effects of dexamethasone, anti-TNF-a, anti-IL-6R, anti-IL-1R and inflammasome inhibition, on TCB-mediated cytokine release and anti-tumor activity. Results: Activated T cells release TNF-α, IFN-γ, IL-2, IL-8 and MIP-1β, which rapidly activate monocytes, neutrophils, DCs and NKs along with surrounding T cells to amplify the cascade further, leading to TNF-α, IL-8, IL-6, IL-1β, MCP-1, MIP-1α, MIP-1β and IP-10 release. Endothelial cells contribute to IL-6 and IL-1β release and at the same time release several chemokines (MCP-1, IP-10, MIP-1α and MIP-1β). Dexamethasone and TNF-α blockade efficiently reduced CD20-TCB-mediated cytokine release while IL-6R blockade, inflammasome inhibition and IL1-R blockade induced a less pronounced effect. Dexamethasone, IL-6R blockade, IL-1R blockade and the inflammasome inhibitor did not interfere with CD20-TCB activity, in contrast to TNF-α blockade, which partially inhibited anti-tumor activity. Conclusion: Our work sheds a new light on the cellular and molecular players involved in cytokine release driven by TCBs and provides rationale for the prevention of CRS in patients treated with TCBs.

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Section: Discussionsupporting

confidence: 92%

Dissecting the Mechanisms Underlying the Cytokine Release Syndrome (CRS) Mediated by T-Cell Bispecific Antibodies

Leclercq-Cohen

Steinhoff

Servera

et al. 2023

Clinical Cancer Research

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Safety and clinical activity of JNJ-78306358, a human leukocyte antigen-G (HLA-G) x CD3 bispecific antibody, for the treatment of advanced stage solid tumors

Geva,

Vieito,

Ramon

et al. 2024

Cancer Immunol Immunother

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Background JNJ-78306358 is a bispecific antibody that redirects T cells to kill human leukocyte antigen-G (HLA-G)-expressing tumor cells. This dose escalation study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of JNJ-78306358 in patients with advanced solid tumors. Methods Adult patients with metastatic/unresectable solid tumors with high prevalence of HLA-G expression were enrolled. Dose escalation was initiated with once-weekly subcutaneous administration with step-up dosing to mitigate cytokine release syndrome (CRS). Results Overall, 39 heavily pretreated patients (colorectal cancer: n = 23, ovarian cancer: n = 10, and renal cell carcinoma: n = 6) were dosed in 7 cohorts. Most patients (94.9%) experienced ≥ 1 treatment-emergent adverse events (TEAEs); 87.2% had ≥ 1 related TEAEs. About half of the patients (48.7%) experienced CRS, which were grade 1/2. Nine patients (23.1%) received tocilizumab for CRS. No grade 3 CRS was observed. Dose-limiting toxicities (DLTs) of increased transaminases, pneumonitis and recurrent CRS requiring a dose reduction were reported in 4 patients, coinciding with CRS. No treatment-related deaths reported. No objective responses were noted, but 2 patients had stable disease > 40 weeks. JNJ-78306358 stimulated peripheral T cell activation and cytokine release. Anti-drug antibodies were observed in 45% of evaluable patients with impact on exposure. Approximately half of archival tumor samples (48%) had expression of HLA-G by immunohistochemistry. Conclusion JNJ-78306358 showed pharmacodynamic effects with induction of cytokines and T cell activation. JNJ-78306358 was associated with CRS-related toxicities including increased transaminases and pneumonitis which limited its dose escalation to potentially efficacious levels. Trial registration number ClinicalTrials.gov (No. NCT04991740).

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Mechanisms of resistance against T-cell engaging bispecific antibodies in multiple myeloma: implications for novel treatment strategies

van de Donk,

Chari,

Mateos

2024

The Lancet Haematology

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T cell‐dependent bispecific antibodies alter organ‐specific endothelial cell–T cell interaction

Cited by 6 publications

References 84 publications

Dissecting the Mechanisms Underlying the Cytokine Release Syndrome (CRS) Mediated by T-Cell Bispecific Antibodies

Dissecting the Mechanisms Underlying the Cytokine Release Syndrome (CRS) Mediated by T-Cell Bispecific Antibodies

Safety and clinical activity of JNJ-78306358, a human leukocyte antigen-G (HLA-G) x CD3 bispecific antibody, for the treatment of advanced stage solid tumors

Mechanisms of resistance against T-cell engaging bispecific antibodies in multiple myeloma: implications for novel treatment strategies

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