Redirecting T cells to treat solid pediatric cancers

Rauwolf, Kerstin K.

doi:10.1007/s10555-019-09821-5

Cited by 4 publications

(3 citation statements)

References 148 publications

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“…Four patients with CNS tumours achieved SD on study, including two patients with low-grade astrocytoma who had ongoing SD lasting > 24 months; however, prestudy tumour assessments suggested that these tumours were growing slowly. The lack of objective responses reported with several ICIs may be due to differences in tumour biology between paediatric and adult cancers, including a lower mutational burden in most paediatric tumours [ 19 ], and differences in immune responses between adults and younger patients [ 20 ]. Additionally, the enrolled population had a high proportion of patients who were Asian, which may have introduced bias.…”

Section: Discussionmentioning

confidence: 99%

Avelumab in paediatric patients with refractory or relapsed solid tumours: dose-escalation results from an open-label, single-arm, phase 1/2 trial

Loeb

Lee

Morgenstern

et al. 2022

Cancer Immunol Immunother

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Background We report dose-escalation results from an open-label, phase 1/2 trial evaluating avelumab (anti-PD-L1) in paediatric patients with refractory/relapsed solid tumours. Methods In phase 1, patients aged < 18 years with solid (including central nervous system [CNS]) tumours for which standard therapy did not exist or had failed were enrolled in sequential cohorts of 3–6 patients. Patients received avelumab 10 or 20 mg/kg intravenously every 2 weeks. Primary endpoints were dose-limiting toxicities (DLTs) and grade ≥ 3 treatment-emergent adverse events (AEs). Results At data cut-off (27 July 2021), 21 patients aged 3–17 years had received avelumab 10 mg/kg (n = 6) or 20 mg/kg (n = 15). One patient had three events that were classified as a DLT (fatigue with hemiparesis and muscular weakness associated with pseudoprogression; 20 mg/kg cohort). Grade ≥ 3 AEs occurred in five (83%) and 11 (73%) patients in the 10 and 20 mg/kg cohorts, respectively, and were treatment-related in one patient (7%; grade 3 [DLT]) in the 20 mg/kg cohort. Avelumab exposure in paediatric patients receiving 20 mg/kg dosing, but not 10 mg/kg, was comparable or higher compared with approved adult dosing (10 mg/kg or 800 mg flat dose). No objective responses were observed. Four patients with CNS tumours (20 mg/kg cohort) achieved stable disease, which was ongoing in two patients with astrocytoma at cut-off (for 24.7 and 30.3 months). Conclusion In paediatric patients with refractory/relapsed solid tumours, avelumab monotherapy showed a safety profile consistent with previous adult studies, but clinical benefits were limited.

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Section: Discussionmentioning

confidence: 99%

Avelumab in paediatric patients with refractory or relapsed solid tumours: dose-escalation results from an open-label, single-arm, phase 1/2 trial

Loeb

Lee

Morgenstern

et al. 2022

Cancer Immunol Immunother

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“…Studies indicate that Wnt5a may promote anti-tumour immune responses by influencing the composition and function of immune cells within the tumour microenvironment [50,51]. Wnt signalling fosters immune suppression within the TME by interacting with other cell signalling transductions, contributing to an immunosuppressive milieu that hampers effective antitumor immune responses [52,53].…”

Section: Wnt Signalling In Cancer Immunotherapiesmentioning

confidence: 99%

Navigating Tumour Microenvironment and Wnt Signalling Crosstalk: Implications for Advanced Cancer Therapeutics

Peri,

Narayanaa Y,

Hubert

et al. 2023

Cancers

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Cancer therapeutics face significant challenges due to drug resistance and tumour recurrence. The tumour microenvironment (TME) is a crucial contributor and essential hallmark of cancer. It encompasses various components surrounding the tumour, including intercellular elements, immune system cells, the vascular system, stem cells, and extracellular matrices, all of which play critical roles in tumour progression, epithelial–mesenchymal transition, metastasis, drug resistance, and relapse. These components interact with multiple signalling pathways, positively or negatively influencing cell growth. Abnormal regulation of the Wnt signalling pathway has been observed in tumorigenesis and contributes to tumour growth. A comprehensive understanding and characterisation of how different cells within the TME communicate through signalling pathways is vital. This review aims to explore the intricate and dynamic interactions, expressions, and alterations of TME components and the Wnt signalling pathway, offering valuable insights into the development of therapeutic applications.

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“…A major goal in the field is to exploit the full potential of CAR T cell targeting also in solid tumors where some clinical responses have been achieved but remained incomplete and transient [ 2 , 3 ]. T cell therapy of solid tumors is challenged by protective mechanisms of the tumor microenvironment (TME) (reviewed in [ 4 ]). Here we designed an innovative strategy that employs CAR T cells as micropharmacies to selectively deliver a therapeutic agent to the TME for a combination strategy that allows more potent control of solid tumors.…”

Section: Introductionmentioning

confidence: 99%

CAR T cells as micropharmacies against solid cancers: Combining effector T-cell mediated cell death with vascular targeting in a one-step engineering process

et al. 2023

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To enhance the potency of chimeric antigen receptor (CAR) engineered T cells in solid cancers, we designed a novel cell-based combination strategy with an additional therapeutic mode of action. CAR T cells are used as micropharmacies to produce a targeted pro-coagulatory fusion protein, truncated tissue factor (tTF)-NGR, which exerts pro-coagulatory activity and hypoxia upon relocalization to the vascular endothelial cells that invade tumor tissues. Delivery by CAR T cells aimed to induce locoregional tumor vascular infarction for combined immune-mediated and hypoxic tumor cell death. Human T cells that were one-vector gene-modified to express a GD2-specific CAR along with CAR-inducible tTF-NGR exerted potent GD2-specific effector functions while secreting tTF-NGR that activates the extrinsic coagulation pathway in a strictly GD2-dependent manner. In murine models, the CAR T cells infiltrated GD2-positive tumor xenografts, secreted tTF-NGR into the tumor microenvironment and showed a trend towards superior therapeutic activity compared with control cells producing functionally inactive tTF-NGR. In vitro evidence supports a mechanism of hypoxia-mediated enhancement of T cell cytolytic activity. We conclude that combined CAR T cell targeting with an additional mechanism of antitumor action in a one-vector engineering strategy is a promising approach to be further developed for targeted treatment of solid cancers.

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Redirecting T cells to treat solid pediatric cancers

Cited by 4 publications

References 148 publications

Avelumab in paediatric patients with refractory or relapsed solid tumours: dose-escalation results from an open-label, single-arm, phase 1/2 trial

Avelumab in paediatric patients with refractory or relapsed solid tumours: dose-escalation results from an open-label, single-arm, phase 1/2 trial

Navigating Tumour Microenvironment and Wnt Signalling Crosstalk: Implications for Advanced Cancer Therapeutics

CAR T cells as micropharmacies against solid cancers: Combining effector T-cell mediated cell death with vascular targeting in a one-step engineering process

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