A novel anti-B7-H3 chimeric antigen receptor from a single-chain antibody library for immunotherapy of solid cancers

Birley, Kathleen; Leboreiro-Babe, Clara; Rota, Enrique Miranda; Buschhaus, Magdalena; Gavriil, Artemis; Vitali, Alice; Alonso-Ferrero, Maria; Hopwood, Lee; Parienti, Lara; Ferry, Gabrielle M.; Flutter, Barry; Himoudi, Nourredine; Chester, Kerry; Anderson, John

doi:10.1016/j.omto.2022.08.008

Cited by 10 publications

(10 citation statements)

References 45 publications

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“…We, therefore, evaluated MGA271 and 376.96-28ζ CAR-T in the LAN-1 in vivo model (Figure 1E). Intriguingly, in contrast with the Med8A model where differences between binders were apparent, 376.96 and MGA271 binders performed similarly against LAN-1 tumors, extending survival similarly to what was to described for TE9-28ζ 20 . Taken together, different in vivo models establish that B7H3 CAR-T functionality can be affected by scFv selection, but in a manner that is dependent on the choice of tumor target.…”

Section: Resultsmentioning

confidence: 61%

“…We have previously shown that MGA271, 376.96 and TE9 28ζ scFv CAR-T are equivalent in short-term single challenge cytotoxicity assays against LAN-1 neuroblastoma cells, and that TE9-28ζ CAR-T significantly enhance survival in a difficult-to-treat subcutaneous LAN1 NSG model 20 . We, therefore, evaluated MGA271 and 376.96-28ζ CAR-T in the LAN-1 in vivo model (Figure 1E).…”

Section: Resultsmentioning

confidence: 99%

“…MGA271, 376.96 and TE9 scFv's mediate divergent CAR-T responses against in vivo models of solid tumours MGA271 18 , 376.98 19 and TE9 20 scFv's were cloned into a CD8-28ζ 2 nd generation CAR format containing a CD8𝛼 hinge-transmembrane, and expressed in SFG γ-retroviral vector with an EF1𝛼 promoter as described previously 20 . A compact epitope tag, RQR8 21 , was co-expressed from the construct to monitor CAR-T transduction efficiency (Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

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Functional avidity of anti-B7H3 CAR-T constructs predicts antigen density thresholds for triggering effector function

Barisa,

Zappa,

Muller

et al. 2024

Preprint

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Chimeric Antigen receptor T cell (CAR-T) treatments for solid cancers have been compromised by limited expansion and survival in the tumor microenvironment following interaction with antigen-expressing target cells. Using B7H3 as a model antigen with broad clinical applicability, we evaluated the relationship between the antibody/antigen affinity of three clinical candidate binders and the three following functional characteristics: functional avidity, prolonged cytotoxicity in tumoroid re-stimulation assays, andin vivoanti-tumoral responses. BEHAV3D video-microscopy assessed distinct CAR-T cell behaviors at single cell resolution. T cell exhaustion did not dictate effector function. Rather, we demonstrated a threshold avidity of CAR-T / tumor cell interaction, characterized by longer cumulative CD8+CAR-T / tumor target interaction times, and required for adequate CAR-T cell expansion to result in sustained tumor control upon re-challenge. These results provide new insights into design of CAR-T cells for antigen-dim cell targeting, and avoidance of antigen-dim tumor relapse.

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Section: Resultsmentioning

confidence: 61%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Functional avidity of anti-B7H3 CAR-T constructs predicts antigen density thresholds for triggering effector function

Barisa,

Zappa,

Muller

et al. 2024

Preprint

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“…In vitro assays found that second-generation CAR-T cells with a structure TE9-CD8 H/Tm-CD28-CD3ζ had the optimal anti-tumor effects against NB cell lines. In repeat challenge and in vivo model of resistant NB, this type of B7-H3 CAR-T cell showed tumor retardation and penetrance superior to GD2 CAR-T cells recently tested in a clinical trial [121].…”

Section: Car-tmentioning

confidence: 91%

Targeting B7-H3—A Novel Strategy for the Design of Anticancer Agents for Extracranial Pediatric Solid Tumors Treatment

Rasic

Jeremic

et al. 2023

Molecules

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Recent scientific data recognize the B7-H3 checkpoint molecule as a potential target for immunotherapy of pediatric solid tumors (PSTs). B7-H3 is highly expressed in extracranial PSTs such as neuroblastoma, rhabdomyosarcoma, nephroblastoma, osteosarcoma, and Ewing sarcoma, whereas its expression is absent or very low in normal tissues and organs. The influence of B7-H3 on the biological behavior of malignant solid neoplasms of childhood is expressed through different molecular mechanisms, including stimulation of immune evasion and tumor invasion, and cell-cycle disruption. It has been shown that B7-H3 knockdown decreased tumor cell proliferation and migration, suppressed tumor growth, and enhanced anti-tumor immune response in some pediatric solid cancers. Antibody-drug conjugates targeting B7-H3 exhibited profound anti-tumor effects against preclinical models of pediatric solid malignancies. Moreover, B7-H3-targeting chimeric antigen receptor (CAR)-T cells demonstrated significant in vivo activity against different xenograft models of neuroblastoma, Ewing sarcoma, and osteosarcoma. Finally, clinical studies demonstrated the potent anti-tumor activity of B7-H3-targeting antibody-radioimmunoconjugates in metastatic neuroblastoma. This review summarizes the established data from various PST-related studies, including in vitro, in vivo, and clinical research, and explains all the benefits and potential obstacles of targeting B7-H3 by novel immunotherapeutic agents designed to treat malignant extracranial solid tumors of childhood.

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“…Currently, several flavors of CAR T-cells are under development for neuroblastoma either in early phase clinical trial or late-phase preclinical testing. Amongst these are a second-generation CAR targeting the signaling co-receptor glypican 2 (GPC2), and a second-generation CAR targeting B7-H3, which is a well-known tumor antigen expressed by multiple pediatric cancers, including neuroblastoma 43,44 .…”

Section: Introductionmentioning

confidence: 99%

Blocking MIF secretion enhances CAR T-cell efficacy against neuroblastoma

Strijker,

Pascual-Pasto,

Kalmeijer

et al. 2024

Preprint

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While chimeric antigen receptor (CAR) T-cell therapies are showing highly promising first results in neuroblastoma, immunosuppressive tumor microenvironments (TME) limit T cell persistence and durable clinical efficacy. To improve CAR T-cell efficacy further, we applied a multi-omics approach including single-cell RNA sequencing and proteomics, which identified 13 targetable immunosuppressive factors in neuroblastoma. Of these, macrophage migration inhibitory factor (MIF) and midkine (MDK) were validated across multiple published RNA datasets. Moreover, they were secreted in high abundance by neuroblastoma tumoroids. Functional validation experiments revealed MIF as a potent inhibitor of CAR T-cells,in vitroandin vivo.Degradation of MIF by PROTAC technology significantly enhanced CAR T-cell activation targeting GPC2 and B7-H3, providing a potential intervention against MIF. By defining the immunosuppressive effects of neuroblastoma’s TME on CAR T-cell efficacy, particularly the pivotal role of MIF, we provide a therapeutic strategy for improving adoptive cell therapies for this pediatric malignancy.

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A novel anti-B7-H3 chimeric antigen receptor from a single-chain antibody library for immunotherapy of solid cancers

Cited by 10 publications

References 45 publications

Functional avidity of anti-B7H3 CAR-T constructs predicts antigen density thresholds for triggering effector function

Functional avidity of anti-B7H3 CAR-T constructs predicts antigen density thresholds for triggering effector function

Targeting B7-H3—A Novel Strategy for the Design of Anticancer Agents for Extracranial Pediatric Solid Tumors Treatment

Blocking MIF secretion enhances CAR T-cell efficacy against neuroblastoma

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