FGFR4-Targeted Chimeric Antigen Receptors Combined with Anti-Myeloid Polypharmacy Effectively Treat Orthotopic Rhabdomyosarcoma

Sullivan, Peter M.; Kumar, Rajesh; Li, Wei; Hoglund, Virginia; Wang, Lingyang; Zhang, Yue; Shi, Megan; Baek, Du-San; Cheuk, Adam; Jensen, Michael C.; Khan, Javed; Dimitrov, Dimiter S.; Orentas, Rimas J.

doi:10.1158/1535-7163.mct-22-0059

Cited by 18 publications

(19 citation statements)

References 51 publications

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“…and was used as a potential therapeutic target in a few in vitro studies using FGFR4-CAR-T cells. 53,54 In one preclinical study, futibatinib, a pan-FGFR inhibitor, showed growth inhibition in RMS cell lines while inhibiting phosphorylation of FGFR4 and its downstream targets. 55 However, an FGFR4 V550L-mutant cell line developed from a patient with ERMS responded to FGFR4-specific inhibitors, but not to a pan-FGFR inhibitor.…”

Section: Discussionmentioning

confidence: 99%

“…In RMS, the most common FGFR alteration occurs in FGFR4 gene, which is altered in 10% of cases, either by amplifications or mutations, and was used as a potential therapeutic target in a few in vitro studies using FGFR4‐CAR‐T cells 53,54 . In one preclinical study, futibatinib, a pan‐FGFR inhibitor, showed growth inhibition in RMS cell lines while inhibiting phosphorylation of FGFR4 and its downstream targets 55 .…”

Section: Discussionmentioning

confidence: 99%

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FGFR1 fusions as a novel molecular driver in rhabdomyosarcoma

de Traux De Wardin,

Cyrta,

Dermawan

et al. 2024

Genes Chromosomes & Cancer

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The wide application of RNA sequencing in clinical practice has allowed the discovery of novel fusion genes, which have contributed to a refined molecular classification of rhabdomyosarcoma (RMS). Most fusions in RMS result in aberrant transcription factors, such as PAX3/7::FOXO1 in alveolar RMS (ARMS) and fusions involving VGLL2 or NCOA2 in infantile spindle cell RMS. However, recurrent fusions driving oncogenic kinase activation have not been reported in RMS. Triggered by an index case of an unclassified RMS (overlapping features between ARMS and sclerosing RMS) with a novel FGFR1::ANK1 fusion, we reviewed our molecular files for cases harboring FGFR1‐related fusions. One additional case with an FGFR1::TACC1 fusion was identified in a tumor resembling embryonal RMS (ERMS) with anaplasia, but with no pathogenic variants in TP53 or DICER1 on germline testing. Both cases occurred in males, aged 7 and 24, and in the pelvis. The 2nd case also harbored additional alterations, including somatic TP53 and TET2 mutations. Two additional RMS cases (one unclassified, one ERMS) with FGFR1 overexpression but lacking FGFR1 fusions were identified by RNA sequencing. These two cases and the FGFR1::TACC1‐positive case clustered together with the ERMS group by RNAseq. This is the first report of RMS harboring recurrent FGFR1 fusions. However, it remains unclear if FGFR1 fusions define a novel subset of RMS or alternatively, whether this alteration can sporadically drive the pathogenesis of known RMS subtypes, such as ERMS. Additional larger series with integrated genomic and epigenetic datasets are needed for better subclassification, as the resulting oncogenic kinase activation underscores the potential for targeted therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

FGFR1 fusions as a novel molecular driver in rhabdomyosarcoma

de Traux De Wardin,

Cyrta,

Dermawan

et al. 2024

Genes Chromosomes & Cancer

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“…The other target of interest, the Fibroblast Growth Factor Receptor 4 (FGFR4) is a receptor tyrosine kinase, that shows very specific expression in RMS, and in normal tissues is only expressed at low levels in liver and in mature skeletal tissue (41, 42, 43, 44). FGFR4-CAR T cells are active in vitro against both aRMS and eRMS cell lines (45, 46), and show effective response against disseminated disease in vivo , but not in an RMS orthotopic model (47). Interestingly, the combination of FGFR4-CAR T cells with pharmacological inhibition of the myeloid component in stroma allowed FGFR4-CAR T cells to eradicate orthotopic RMS tumors in mice (47).…”

Section: Introductionmentioning

confidence: 99%

“…FGFR4-CAR T cells are active in vitro against both aRMS and eRMS cell lines (45, 46), and show effective response against disseminated disease in vivo , but not in an RMS orthotopic model (47). Interestingly, the combination of FGFR4-CAR T cells with pharmacological inhibition of the myeloid component in stroma allowed FGFR4-CAR T cells to eradicate orthotopic RMS tumors in mice (47).…”

Section: Introductionmentioning

confidence: 99%

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CAR T cells recognizing CD276 and Dual-CAR T cells against CD276/FGFR4 promote rhabdomyosarcoma clearance in orthotopic mouse models

Timpanaro,

Piccand,

Dzhumashev

et al. 2023

Preprint

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Background: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood, whose prognosis is still poor especially for metastatic, high-grade, and relapsed RMS. New treatments are urgently needed, especially systemic therapies. Chimeric Antigen Receptor T cells (CAR Ts) are very effective against hematological malignancies, but their efficacy against solid tumors needs to be improved. CD276 is a target upregulated in RMS and detected at low levels in normal tissues. FGFR4 is a very specific target for RMS. Here, we optimized CAR Ts for these two targets, alone or in combination, and tested their anti-tumor activity in vitro and in vivo. Methods: Four different single-domain antibodies were used to select the most specific FGFR4-CAR construct. RMS cell killing and cytokine production by CD276- and FGFR4-CAR Ts expressing CD8α or CD28 HD/TM domains in combination with 4-1BB and/or CD28 co-stimulatory domains were tested in vitro. The most effective CD276- and FGFR4-CAR Ts were used to generate Dual-CAR Ts. Tumor killing was evaluated in vivo in three orthotopic RMS mouse models. Results: CD276.V-CAR Ts (276.MG.CD28HD/TM.CD28CSD.3z) showed the strongest killing of RMS cells, and the highest release of IFN-γ and Granzyme B in vitro. FGFR4.V-CAR Ts (F8-FR4.CD28HD/TM.CD28CSD.3z) showed the most specific killing. CD276-CAR Ts successfully eradicated RD- and Rh4-derived RMS tumors in vivo, achieving complete remission in 3/5 and 5/5 mice, respectively. In CD276low JR-tumors, however, they achieved complete remission in only 1/5 mice. FGFR4 CAR Ts instead delayed of Rh4 tumor growth. Dual-CAR Ts promoted Rh4-tumors clearance in 5/5 mice. Conclusions: CD276- and CD276/FGFR4-directed CAR Ts showed effective RMS cell killing in vitro and eradication of CD276high RMS tumors in vivo. CD276low tumors escaped the therapy showing a correlation of antigen density and effectiveness. FGFR4-CAR Ts showed specific killing in vitro but could only delay RMS growth in vivo. Our results show that combined expression of CD276-CAR with other CAR does not reduce its benefit. Introducing immunotherapy with CD276-CAR Ts in RMS seems to be feasible and promising, although CAR constructs design and target combinations have to be further improved to eradicate tumors with low target expression.

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Targeted immunotherapy and nanomedicine for rhabdomyosarcoma: The way of the future

Morel,

Rössler,

Bernasconi

2024

Medicinal Research Reviews

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Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. Histology separates two main subtypes: embryonal RMS (eRMS; 60%–70%) and alveolar RMS (aRMS; 20%–30%). The aggressive aRMS carry one of two characteristic chromosomal translocations that result in the expression of a PAX3::FOXO1 or PAX7::FOXO1 fusion transcription factor; therefore, aRMS are now classified as fusion‐positive (FP) RMS. Embryonal RMS have a better prognosis and are clinically indistinguishable from fusion‐negative (FN) RMS. Next to histology and molecular characteristics, RMS risk groupings are now available defining low risk tumors with excellent outcomes and advanced stage disease with poor prognosis, with an overall survival of about only 20% despite intensified multimodal treatment. Therefore, development of novel effective targeted strategies to increase survival and to decrease long‐term side effects is urgently needed. Recently, immunotherapies and nanomedicine have been emerging for potent and effective tumor treatments with minimal side effects, raising hopes for effective and safe cures for RMS patients. This review aims to describe the most relevant preclinical and clinical studies in immunotherapy and targeted nanomedicine performed so far in RMS and to provide an insight in future developments.

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FGFR4-Targeted Chimeric Antigen Receptors Combined with Anti-Myeloid Polypharmacy Effectively Treat Orthotopic Rhabdomyosarcoma

Cited by 18 publications

References 51 publications

FGFR1 fusions as a novel molecular driver in rhabdomyosarcoma

FGFR1 fusions as a novel molecular driver in rhabdomyosarcoma

CAR T cells recognizing CD276 and Dual-CAR T cells against CD276/FGFR4 promote rhabdomyosarcoma clearance in orthotopic mouse models

Targeted immunotherapy and nanomedicine for rhabdomyosarcoma: The way of the future

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