649. Developing FGFR4 Chimeric Antigen Receptor CAR T Cell Therapy Against Rhabdomyosarcoma

Shivaprasad, Nityashree; Xiong, Ying; Yohe, Marielle E.; Schneider, Dina; Shern, Jack F.; Baskar, Sivasubramanian; Dimitrov, Dimiter S.; Sorenson, Paul; Orentas, Rimas J.; Khan, Javed

doi:10.1016/s1525-0016(16)33457-8

Cited by 8 publications

(5 citation statements)

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“…In particular, T cells genetically modified to express a CAR that targets FGFR4 have been developed for treatment of RMS tumors [ 151 ]. Testing of these FGFR4-specific CAR T cells in vitro and in mouse models revealed promising effects of these T cells in killing tumor cells and suggested that these agents could be beneficial for treatment of high-risk, refractory and relapsed RMS [ 126 , 127 , 163 ]. In addition, IGFR1-specific CAR T cells were recently developed, and initial results indicated that they suppress growth of several sarcoma categories expressing this receptor in both cell line and xenograft systems [ 164 ].…”

Section: Immunotherapy Applications To Target Pax3-foxo1 and Downsmentioning

confidence: 99%

Therapeutic Approaches Targeting PAX3-FOXO1 and Its Regulatory and Transcriptional Pathways in Rhabdomyosarcoma

Nguyen

Barr

2018

Molecules

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Rhabdomyosarcoma (RMS) is a family of soft tissue cancers that are related to the skeletal muscle lineage and predominantly occur in children and young adults. A specific chromosomal translocation t(2;13)(q35;q14) that gives rise to the chimeric oncogenic transcription factor PAX3-FOXO1 has been identified as a hallmark of the aggressive alveolar subtype of RMS. PAX3-FOXO1 cooperates with additional molecular changes to promote oncogenic transformation and tumorigenesis in various human and murine models. Its expression is generally restricted to RMS tumor cells, thus providing a very specific target for therapeutic approaches for these RMS tumors. In this article, we review the recent understanding of PAX3-FOXO1 as a transcription factor in the pathogenesis of this cancer and discuss recent developments to target this oncoprotein for treatment of RMS.

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Section: Immunotherapy Applications To Target Pax3-foxo1 and Downsmentioning

confidence: 99%

Therapeutic Approaches Targeting PAX3-FOXO1 and Its Regulatory and Transcriptional Pathways in Rhabdomyosarcoma

Nguyen

Barr

2018

Molecules

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“…Moreover, we could achieve effective cell-mediated cytotoxicity with FGFR4-CAR T cells in vitro. Therapies for RMS based on FGFR4 antibodies have been investigated pre-clinically with promising results, either as antibody–drug conjugates (ADC) [ 56 , 57 , 58 ], or with the antigen-binding domain grafted on chimeric antigen receptors (CARs) to generate CAR T cells [ 59 ]. With our work, we show here a novel FGFR4-targeting based on sdAb by active drug delivery and T cell recruitment.…”

Section: Resultsmentioning

confidence: 99%

Novel FGFR4-Targeting Single-Domain Antibodies for Multiple Targeted Therapies against Rhabdomyosarcoma

Alijaj

Moutel

Gouveia

et al. 2020

Cancers

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The fibroblast growth factor receptor 4 (FGFR4) is overexpressed in rhabdomyosarcoma (RMS) and represents a promising target for treatments based on specific and efficient antibodies. Despite progress, there is an urgent need for targeted treatment options to improve survival rates, and to limit long-term side effects. From phage display libraries we selected FGFR4-specific single-domain antibodies (sdAb) binding to recombinant FGFR4 and validated them by flow cytometry, surface plasmon resonance, and fluorescence microscopy. The specificity of the selected sdAb was verified on FGFR4-wild type and FGFR4-knock out cells. FGFR4-sdAb were used to decorate vincristine-loaded liposomes and to generate chimeric antigen receptor (CAR) T cells. First, incubation of RMS cells with FGFR4-sdAb revealed that FGFR4-sdAb can block FGF19-FGFR4 signaling via the MAPK pathway and could therefore serve as therapeutics for FGFR4-dependent cancers. Second, FGFR4-targeted vincristine-loaded liposomes bound specifically to RMS cells and were internalized by the receptor, demonstrating the potential for active drug delivery to the tumor. Third, FGFR4-CAR T cells, generated with one sdAb candidate, demonstrated strong and specific cytotoxicity against FGFR4 expressing RMS cells. We selected novel FGFR4-sdAb with high specificity and nano- to picomolar affinities for FGFR4 which have the potential to enable multiple FGFR4-targeted cancer therapy approaches.

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“…FGFR4 inhibition was effective in preclinical studies of FN-RMS and FP-RMS and FGFR4 is differentially expressed in RMS compared to mature skeletal muscle, therefore it may be a beneficial target for immunotherapy [ 109 , 110 ]. FGFR4 targeted chimeric antigen receptor (CAR) T-cells are currently in pre-clinical development and were effective against RMS in both in vitro and in vivo studies [ 111 , 112 , 113 ].…”

Section: Other Targeted Agentsmentioning

confidence: 99%

Prioritization of Novel Agents for Patients with Rhabdomyosarcoma: A Report from the Children’s Oncology Group (COG) New Agents for Rhabdomyosarcoma Task Force

Pacenta

Allen‐Rhoades

Langenau

et al. 2021

JCM

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Rhabdomyosarcoma is the most common soft tissue sarcoma diagnosed in children and adolescents. Patients that are diagnosed with advanced or relapsed disease have exceptionally poor outcomes. The Children’s Oncology Group (COG) convened a rhabdomyosarcoma new agent task force in 2020 to systematically evaluate novel agents for inclusion in phase 2 or phase 3 clinical trials for patients diagnosed with rhabdomyosarcoma, following a similar effort for Ewing sarcoma. The task force was comprised of clinicians and basic scientists who collectively identified new agents for evaluation and prioritization in clinical trial testing. Here, we report the work of the task force including the framework upon which the decisions were rendered and review the top classes of agents that were discussed. Representative agents include poly-ADP-ribose polymerase (PARP) inhibitors in combination with cytotoxic agents, mitogen-activated protein kinase (MEK) inhibitors in combination with type 1 insulin-like growth factor receptor (IGFR1) inhibitors, histone deacetylase (HDAC) inhibitors, and novel cytotoxic agents.

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649. Developing FGFR4 Chimeric Antigen Receptor CAR T Cell Therapy Against Rhabdomyosarcoma

Cited by 8 publications

References 0 publications

Therapeutic Approaches Targeting PAX3-FOXO1 and Its Regulatory and Transcriptional Pathways in Rhabdomyosarcoma

Therapeutic Approaches Targeting PAX3-FOXO1 and Its Regulatory and Transcriptional Pathways in Rhabdomyosarcoma

Novel FGFR4-Targeting Single-Domain Antibodies for Multiple Targeted Therapies against Rhabdomyosarcoma

Prioritization of Novel Agents for Patients with Rhabdomyosarcoma: A Report from the Children’s Oncology Group (COG) New Agents for Rhabdomyosarcoma Task Force

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