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AACR 2021 | FGFR-4-targeted CARs for rhabdomyosarcoma

Rimas J. Orentas, PhD, Seattle Children’s Research Institute, Seattle, WA, outlines the development of FGFR4-targeted chimeric antigen receptor (CAR) T-cells for the treatment of rhabdomyosarcoma. FGFR4 is upregulated in rhabdomyosarcoma tumors compared to normal tissue, making it a suitable candidate for CAR-T therapy. Two novel CAR-T therapies targeting FGFR4 which demonstrated high cellular toxicity and tumor specificity in vitro are being further developed and will be tested for in vivo efficacy against metastatic and intramuscular rhabdomyosarcoma. This interview took place at the virtual American Association for Cancer Research (AACR) Annual Meeting 2021.

Transcript (edited for clarity)

Rhabdomyosarcoma is a disease of children. It’s one of the pediatric solid tumors. They’re the most challenging to treat. So we’ve been looking for years for new avenues for treating rhabdomyosarcoma. Unlike the leukemias or a few other of the pediatric cancers, both rhabdomyosarcoma and Ewing’s sarcoma have not have improved outcomes in decades, more than 30 years. So we definitely need new therapies other than the highly genotoxic chemotherapy based agents that are currently being used...

Rhabdomyosarcoma is a disease of children. It’s one of the pediatric solid tumors. They’re the most challenging to treat. So we’ve been looking for years for new avenues for treating rhabdomyosarcoma. Unlike the leukemias or a few other of the pediatric cancers, both rhabdomyosarcoma and Ewing’s sarcoma have not have improved outcomes in decades, more than 30 years. So we definitely need new therapies other than the highly genotoxic chemotherapy based agents that are currently being used. And one of those avenues is chimeric antigen receptor T-cells. These have had a great impact on the most hard-to-treat pediatric leukemias. So our lab is trying to apply that technology of using chimeric antigen receptor-modified T-cells to target rhabdomyosarcoma. And the first thing you need to do to do that kind of targeting is identify what’s on the surface that we could possibly kill without destroying normal cells or causing unwarranted toxicities.

So, one of those molecules on the surface of rhabdomyosarcoma is fibroblasts growth factor receptor 4,-FGFR4. So we found that it’s preferentially expressed on the rhabdomyosarcoma as opposed to normal tissues, and therefore is a good target for Chimeric antigen receptor-modified T-cells. In our work in which we started to do this, we created the specific chimeric antigen receptor T-cells. We showed that they’re highly active against FGFR4 targets in a tissue culture dish. And then we started to evaluate them in animal models. And this presentation that we have is really about how we’re learning the hurdles or the barriers to treating rhabdomyosarcoma in those animal models.

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Disclosures

Rimas J. Orentas, PhD, has received research support from Lentigen, a Miltenyi Biotec Company; and has participated in a consultancy role for Umoja Biopharma.

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