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GPC2-CAR T cells tuned for low antigen density mediate potent activity against neuroblastoma without toxicity

  1. Author:
    Heitzeneder, Sabine
    Bosse, Kristopher R.
    Zhu, Zhongyu
    Zhelev, Doncho
    Majzner, Robbie G.
    Radosevich, Molly T.
    Dhingra, Shaurya
    Sotillo, Elena
    Buongervino, Samantha
    Pascual-Pasto, Guillem
    Garrigan, Emily
    Xu, Peng
    Huang, Jing
    Salzer, Benjamin
    Delaidelli, Alberto
    Raman, Swetha
    Cui, Hong
    Martinez, Benjamin
    Bornheimer, Scott J.
    Sahaf, Bita
    Alag, Anya
    Fetahu, Irfete S.
    Hasselblatt, Martin
    Parker, Kevin R.
    Anbunathan, Hima
    Hwang, Jennifer
    Huang, Min
    Sakamoto, Kathleen
    Lacayo, Norman J.
    Klysz, Dorota D.
    Theruvath, Johanna
    Vilches-Moure, Jose G.
    Satpathy, Ansuman T.
    Chang, Howard Y.
    Lehner, Manfred
    Taschner-Mandl, Sabine
    Julien, Jean-Phillipe
    Sorensen, Poul H.
    Dimitrov, Dimiter S.
    Maris, John M.
    Mackall, Crystal L.

  2. Author Address

    Stanford Univ, Ctr Canc Cell Therapy, Stanford Canc Inst, Sch Med, Lorry Lokey Bldg,Suite G3141,MC 5456, Stanford, CA 94305 USA.Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA.Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA.Univ Penn, Perelman Sch Med, Dept Pediat, Philadelphia, PA 19104 USA.NCI, Frederick, MD 21702 USA.Univ Pittsburgh, Dept Med, Pittsburgh, PA 15261 USA.St Anna Childrens Canc Res Inst, Vienna, Austria.Christian Doppler Lab Next Generat CAR T Cells, Vienna, Austria.British Columbia Canc Res Ctr, Dept Mol Oncol, Vancouver, BC V5Z 1L3, Canada.Hosp Sick Children Res Inst, Program Mol Med, Toronto, ON M5G 0A4, Canada.BD Biosci, San Jose, CA 95131 USA.Univ Hosp Munster, Inst Neuropathol, Munster, Germany.Stanford Univ, Ctr Personal Dynam Regulomes, Stanford, CA 94305 USA.Stanford Univ, Dept Pediat, Sch Med, Stanford, CA 94305 USA.Stanford Univ, Anim Histol Serv, Sch Med, Dept Comparat Med, Stanford, CA 94305 USA.Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA.Parker Inst Canc Immunotherapy, San Francisco, CA 94129 USA.Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA.Univ Toronto, Dept Biochem, Toronto, ON M5S 1A8, Canada.Univ Toronto, Dept Immunol, Toronto, ON M5S 1A8, Canada.Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA.Lentigen Technol Inc, Gaithersburg, MD 20878 USA.Cartog Biosci Inc, San Carlos, CA 94070 USA.
    1. Year: 2022
    2. Date: Jan 10
  2. Journal: Cancer Cell
  3. Cell Press
    1. 40
    2. 1
    3. Pages: 53-+
  5. Type of Article: Article
  6. ISSN: 1535-6108
  1. Abstract:

    Pediatric cancers often mimic fetal tissues and express proteins normally silenced postnatally that could serve as immune targets. We developed T cells expressing chimeric antigen receptors (CARs) targeting glypican-2 (GPC2), a fetal antigen expressed on neuroblastoma (NB) and several other solid tumors. CARs engineered using standard designs control NBs with transgenic GPC2 overexpression, but not those expressing clinically relevant GPC2 site density (similar to 5,000 molecules/cell, range 1-6 x 10(3)). Iterative engineering of transmembrane (TM) and co-stimulatory domains plus overexpression of c-Jun lowered the GPC2-CAR antigen density threshold, enabling potent and durable eradication of NBs expressing clinically relevant GPC2 antigen density, without toxicity. These studies highlight the critical interplay between CAR design and antigen density threshold, demonstrate potent efficacy and safety of a lead GPC2-CAR candidate suitable for clinical testing, and credential oncofetal antigens as a promising class of targets for CAR T cell therapy of solid tumors.

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External Sources

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  2. DOI: 10.1016/j.ccell.2021.12-005
  3. PMID: 34971569
  4. View record in Web of Science®
  5. WOS: 000744691500012

Library Notes

  1. Fiscal Year: FY2021-2022
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