Genetic mechanisms of target antigen loss in CAR19 therapy of acute lymphoblastic leukemia

Elena J Orlando; Xia Han; Catherine Tribouley; Patricia A Wood; Rebecca J Leary; Markus Riester; John E Levine; Muna Qayed; Stephan A Grupp; Michael Boyer; Barbara De Moerloose; Eneida R Nemecek; Henrique Bittencourt; Hidefumi Hiramatsu; Jochen Buechner; Stella M Davies; Michael R Verneris; Kevin Nguyen; Jennifer L Brogdon; Hans Bitter; Michael Morrissey; Piotr Pierog; Serafino Pantano; Jeffrey A Engelman; Wendy Winckler

doi:10.1038/s41591-018-0146-z

Genetic mechanisms of target antigen loss in CAR19 therapy of acute lymphoblastic leukemia

Nat Med. 2018 Oct;24(10):1504-1506. doi: 10.1038/s41591-018-0146-z. Epub 2018 Oct 1.

Authors

Elena J Orlando¹, Xia Han², Catherine Tribouley², Patricia A Wood², Rebecca J Leary³, Markus Riester³, John E Levine⁴, Muna Qayed⁵, Stephan A Grupp⁶, Michael Boyer⁷, Barbara De Moerloose⁸, Eneida R Nemecek⁹, Henrique Bittencourt¹⁰, Hidefumi Hiramatsu¹¹, Jochen Buechner¹², Stella M Davies¹³, Michael R Verneris¹⁴, Kevin Nguyen¹⁵, Jennifer L Brogdon³, Hans Bitter³, Michael Morrissey³, Piotr Pierog², Serafino Pantano¹⁶, Jeffrey A Engelman³, Wendy Winckler³

Affiliations

¹ Novartis Institutes for BioMedical Research, Cambridge, MA, USA. [email protected].
² Novartis Pharmaceutical Corporation, East Hanover, NJ, USA.
³ Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
⁴ Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵ Aflac Cancer and Blood Disorders Center, Emory University, Atlanta, GA, USA.
⁶ Divison of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁷ University of Utah, Salt Lake City, UT, USA.
⁸ Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium.
⁹ Oregon Health & Science University, Portland, OR, USA.
¹⁰ Sainte-Justine University Health Center, Montreal, Quebec, Canada.
¹¹ Department of Pediatrics, Kyoto University, Kyoto, Japan.
¹² Department of Pediatric Hematology and Oncology, Oslo University Hospital, Oslo, Norway.
¹³ Divison of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
¹⁴ Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.
¹⁵ Navigate BioPharma Services, Inc., A Novartis Subsidiary, Carlsbad, CA, USA.
¹⁶ Novartis Pharma AG, Basel, Switzerland.

PMID: 30275569
DOI: 10.1038/s41591-018-0146-z

Abstract

We identified genetic mutations in CD19 and loss of heterozygosity at the time of CD19^- relapse to chimeric antigen receptor (CAR) therapy. The mutations are present in the vast majority of resistant tumor cells and are predicted to lead to a truncated protein with a nonfunctional or absent transmembrane domain and consequently to a loss of surface antigen. This irreversible loss of CD19 advocates for an alternative targeting or combination CAR approach.

MeSH terms

Antigens, CD19 / genetics
Antigens, CD19 / immunology
Drug Resistance, Neoplasm / genetics*
Humans
Immunotherapy, Adoptive
Loss of Heterozygosity / genetics
Mutation
Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma / immunology
Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
Receptors, Antigen, T-Cell / genetics*
Receptors, Chimeric Antigen / genetics*
Receptors, Chimeric Antigen / immunology
Receptors, Chimeric Antigen / therapeutic use
T-Lymphocytes / immunology

Substances

Antigens, CD19
Receptors, Antigen, T-Cell
Receptors, Chimeric Antigen