Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell

Marco Ruella; Jun Xu; David M Barrett; Joseph A Fraietta; Tyler J Reich; David E Ambrose; Michael Klichinsky; Olga Shestova; Prachi R Patel; Irina Kulikovskaya; Farzana Nazimuddin; Vijay G Bhoj; Elena J Orlando; Terry J Fry; Hans Bitter; Shannon L Maude; Bruce L Levine; Christopher L Nobles; Frederic D Bushman; Regina M Young; John Scholler; Saar I Gill; Carl H June; Stephan A Grupp; Simon F Lacey; J Joseph Melenhorst

doi:10.1038/s41591-018-0201-9

Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell

Nat Med. 2018 Oct;24(10):1499-1503. doi: 10.1038/s41591-018-0201-9. Epub 2018 Oct 1.

Authors

Marco Ruella^#^{1

2

3

4

5}, Jun Xu^#^{1

2

3}, David M Barrett^#⁶, Joseph A Fraietta^{1

2

3

4}, Tyler J Reich¹, David E Ambrose¹, Michael Klichinsky^{1

7}, Olga Shestova¹, Prachi R Patel¹, Irina Kulikovskaya¹, Farzana Nazimuddin¹, Vijay G Bhoj^{1

2

3}, Elena J Orlando⁸, Terry J Fry⁹, Hans Bitter⁸, Shannon L Maude⁶, Bruce L Levine^{1

2

3}, Christopher L Nobles¹⁰, Frederic D Bushman¹⁰, Regina M Young¹, John Scholler¹, Saar I Gill^{1

3

5}, Carl H June^{11

12

13

14}, Stephan A Grupp⁶, Simon F Lacey^{1

2

3}, J Joseph Melenhorst^{15

16

17}

Affiliations

¹ Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
² Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
³ Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
⁴ Parker Institute for Cellular Immunotherapy at the University of Pennsylvania, Philadelphia, PA, USA.
⁵ Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
⁶ Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁷ Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁸ Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
⁹ University of Colorado, Children's Hospital Colorado, Denver, CO, USA.
¹⁰ Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
¹¹ Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. cjune@upenn.edu.
¹² Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. cjune@upenn.edu.
¹³ Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. cjune@upenn.edu.
¹⁴ Parker Institute for Cellular Immunotherapy at the University of Pennsylvania, Philadelphia, PA, USA. cjune@upenn.edu.
¹⁵ Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. mej@upenn.edu.
¹⁶ Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. mej@upenn.edu.
¹⁷ Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. mej@upenn.edu.

^# Contributed equally.

Abstract

We report a patient relapsing 9 months after CD19-targeted CAR T cell (CTL019) infusion with CD19^- leukemia that aberrantly expressed the anti-CD19 CAR. The CAR gene was unintentionally introduced into a single leukemic B cell during T cell manufacturing, and its product bound in cis to the CD19 epitope on the surface of leukemic cells, masking it from recognition by and conferring resistance to CTL019.

Publication types

Case Reports
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Antigens, CD19 / immunology*
Antigens, CD19 / therapeutic use
B-Lymphocytes / immunology
Cell- and Tissue-Based Therapy
Drug Resistance, Neoplasm / immunology*
Epitopes / immunology*
Humans
Leukemia / drug therapy*
Leukemia / immunology
Leukemia / pathology
Male
Receptors, Antigen, T-Cell / immunology
Receptors, Antigen, T-Cell / therapeutic use
Receptors, Chimeric Antigen
T-Lymphocytes / immunology
Young Adult

Substances

Antigens, CD19
CD19 molecule, human
Epitopes
Receptors, Antigen, T-Cell
Receptors, Chimeric Antigen
tisagenlecleucel

Abstract

Publication types

MeSH terms

Substances

Grants and funding