Replication competent retrovirus testing (RCR) in the National Gene Vector Biorepository: No evidence of RCR in 1,595 post-treatment peripheral blood samples obtained from 60 clinical trials

Kenneth Cornetta; Jing Yao; Kimberley House; Lisa Duffy; Prasad S Adusumilli; Rachel Beyer; Claire Booth; Malcolm Brenner; Kevin Curran; Bambi Grilley; Helen Heslop; Christian S Hinrichs; Rosandra N Kaplan; Hans-Peter Kiem; James Kochenderfer; Donald B Kohn; Sham Mailankody; Scott M Norberg; Roisin E O'Cearbhaill; Jennifer Pappas; Jae Park; Carlos Ramos; Antonio Ribas; Isabelle Rivière; Steven A Rosenberg; Craig Sauter; Nirali N Shah; Susan F Slovin; Adrian Thrasher; David A Williams; Tsai-Yu Lin

doi:10.1016/j.ymthe.2022.12.006

Replication competent retrovirus testing (RCR) in the National Gene Vector Biorepository: No evidence of RCR in 1,595 post-treatment peripheral blood samples obtained from 60 clinical trials

Mol Ther. 2023 Mar 1;31(3):801-809. doi: 10.1016/j.ymthe.2022.12.006. Epub 2022 Dec 14.

Authors

Kenneth Cornetta¹, Jing Yao², Kimberley House², Lisa Duffy², Prasad S Adusumilli³, Rachel Beyer⁴, Claire Booth⁵, Malcolm Brenner⁶, Kevin Curran⁷, Bambi Grilley⁶, Helen Heslop⁶, Christian S Hinrichs⁸, Rosandra N Kaplan⁹, Hans-Peter Kiem¹⁰, James Kochenderfer¹¹, Donald B Kohn¹², Sham Mailankody¹³, Scott M Norberg¹⁴, Roisin E O'Cearbhaill³, Jennifer Pappas⁴, Jae Park³, Carlos Ramos⁶, Antonio Ribas¹⁵, Isabelle Rivière³, Steven A Rosenberg⁴, Craig Sauter¹⁶, Nirali N Shah⁹, Susan F Slovin¹⁷, Adrian Thrasher⁵, David A Williams¹⁸, Tsai-Yu Lin¹⁹

Affiliations

¹ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA; Brown Center for Immunotherapy, Indiana University School of Medicine, Indianapolis, IN, USA. Electronic address: kcornett@iu.edu.
² Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
³ Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁴ Surgery Branch, NCI, Bethesda, MD 20892, USA.
⁵ Molecular and Cellular Immunology, UCL Great Ormond Street Institute of Child Health, London, UK.
⁶ Center for Cell and Gene Therapy Baylor College of Medicine, Houston TX, USA.
⁷ Memorial Sloan Kettering Cancer Center, Department of Pediatrics, New York, NY, USA; Weill Cornell Medical College, Department of Pediatrics, New York, NY, USA.
⁸ Duncan and Nancy MacMillan Cancer Immunology and Metabolism Center of Excellence, New Brunswick, NJ 08901, USA; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA.
⁹ Pediatric Oncology Branch, Center for Cancer Research, NCI, Bethesda, MD 20892, USA.
¹⁰ Fred Hutchison Cancer Center and University of Washington, Seattle, WA, USA.
¹¹ Center for Cancer Research, Surgery Branch, NCI, NIH, Bethesda MD, USA.
¹² Departments of Microbiology, Immunology and Molecular Genetics, Pediatrics (Hematology/Oncology) and Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA.
¹³ Myeloma and Cellular Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁴ NCI, Center for Immuno-Oncology, Bethesda, MD 20892, USA.
¹⁵ Jonsson Comprehensive Cancer Center at the University of California Los Angeles (UCLA), Los Angeles, CA 90095, USA.
¹⁶ Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
¹⁷ Genitourinary Oncology Service, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁸ Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
¹⁹ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA; Brown Center for Immunotherapy, Indiana University School of Medicine, Indianapolis, IN, USA.

Abstract

The clinical impact of any therapy requires the product be safe and effective. Gammaretroviral vectors pose several unique risks, including inadvertent exposure to replication competent retrovirus (RCR) that can arise during vector manufacture. The US FDA has required patient monitoring for RCR, and the National Gene Vector Biorepository is an NIH resource that has assisted eligible investigators in meeting this requirement. To date, we have found no evidence of RCR in 338 pre-treatment and 1,595 post-treatment blood samples from 737 patients associated with 60 clinical trials. Most samples (75%) were obtained within 1 year of treatment, and samples as far out as 9 years after treatment were analyzed. The majority of trials (93%) were cancer immunotherapy, and 90% of the trials used vector products produced with the PG13 packaging cell line. The data presented here provide further evidence that current manufacturing methods generate RCR-free products and support the overall safety profile of retroviral gene therapy.

Keywords: cancer immunotherapy; gene therapy; patient monitoring; replication competent retrovirus; safety.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural

MeSH terms

Cell Line
Genetic Therapy / adverse effects
Genetic Vectors / genetics
Humans
Retroviridae* / genetics
Virus Replication*

Abstract

Publication types

MeSH terms

Grants and funding