Autologous Adoptive T-cell Therapy for Recurrent or Drug-resistant Cytomegalovirus Complications in Solid Organ Transplant Recipients: A Single-arm Open-label Phase I Clinical Trial.

Abstract

Background:

Opportunistic infections including cytomegalovirus (CMV) are a major cause of morbidity and mortality in solid organ transplant (SOT) recipients. The recurrent and protracted use of antiviral drugs with eventual emergence of drug resistance represents a significant constraint to therapy. Although adoptive T-cell therapy has been successfully used in hematopoietic stem cell transplant recipients, its extension to the SOT setting poses a considerable challenge because of the inhibitory effects of immunosuppressive drugs on the virus-specific T-cell response in vivo and the perceived risk of graft rejection.

Methods:

In this prospective study, 22 SOT recipients (13 renal and 8 lung and 1 heart transplants) with recurrent or ganciclovir-resistant CMV infection were recruited, and 13 of them were treated with in vitro-expanded autologous CMV-specific T cells. These patients were monitored for safety, clinical symptoms, and immune reconstitution.

Results:

Autologous CMV-specific T-cell manufacture was attempted for 21 patients, and was successful in 20. The use of this adoptive immunotherapy was associated with no therapy-related serious adverse events. Eleven (84%) of the 13 treated patients showed improvement in symptoms, including complete resolution or reduction in DNAemia and CMV-associated end-organ disease and/or the cessation or reduced use of antiviral drugs. Furthermore, four of these patients showed coincident increased frequency of CMV-specific T cells in peripheral blood after completion of T-cell therapy.

Conclusions:

The data presented here demonstrate for the first time the clinical safety of CMV-specific adoptive T-cell therapy and its potential therapeutic benefit for SOT recipients with recurrent and/or drug-resistant CMV infection or disease.

Clinical Trials Registration:

ACTRN12613000981729.

• Authors: Corey Smith, Leone Beagley, Sweera Rehan, Michelle A Neller, Pauline Crooks, Matthew Solomon, Chien-Li Holmes-Liew, Mark Holmes, Scott C McKenzie, Peter Hopkins, Scott Campbell, Ross S Francis, Daniel C Chambers, Rajiv Khanna
• Journal: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America (Clin Infect Dis) Vol. 68 Issue 4 Pg. 632-640 (02 01 2019) ISSN: 1537-6591 [Electronic] United States
• PMID: 29982441 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Topics

• Adoptive Transfer (methods)
• Adult
• Cytomegalovirus (immunology)
• Cytomegalovirus Infections (therapy)
• Female
• Humans
• Male
• Middle Aged
• Prospective Studies
• Recurrence
• T-Lymphocytes (immunology)
• Transplantation, Autologous (methods)
• Treatment Outcome
• Young Adult