Corey Smith1, Leone Beagley1, Sweera Rehan1, Michelle A Neller1, Pauline Crooks1, Matthew Solomon1, Chien-Li Holmes-Liew2,3, Mark Holmes2,3, Scott C McKenzie4,5, Peter Hopkins6,5, Scott Campbell7,5, Ross S Francis7,5, Daniel C Chambers6,5, Rajiv Khanna1,5. 1. QIMR Centre for Immunotherapy and Vaccine Development, QIMR Berghofer Medical Research Institute, Brisbane, Australia. 2. South Australian Lung Transplant Unit, Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, Australia. 3. Faculty of Medicine, University of Adelaide, South Australia. 4. Advanced Heart Failure and Cardiac Transplant Unit. 5. School of Medicine, University of Queensland, Brisbane, Australia. 6. Queenland Lung Transplant Service, The Prince Charles Hospital, Brisbane. 7. Department of Nephrology, Princess Alexandra Hospital, Brisbane, Australia.
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.
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; Dillon Corvino; Leone Beagley; Sweera Rehan; Michelle A Neller; Pauline Crooks; Katherine K Matthews; Matthew Solomon; Laetitia Le Texier; Scott Campbell; Ross S Francis; Daniel Chambers; Rajiv Khanna Journal: J Clin Invest Date: 2019-11-01 Impact factor: 14.808
Authors: Vanessa A Fabrizio; M Irene Rodriguez-Sanchez; Audrey Mauguen; Parastoo B Dahi; Ekaterina Doubrovina; Richard J O'Reilly; Susan E Prockop Journal: Blood Adv Date: 2021-01-26