Publications by authors named "Gaurav Sutrave"

6 Publications

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Successful treatment of CMV, EBV, and adenovirus tissue infection following HLA-mismatched allogeneic stem cell transplant using infusion of third-party T cells from multiple donors in addition to antivirals, rituximab, and surgery.

Transpl Infect Dis 2020 Nov 24:e13528. Epub 2020 Nov 24.

Department of Haematology, Westmead Hospital, Sydney, NSW, Australia.

Viral infections, principally cytomegalovirus, Epstein Barr virus (EBV) and adenovirus, are a leading cause of morbidity and mortality after allogeneic stem cell transplantation. The use of systemic antivirals is limited by limited efficacy and organ toxicities. Inability to clear infection is exacerbated by transplant-related immunosuppression and prophylaxis or treatment of acute graft versus host disease. We report the first patient to clear three serious viral infections after stem cell transplant using third-party donor partially human leukocyte antigen (HLA) matched virus-specific cytotoxic T cells. The patient, a 53 year old female with transplanted for relapsed leukemia, with severe graft versus host disease received five T cell infusions from three separate donors that ultimately cleared serious systemic infections with cytomegalovirus and adenovirus, and an EBV-driven lymphoma. Systemic antivirals had resulted in failed clinical responses. Use of repeated infusions of partially HLA matched virus-specific T cells from banks containing cryopreserved cells should be strongly considered in transplant recipients with single or multiple refractory viral infections.
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http://dx.doi.org/10.1111/tid.13528DOI Listing
November 2020

Adoptive cell therapies for posttransplant infections.

Curr Opin Oncol 2019 11;31(6):574-590

Department of Haematology, Westmead Hospital.

Purpose Of Review: Viral and fungal infections cause significant morbidity and mortality following hematopoietic stem-cell transplantation (HSCT), primarily due to the prolonged and complex immunodeficient state that results from conditioning chemo-radiotherapy and subsequent prophylaxis of graft vs. host disease. Although currently available antimicrobial pharmacotherapies have demonstrated short-term efficacy, their toxicities often preclude long-term use, and cessation if frequently associated with recurrent infection. Adoptive cell therapy (ACT) offers the potential to more rapidly reconstitute antimicrobial immune responses in the posttransplant setting.

Recent Findings: Traditional approaches to manufacture of adoptive T-cell therapies are time consuming and limited to single pathogen specificity. Recent advances in the understanding of immunogenic epitopes, improved methods for pathogen-specific T-cell isolation and cultureware technologies is allowing for rapid generation of ACTs for clinical use.

Summary: The current review summarizes the potential infectious targets and manufacturing methodologies for ACTs and contrasts their clinical efficacy and safety to currently available pharmacotherapies for patients recovering after HSCT.
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http://dx.doi.org/10.1097/CCO.0000000000000580DOI Listing
November 2019

Pathogen-Specific T Cells Beyond CMV, EBV and Adenovirus.

Curr Hematol Malig Rep 2019 08;14(4):247-260

Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia.

Purpose Of Review: Infectious diseases contribute significantly to morbidity and mortality in recipients of allogeneic haematopoietic stem cell transplantation (aHSCT), particularly in the era of highly immunosuppressive transplant regimens and alternate donor transplants. Delayed cellular immune recovery is a major mechanism for the increased risk in these patients. Adoptive cell therapy with ex vivo manipulated pathogen-specific T cells (PSTs) is increasingly taking its place as a treatment strategy using donor-derived or third party-banked cells.

Recent Findings: The majority of clinical trial data in the form of early-phase studies has been in the prophylaxis or treatment of cytomegalovirus (CMV), Epstein-Barr virus (EBV) and adenovirus (AdV). Advancements in methods to select and enrich PSTs offer the opportunity to target the less common viral pathogens as well as fungi with this technology. Early clinical studies of PSTs targeting polyomaviruses (BK virus and JC virus), human herpesvirus 6 (HHV6), varicella zoster virus (VZV) and Aspergillus spp. have shown promising results in small numbers of patients. Other potential targets include herpes simplex virus (HSV), respiratory viruses and other invasive fungal species. In this review, we describe the burden of disease of this wider spectrum of pathogens, the progress in the development of manufacturing capability, early clinical results and the opportunities and challenges for implementation in the clinic.
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http://dx.doi.org/10.1007/s11899-019-00521-zDOI Listing
August 2019

Anncaliia algerae Microsporidial Myositis, New South Wales, Australia.

Emerg Infect Dis 2018 08;24(8):1528-1531

We describe the successful management of Anncaliia algerae microsporidial myositis in a man with graft versus host disease after hemopoietic stem cell transplantation. We also summarize clinical presentation and management approaches and discuss the importance of research into the acquisition of this infection and strategies for prevention.
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http://dx.doi.org/10.3201/eid2408.172002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056123PMC
August 2018

Long-term control of recurrent or refractory viral infections after allogeneic HSCT with third-party virus-specific T cells.

Blood Adv 2017 Nov 2;1(24):2193-2205. Epub 2017 Nov 2.

Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia.

Donor-derived adoptive T-cell therapy is a safe and effective treatment of viral infection posttransplant, but it is limited by donor serostatus and availability and by its personalized nature. Off-the-shelf, third-party virus-specific T cells (VSTs) appear promising, but the long-term safety and durability of responses have yet to be established. We conducted a prospective study of 30 allogeneic hemopoietic stem cell transplant (HSCT) patients with persistent or recurrent cytomegalovirus (CMV) (n = 28), Epstein-Barr virus (n = 1), or adenovirus (n = 1) after standard therapy. Patients were treated with infusions of partially HLA-matched, third-party, ex vivo-expanded VSTs (total = 50 infusions) at a median of 75 days post-HSCT (range, 37 to 349 days). Safety, viral dynamics, and immune recovery were monitored for 12 months. Infusions were safe and well tolerated. Acute graft versus host disease occurred in 2 patients, despite a median HLA match between VSTs and the recipient of 2 of 6 antigens. At 12 months, the cumulative incidence of overall response was 93%. Virological control was durable in the majority of patients; the reintroduction of antiviral therapy after the final infusion occurred in 5 patients. CMV-specific T-cell immunity rose significantly and coincided with a rise in CD8 terminal effector cells. PD-1 expression was elevated on CD8 lymphocytes before the administration of third-party T cells and remained elevated at the time of viral control. Third-party VSTs show prolonged benefit, with virological control achieved in association with the recovery of CD8 effector T cells possibly facilitated by VST infusion. This trial was registered at www.clinicaltrials.gov as #NCT02779439 and www.anzctr.org.au as #ACTRN12613000603718.
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http://dx.doi.org/10.1182/bloodadvances.2017010223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5737128PMC
November 2017

Cellular therapy for multiple pathogen infections after hematopoietic stem cell transplant.

Cytotherapy 2017 11 15;19(11):1284-1301. Epub 2017 Sep 15.

Department of Haematology, Westmead Hospital, Sydney, Australia; The Westmead Institute for Medical Research, The University of Sydney, Sydney, Australia. Electronic address:

Hematopoietic stem cell transplantation (HSCT) represents the only crative treatment option for many hematological conditions but results in a profound T-cell deficiency in the post-HSCT period. Infections account for a significant proportion of non-relapse morbidity and mortality, and infections with multiple organisms either simultaneously or at different times after transplant are common. Adoptive cellular therapy (ACT) with prophylactic or therapeutic infusion of donor derived or third-party, pathogen-specific T-cells represents a novel methodology to rapidly reconstitute T-cell mediated immunity in this context. For cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infection, clear evidence of efficacy with limited toxicity has been observed, with response rates up to 90%. Infusion of third-party, partially human leukocyte antigen-matched pathogen-specific T-cells have also demonstrated remarkable efficacy with responses seen in up to 70% of patients with resistant CMV, EBV and adenoviral infection. This review addresses the nature of post-HSCT immune deficiency, the common infections that occur in the post-HSCT period and how advances in ACT manufacturing methodologies is allowing for wider implementation of T-cell therapies targeting multiple pathogens in HSCT recipients.
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http://dx.doi.org/10.1016/j.jcyt.2017.07.012DOI Listing
November 2017