Allogeneic cytotoxic T-cell therapy for EBV-positive posttransplantation lymphoproliferative disease: results of a phase 2 multicenter clinical trial

Haque, Tanzina; Wilkie, Gwen; Jones, Marie M.; Higgins, Craig; Urquhart, G. E. D.; Wingate, Phoebe; Burns, David M.; McAulay, Karen A.; Turner, Marc; Bellamy, Christopher; Amlot, Peter; Kelly, Déirdre; MacGilchrist, Alastair; Gandhi, Maher K.; Swerdlow, Anthony; Crawford, Dorothy H.

doi:10.1182/blood-2006-12-063008

Cited by 589 publications

(509 citation statements)

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“…A recent study suggests low numbers of CD4 1 cells as a risk factor for the development of PTLD in solid organ transplant recipients [60]. Patients receiving T-cell therapy for EBV-positive PTLD have better responses when the infused CTL lines have higher numbers of CD4 1 T cells [61]. The fact that a substantial number of EBVspecific T cells are non-IFNgproducers is of relevance for adoptive immunotherapy as well.…”

mentioning

confidence: 99%

Human peripheral blood and bone marrow Epstein–Barr virus‐specific T‐cell repertoire in latent infection reveals distinct memory T‐cell subsets

Guerreiro

Letsch

et al. 2010

Eur J Immunol

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EBV infection leads to life-long viral persistence. Although EBV infection can result in chronic disease and malignant transformation, most carriers remain disease-free as a result of effective control by T cells. EBV-specific IFN-c-producing T cells could be demonstrated in acute and chronic infection as well as during latency. Recent studies, however, provide evidence that assessing IFN-c alone is insufficient to assess the quantity and quality of a T-cell response. Using overlapping peptide pools of latent EBV nuclear antigen 1 and lytic BZLF-1 protein and multicolor flow cytometry, we demonstrate that the majority of ex vivo EBV-reactive T cells in healthy virus carriers are indeed IL-2-and/or TNF-producing memory cells, the latter being significantly more frequent in BM. After in vitro expansion, a substantial number of EBV-specific CD4 1 and CD8 1 T cells retained a CC-chemokine receptor 7 (CCR7)-positive memory phenotype. Based on their cytokine profiles, six different EBV-specific T-cell subsets could be distinguished with TNF-single or TNF/IL-2-double producing cells expressing the highest CCR7 levels resembling earlydifferentiated memory T cells. Our study delineates the memory T-cell profile of a protective immune response and provides a basis for analyzing T-cell responses in EBVassociated diseases.Key words: BM . EBV . Immune monitoring . Multifunctional T cells . T-cell memory IntroductionEBV is a human gamma herpesvirus that is widespread in all human populations. Following oral transmission, EBV replicates in the oropharyngeal epithelial cells and infects mucosal B cells, leading to a life-long persistence in the memory B-cell pool [1,2]. The primary infection occurs usually during childhood and is often asymptomatic; however, infection is manifested as acute infectious mononucleosis in a subset of patients [3]. Despite the relatively benign course in most carriers, EBV reactivation is considered as a risk-factor both for malignant transformation and autoimmune diseases. The ability of the EBV encoded protein 1566LMP-1 to induce T-cell-independent immunoglobulin class switch DNA recombination and BAFF, a B-cell activating factor, that rescues self-reactive T cells, is considered to play an important role in the pathogenesis of EBV-related autoimmune and lymphoproliferative disease [4]. EBV is causatively linked to nasopharyngeal carcinoma and B-cell malignant diseases such as endemic Burkitt's lymphoma, Hodgkin's lymphoma and posttransplant lymphoproliferative diseases (PTLD) [5][6][7]. Recent data suggest that EBV is associated with various autoimmune diseases as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis and primary Sjögren's syndrome [8,9]. Chronic active EBV infection can also cause Chronic Fatigue Syndrome, which is frequently associated with autoimmune thyreoiditis [10].The EBV cycle has two distinct stages, the latent infection where the genome is maintained at a constant copy number per cell and limited regions of the genome are expressed and the lytic cycle w...

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mentioning

confidence: 99%

Human peripheral blood and bone marrow Epstein–Barr virus‐specific T‐cell repertoire in latent infection reveals distinct memory T‐cell subsets

Guerreiro

Letsch

et al. 2010

Eur J Immunol

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“…This approach has been tested in the clinic in patients with EBV-associated post transplant lymphoma with response rates of 60–80%. (Doubrovina et al 2012, Haque et al 2007, Leen et al 2013, Vickers et al 2014)…”

Section: Targeting Tumour-associated Antigens With Native T-cell Recementioning

confidence: 99%

Recent advances in T‐cell immunotherapy for haematological malignancies

et al. 2016

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In vitro discoveries have paved the way for bench-to-bedside translation in adoptive T cell immunotherapy, resulting in remarkable clinical responses in a variety of haematological malignancies. Adoptively transferred T cells genetically modified to express CD19 CARs have shown great promise, although many unanswered questions regarding how to optimize T-cell therapies for both safety and efficacy remain. Similarly, T cells that recognize viral or tumour antigens though their native receptors have produced encouraging clinical responses. Honing manufacturing processes will increase the availability of T-cell products, while combining T-cell therapies has the ability to increase complete response rates. Lastly, innovative mechanisms to control these therapies may improve safety profiles while genome editing offers the prospect of modulating T-cell function. This review will focus on recent advances in T-cell immunotherapy, highlighting both clinical and pre-clinical advances, as well as exploring what the future holds.

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“…Adoptive cellular immunotherapy has thus been investigated for the prevention or treatment of EBV-associated PTLD arising after marrow or solid organ transplantation [11,[27][28][29]. For example, in allogeneic marrow transplant recipients with EBV+ PTLD, infusion of donor leukocytes (which should include T cells presensitized to the virus) has produced sustained clinical responses in a small number of patients [28].…”

Section: Adoptive Immunotherapymentioning

confidence: 99%

“…Also reported is regression of PTLD after infusion of donorderived, ex vivo expanded, polyclonal EBV-specific CTL [11]. Impressively, in a recently reported multicenter study of 33 cases that failed conventional therapy, serial infusions of allogeneic, partially HLA-matched EBV-specific CTL from a CTL bank produced objective responses in 52% at 6 months [29]. Interestingly the rate of decline in EBV viral load did not correlate with tumor response [29].…”

Section: Adoptive Immunotherapymentioning

confidence: 99%