Preventing Stem Cell Transplantation-Associated Viral Infections Using T-Cell Therapy

Tzannou, Ifigeneia; Leen, Ann M.

doi:10.2217/imt.15.43

Cited by 14 publications

(8 citation statements)

References 107 publications

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“…When adequate sequencing depth is available, NGS can be applied to study viral subpopulations associated with virulence and drug resistance. The emergence of viruses harboring mutations conferring resistance may also provide insight into the appropriate usage of antiviral prophylaxis regimens and the efficacy of emerging novel immunomodulatory therapies like adoptive transfer of virus-specific T cells in transplant recipients (76,77). These results could lead to diagnostic assays that provide information on not just the viral species, or viral load, but also viral genotype and phenotype.…”

Section: Virome and Transplantationmentioning

confidence: 99%

The Human Virome: Implications for Clinical Practice in Transplantation Medicine

Relman

Pinsky

2017

J Clin Microbiol

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Advances in DNA sequencing technology have provided an unprecedented opportunity to study the human virome. Transplant recipients and other immunocompromised hosts are at particular risk for developing virus-related pathology; thus, the impact of the virome on health and disease may be even more relevant in this population. Here, we discuss technical considerations in studying the human virome, the current literature on the virome in transplant recipients, and near-future applications of sequence-based findings that can further our understanding of viruses in transplantation medicine.

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Section: Virome and Transplantationmentioning

confidence: 99%

The Human Virome: Implications for Clinical Practice in Transplantation Medicine

Relman

Pinsky

2017

J Clin Microbiol

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“…Viral infections continue to account for substantial post-transplant morbidity and mortality after allogeneic HSCT, as reviewed elsewhere [ 62 ]. Immunotherapeutic strategies are increasingly being exploited to prevent and treat viral infections when anti-viral drugs are ineffective or cause excessive toxicity.…”

Section: T-cell Depleted (Tcd) Haploidentical Haematopoietic Stem mentioning

confidence: 99%

T-Cell Manipulation Strategies to Prevent Graft-Versus-Host Disease in Haploidentical Stem Cell Transplantation

Vadakekolathu

Rutella

2017

Biomedicines

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Allogeneic haematopoietic stem cell transplantation (HSCT) from an human leukocyte antigen (HLA)-identical donor can be curative for eligible patients with non-malignant and malignant haematological disorders. HSCT from alternative donor sources, such as HLA-mismatched haploidentical donors, is increasingly considered as a viable therapeutic option for patients lacking HLA-matched donors. Initial attempts at haploidentical HSCT were associated with vigorous bidirectional alloreactivity, leading to unacceptably high rates of graft rejection and graft-versus-host disease (GVHD). More recently, new approaches for mitigating harmful T-cell alloreactivity that mediates GVHD, while preserving the function of tumour-reactive natural killer (NK) cells and γδ T cells, have led to markedly improved clinical outcomes, and are successfully being implemented in the clinic. This article will provide an update on in vitro strategies and in vivo approaches aimed at preventing GVHD by selectively manipulating key components of the adaptive immune response, such as T-cell receptor (TCR)-αβ T cells and CD45RA-expressing naive T cells.

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“…Since unselected donor T cells may induce GVHD when infused into patients after alloSCT, we hypothesized that engineering virus-specific T cells from donor origin to express the HA-1H TCR would create a therapeutic product unlikely to induce GVHD. We and others have illustrated that the infusion of virus-specific T cells from donor origin into patients after alloSCT can have a profound anti-viral reactivity without toxicity (26)(27)(28)(29)(30)(31)(32). In addition, virus-specific T cells engineered to coexpress tumorspecific receptors demonstrated improved persistence after treatment of individuals with neuroblastoma (33).…”

Section: Introductionmentioning

confidence: 99%

HA-1H T-Cell Receptor Gene Transfer to Redirect Virus-Specific T Cells for Treatment of Hematological Malignancies After Allogeneic Stem Cell Transplantation: A Phase 1 Clinical Study

et al. 2020

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Graft-vs.-leukemia (GVL) reactivity after HLA-matched allogeneic stem cell transplantation (alloSCT) is mainly mediated by donor T cells recognizing minor histocompatibility antigens (MiHA). If MiHA are targeted that are exclusively expressed on hematopoietic cells of recipient origin, selective GVL reactivity without severe graft-vs.-host-disease (GVHD) may occur. In this phase I study we explored HA-1H TCR gene transfer into T cells harvested from the HA-1H negative stem-cell donor to treat HA-1H positive HLA-A * 02:01 positive patients with high-risk leukemia after alloSCT. HA-1H is a hematopoiesis-restricted MiHA presented in HLA-A * 02:01. Since we previously demonstrated that donor-derived virus-specific T-cell infusions did not result in GVHD, we used donor-derived EBV and/or CMV-specific T-cells to be redirected by HA-1H TCR. EBV and/or CMV-specific T-cells were purified, retrovirally transduced with HA-1H TCR, and expanded. Validation experiments illustrated dual recognition of viral antigens and HA-1H by HA-1H TCR-engineered virus-specific T-cells. Release criteria included products containing more than 60% antigen-specific T-cells. Patients with high risk leukemia following T-cell depleted alloSCT in complete or partial remission were eligible. HA-1H TCR T-cells were infused 8 and 14 weeks after alloSCT without additional pre-conditioning chemotherapy. For 4/9 included patients no appropriate products could be made. Their donors were all CMV-negative, thereby restricting the production process to EBV-specific T-cells. For 5 patients a total of 10 products could be made meeting the release criteria containing 3-280 × 10 6 virus and/or HA-1H TCR T-cells. No infusion-related toxicity, delayed toxicity or GVHD occurred. One patient with relapsed AML at time of infusions died due to rapidly progressing disease. Four patients were in remission at time of infusion. Two patients died of infections during follow-up, not van Balen et al. HA-1H TCR Gene Transfer likely related to the infusion. Two patients are alive and well without GVHD. In 2 patients persistence of HA-1H TCR T-cells could be illustrated correlating with viral reactivation, but no overt in-vivo expansion of infused T-cells was observed. In conclusion, HA-1H TCR-redirected virus-specific T-cells could be made and safely infused in 5 patients with high-risk AML, but overall feasibility and efficacy was too low to warrant further clinical development using this strategy. New strategies will be explored using patient-derived donor T-cells isolated after transplantation transduced with HA-1H-specific TCR to be infused following immune conditioning.

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Preventing Stem Cell Transplantation-Associated Viral Infections Using T-Cell Therapy

Cited by 14 publications

References 107 publications

The Human Virome: Implications for Clinical Practice in Transplantation Medicine

The Human Virome: Implications for Clinical Practice in Transplantation Medicine

T-Cell Manipulation Strategies to Prevent Graft-Versus-Host Disease in Haploidentical Stem Cell Transplantation

HA-1H T-Cell Receptor Gene Transfer to Redirect Virus-Specific T Cells for Treatment of Hematological Malignancies After Allogeneic Stem Cell Transplantation: A Phase 1 Clinical Study

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