Hematopoietic Stem Cell Transplant (HSCT) is a therapeutic strategy used to treat blood cell malignancies, as well as genetic disorders that involve hematopoietic development and autoimmune diseases. Recipients are “conditioned” with chemotherapy and/or radiation prior to transplant in order to eliminate the preexisting disease, provide a niche for the donor stem cells and provide the immunosuppression necessary to prevent transplant rejection. Following conditioning for HSCT, patients are severely immunocompromised and can be further immunosuppressed by prophylaxis for and/or treatment of Graft versus Host Disease (GvHD). During this immune suppressed period, an HSCT recipient is at risk of life-threatening disease from reactivating herpesviruses, adenoviruses and polyomaviruses. Although diagnostic and therapeutic approaches vary by center, patients are typically monitored closely with serial diagnostic tests for some of these viruses with the goal of identifying the presence of a virus at early onset and allowing time for aggressive intervention. Antiviral agents can be administered as prophylaxis, pre-emptive therapy prior to the onset of clinical symptoms or as directed therapy for active disease. Unfortunately, many antiviral agents retain undesirable side effects such as the risk of myelosuppression and nephrotoxicity. Furthermore, in many instances patients are unresponsive to these therapies and the infections progress to significant morbidity and mortality. Novel antiviral agents with improved side effect profiles and clinical effectiveness are needed. Some candidate agents are already in development. Novel therapeutic approaches to manage reactivating viruses are also under development and appear to have significant promise. Such therapeutic approaches include targeted adoptive immunotherapies to be administered to patients at risk for poor outcomes from particular viruses. Adoptive immunotherapy typically involves harvesting T cells from donors, selecting antiviral T cells and expanding these T cells from the total pool. These expanded antiviral T-cells are then infused into the patient or banked for future use. Ideally, these T cells will provide long-term protection, or serve as a bridge until the patient’s immune system reconstitutes. However, the stimulation of these T cells during the isolation, selection and expansion process can promote their terminal differentiation, reducing their survival and proliferative capacity, and possibly limiting their effectiveness. Additional strategies to better select and expand antiviral T cells without inducing terminal differentiation, or to directly isolate antiviral T cells without expansion are being pursued and might markedly extend the duration of T cell function after infusion into the patients.
The present Research Topic is meant to highlight both basic and clinical research in this area, to provide an overview of the current epidemiology, to discuss antiviral pharmaceutical options and their challenges, and to review the current state of novel adoptive immunotherapies for the treatment of these pathogens that currently result in significant morbidity and mortality in HSCT recipients.
Hematopoietic Stem Cell Transplant (HSCT) is a therapeutic strategy used to treat blood cell malignancies, as well as genetic disorders that involve hematopoietic development and autoimmune diseases. Recipients are “conditioned” with chemotherapy and/or radiation prior to transplant in order to eliminate the preexisting disease, provide a niche for the donor stem cells and provide the immunosuppression necessary to prevent transplant rejection. Following conditioning for HSCT, patients are severely immunocompromised and can be further immunosuppressed by prophylaxis for and/or treatment of Graft versus Host Disease (GvHD). During this immune suppressed period, an HSCT recipient is at risk of life-threatening disease from reactivating herpesviruses, adenoviruses and polyomaviruses. Although diagnostic and therapeutic approaches vary by center, patients are typically monitored closely with serial diagnostic tests for some of these viruses with the goal of identifying the presence of a virus at early onset and allowing time for aggressive intervention. Antiviral agents can be administered as prophylaxis, pre-emptive therapy prior to the onset of clinical symptoms or as directed therapy for active disease. Unfortunately, many antiviral agents retain undesirable side effects such as the risk of myelosuppression and nephrotoxicity. Furthermore, in many instances patients are unresponsive to these therapies and the infections progress to significant morbidity and mortality. Novel antiviral agents with improved side effect profiles and clinical effectiveness are needed. Some candidate agents are already in development. Novel therapeutic approaches to manage reactivating viruses are also under development and appear to have significant promise. Such therapeutic approaches include targeted adoptive immunotherapies to be administered to patients at risk for poor outcomes from particular viruses. Adoptive immunotherapy typically involves harvesting T cells from donors, selecting antiviral T cells and expanding these T cells from the total pool. These expanded antiviral T-cells are then infused into the patient or banked for future use. Ideally, these T cells will provide long-term protection, or serve as a bridge until the patient’s immune system reconstitutes. However, the stimulation of these T cells during the isolation, selection and expansion process can promote their terminal differentiation, reducing their survival and proliferative capacity, and possibly limiting their effectiveness. Additional strategies to better select and expand antiviral T cells without inducing terminal differentiation, or to directly isolate antiviral T cells without expansion are being pursued and might markedly extend the duration of T cell function after infusion into the patients.
The present Research Topic is meant to highlight both basic and clinical research in this area, to provide an overview of the current epidemiology, to discuss antiviral pharmaceutical options and their challenges, and to review the current state of novel adoptive immunotherapies for the treatment of these pathogens that currently result in significant morbidity and mortality in HSCT recipients.