Adoptive T cell immunotherapy therapy for adenovirus infection in transplant patients
Lead Research Organisation:
University of Birmingham
Department Name: Medical Sciences - Medicine
Abstract
Bone marrow transplantation is used to treat leukaemia and involves the transfer of blood or bone marrow from a donor to the patient. Unfortunately patients have to be immunosuppressed to ensure that the graft is not rejected and this allows viruses that normally cause only mild symptoms to become a major threat to health. There are antiviral drugs available to treat some of these viruses (eg Epstein Barr Virus or cytomegalovirus) but for adenovirus there is no effective and approved treatment. Adenovirus normally causes mild respiratory infections in young children and most people have had at least one adenovirus infection by adolescence. As such we normally have a long lasting immunity to further infections with the same virus strain.
We know that in the transplant setting, if the immune response to the virus can be restored, the patient has a good chance of controlling the infection. One way to do this is to use white (T) cells from the transplant donor, selecting just those cells that can recognise the virus, thereby halting the infectious cycle.
This proposal aims to select adenovirus-specific T cells from the donor by binding them to a molecule that mimics the part of the virus that they would normally recognise. This molecule is itself tagged to a microscopic magnetic particle so that the required cells can be separated from other cells and transplanted into the bone marrow recipient. This work has proven safe and effective in situations in which the donor has a large immune response to the virus but now we wish to develop it in a more challenging situation in which the level of the immune response is much smaller. The research will be conducted as an early phase clinical trial which aims to establish the feasibility of the method but will also have the secondary objective of minimising the adenovirus infection.
We know that in the transplant setting, if the immune response to the virus can be restored, the patient has a good chance of controlling the infection. One way to do this is to use white (T) cells from the transplant donor, selecting just those cells that can recognise the virus, thereby halting the infectious cycle.
This proposal aims to select adenovirus-specific T cells from the donor by binding them to a molecule that mimics the part of the virus that they would normally recognise. This molecule is itself tagged to a microscopic magnetic particle so that the required cells can be separated from other cells and transplanted into the bone marrow recipient. This work has proven safe and effective in situations in which the donor has a large immune response to the virus but now we wish to develop it in a more challenging situation in which the level of the immune response is much smaller. The research will be conducted as an early phase clinical trial which aims to establish the feasibility of the method but will also have the secondary objective of minimising the adenovirus infection.
Technical Summary
Allogeneic stem cell transplantation (SCT) is used widely in the treatment of haematological malignancies and inherited diseases of the haemopoietic system. Unfortunately recipients are heavily immunosuppressed following transplantation and infection remains the major cause of morbidity and mortality. Although anti-viral drugs play an important role in the management of herpesvirus infections their role in other viral infections is less certain. In particular adenovirus is emerging as a significant pathogen in patients following SCT and is particularly frequent in patients who have received highly immunosuppressive conditioning regimens such as used in non-myeloablative, unrelated donor or haploidentical transplantation. There is no proven drug therapy for adenoviraemia in this setting and mortality rates remain very high. Alternative approaches, such as cellular therapy, are therefore being explored.
The adoptive transfer of virus-specific T cells from the SCT donor to the patient is an attractive prospect for the management of viral infection in this setting. However, despite encouraging reports of large scale in vitro expansion and infusion of donor-derived CMV or EBV-specific T cell clones, this procedure has not been adopted into clinical practice due to technical and financial constraints. We have recently completed the first trial of a novel form of cellular therapy in which antigen-specific T cells are selected from the donor and infused directly into the patient. Antigen-specific CD8+ T cells are identified by staining with HLA-peptide tetramers and are then purified by magnetic selection using technology utilized in routine clinical processing of the stem cell product. This approach can deliver antigen-specific cellular therapy within 12 hours and, in addition to major logistical benefits, offers many potential biological advantages for cellular therapy including improved survival, homing and effector function of transferred cells.
There is now a requirement to extend this experience to determine if direct T cell infusion could be applicable against antigens to which the donor carries a low level of endogenous immunity and to compare the process, either alone or in combination, with the cytokine secretion assay which allows selection of antigen-specific CD4+ T cells.
In this proposal we bring together our extensive expertise in cellular therapy, haematology and adenoviral biology to focus these questions on the treatment of adenoviral infection in the SCT setting. This translational programme will be of significant value in optimising management of adenoviral infection but will also contribute to development of an approach to adoptive T cell therapy that could have wide clinical application.
The adoptive transfer of virus-specific T cells from the SCT donor to the patient is an attractive prospect for the management of viral infection in this setting. However, despite encouraging reports of large scale in vitro expansion and infusion of donor-derived CMV or EBV-specific T cell clones, this procedure has not been adopted into clinical practice due to technical and financial constraints. We have recently completed the first trial of a novel form of cellular therapy in which antigen-specific T cells are selected from the donor and infused directly into the patient. Antigen-specific CD8+ T cells are identified by staining with HLA-peptide tetramers and are then purified by magnetic selection using technology utilized in routine clinical processing of the stem cell product. This approach can deliver antigen-specific cellular therapy within 12 hours and, in addition to major logistical benefits, offers many potential biological advantages for cellular therapy including improved survival, homing and effector function of transferred cells.
There is now a requirement to extend this experience to determine if direct T cell infusion could be applicable against antigens to which the donor carries a low level of endogenous immunity and to compare the process, either alone or in combination, with the cytokine secretion assay which allows selection of antigen-specific CD4+ T cells.
In this proposal we bring together our extensive expertise in cellular therapy, haematology and adenoviral biology to focus these questions on the treatment of adenoviral infection in the SCT setting. This translational programme will be of significant value in optimising management of adenoviral infection but will also contribute to development of an approach to adoptive T cell therapy that could have wide clinical application.