CMV TCR Gene Therapy: A Phase I/II Safety, Toxicity and Feasibility Study of Adoptive Immunotherapy in Allo-HSCT

Patients with cancers of the blood and bone marrow are often given a form of treatment called a stem cell (or bone marrow) transplant. During the transplant procedure the patient will be given potent chemotherapy and/or radiotherapy to kill off residual cancer cells before the new stem cells are re-infused from the bone marrow donor, often a sibling. In order for the new stem cells to persist in the patient, powerful drugs need to be given to suppress the patient?s own immune system. The period of profound immune suppression can last for up to 6 months post transplant. During this time the reactivation of viruses, such as cytomegalovirus (CMV) is very common. CMV reactivation in immunosuppressed patients can lead to progressive infection and even death. In healthy individuals CMV rarely causes any problems as the T cells of the immune system are able to keep the virus in check. Individuals who have previously been infected with CMV (50% UK adults) have small numbers of T cells in their blood which can recognise and kill CMV-infected cells. Recently, researchers in the UK and Europe have shown that these CMV-specific T cells taken from bone marrow donors can be infused into the transplant patient and control CMV infection in the patient. Typically, a single infusion of the donor?s T cells is effective. This approach avoids the need for repeated anti-viral drugs, which have significant side effects and usually require the patient to be re-admitted to hospital for prolonged periods.
However, many patients have transplant donors who have not been previously infected with CMV. These donors will not have any pre-made immune T cells which can recognise CMV. We propose to take the T cells of CMV negative donors and genetically modify them so that they are able to recognise and kill CMV-infected cells. This will be done by growing the donor T cells in the laboratory in the presence of a specially modified virus called a retroviral vector. This procedure will transfer a gene to the T cells, which allows them to recognize protein fragments (peptides) of the CMV virus called CMV pp65. The gene transferred to the T cells enables them to make a new T cell receptor (CMV TCR), which specifically recognises the CMV pp65 peptide. The CMV TCR gene-modified T cells will be infused into the patient if they reactivate CMV as part of this Phase I/II clinical trial.

The proposed Phase I/II proof of concept pilot study will test the feasibility of generating donor-derived CMV-specific T cells via the ex vivo introduction of a CMV-specific T cell receptor using a GMP grade retroviral vector. It will also determine the safety, toxicity and efficacy of CMV TCR-transduced T cells used for the pre-emptive treatment of CMV reactivation following HLA-matched sibling allogeneic haematopoietic stem cell transplantation (Allo-HSCT).
Reactivation of the latent human herpes virus, Cytomegalovirus (CMV) post allogeneic haematopoietic stem cell transplantation (Allo-HSCT) can result in significant morbidity and mortality unless treated promptly. Anti-viral therapy is usually effective, but has serious side effects, such as myelosuppression (Ganciclovir) or nephrotoxicity (Foscarnet). Cellular immunotherapy for CMV has been tested in Phase I/II trials in the UK and Europe. In these trials CMV-specific T cells were isolated from the peripheral blood of CMV seropositive donors and re-infused into recipients following CMV reactivation resulting in sustained anti-viral responses. Transplant recipients with CMV seronegative donors cannot benefit from currently available cellular immunotherapy approaches due to the lack of CMV-specific memory T cells in these donors. At present, there is no reliable strategy to isolate virus specific T cells from uninfected na?ve individuals, as the precursor frequency is low or absent and the in vitro priming of T-cell responses is inefficient. T-cell receptor (TCR) gene transfer offers a strategy to produce antigen-specific T cells independent of precursor frequency and without the need for T-cell priming. We propose that CMV TCR-transduced T cells, generated from CMV-seronegative donors, can generate protective CMV immunity in post-transplant patients.