The rationale for T cell therapy for cancer is that tumour cells express a different repertoire of proteins, compared to healthy tissue, which may be targeted by the immune response. Heather’s long-term research interest lies in developing immune T cell-based therapies for the treatment of lymphoma, the 5th most common cancer world-wide. This interest stems from her earlier work studying the CD4+ T cell response to the Epstein-Barr virus (EBV), a wide-spread human virus that, in a small minority of people, is associated with a number of different B cell lymphomas.
CD4+ T cells are key orchestrators of the cellular immune system, where they perform several critical helper roles in the processes that lead to development and maintenance of long-term immunity. In addition, it is now clear that many CD4+ T cells can also directly recognise MHC class II positive target cells expressing their target antigen. For infections or malignancies occurring within MHC class II positive cells, such as B cells, this opens up exciting possibilities for therapeutic exploitation of CD4+ T cells; if suitable target antigens can be identified.
The B cell-tropic Epstein-Barr virus (EBV) has provided an instructive model in which to study the human immune response to an oncogenic virus. In recent years, we have characterised the CD4+ T cell response to EBV, from primary to persistent infection and have demonstrated that some EBV-specific CD4+ T cells can directly recognise and kill virus-infected cells. These important observations may well explain the increased clinical efficacy of virus-specific T cell preparations (CTLs) containing higher percentages of CD4+ T cells to treat EBV-associated post-transplant lymphoproliferative disease (PTLD). Ongoing projects are investigating the identity/functional characteristics of the CD4+ T cells present in adoptively transferred therapeutic CTLs and are following their kinetics in vivo. In this way, we hope to identify the virus-specific CD4+ T cells with the greatest potential to target virus-infected cells.
However, many B cell lymphomas are not associated with viral infection, and T cell therapy relies on immune targeting of cellular antigens. We have recently shown that EBV transformation leads to up-regulation of not only viral antigens, but also cellular antigens that can be recognised by the CD4+ immune system. Importantly, these cellular targets are also expressed in at least some other non-virus-associated lymphomas, and may provide novel therapeutic targets for lymphoma. Therefore, in a separate project, we are exploring the identity of these novel target antigens and assessing their potential as therapeutic target antigens for immune therapy of wider non-virus associated lymphoma.