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Find out about Professor Emma Morris' research on experimental and clinical cell and gene therapy.
We are interested in developing new immunotherapeutic approaches to treating cancer. Much of our research focus is on understanding immune responses to cancer and infection. We use genetic engineering technologies to improve the function and specificity of T cells, with the aim of generating modified T cells, which have enhanced ability to recognise cancer cells in vivo and deliver a more effective anti-tumour response.
Genetic modification of immune cells may allow us to improve functional avidity, homing and persistence of T cells.
Retroviruses and lentiviruses can be used to deliver genes of interest (TCR alpha and beta chain genes shown here).
Virally infected or malignant cells express altered or non-self peptide epitopes on their cell surface in the groove of an MHC molecule. In health, immune tolerance mechanisms exist to prevent T cells recognising self antigens (as this leads to autoimmunity).
We have demonstrated that TCR gene-modified T cells can function in vitro and in vivo in an antigen-specific manner, conferring in vivo tumour protection in mouse models of leukaemia and lymphoma.
CD4 T cells are likely to have multiple roles in the immune response to tumours. One of the most important toles may be the generation and maintenance of CD8 memory cells. Classically, CD4 T cells rarely recognise tumour cells directly as most tumours do not express MHC class II.
Equipping CD4 T cells with class I restricted TCR (which are normally expressed by CD8 T cells) has the advantage of generating CD4 T cells that may be able to target tumour cells directly.
In vitro functional analysis of TCR-td bulk T cells, CD8 T cells, CD4 T cells and CD4 8 T cells.
One way to improve the function is to transduce additional DC3 molecules with the TCR. CD3 forms a multi-chain complex with the TCR and is essential for cell surface expression and signal transuction following TCR ligation. When a TCR is introduced by retroviral transuctio it must compete with the endogenous TCR for binding to CD3. The functional avidity of a T cell depends on the level of TCR expression.
CD4 T cells modified to express additional CD3 together with the TCR secrete higher concentrations of IFN gamma and IL-2 after stimulation with specific antigen. They are also able to recognise lower concentration of target antigen.
We now have phase I (first in man) clinical trials currently recruiting for adults with acute myeloid leukaemia or undergoing haematopoietic stem cell transplantation. In 2015 we will also have a trial open for paitents with myeloysplasia. We are developing approaches for paitents with EBV malignancies, sich as nasopharyngeal carcinoma and lymphoma.
Patient's immune cells are collected using an apheresisi machine, which separates out specific cell types. The cells are genetically modified in a GMP sterile laboratory to produce clinical grade T cells expressing the new TCR.
The genetically engineered T cells are produced from patient's own blood cells and re-infused after a short course of lymphodepleting chemotherapy.