Immune Cell Therapy

Immune cell therapies aim to utilize and enhance the normal capacity of a patient's immune system to treat a wide range of disorders including cancer, autoimmune diseases and organ rejection. All immune cell therapies are examples of adoptive cell transfer (ACT), where cells are extracted from a patient, modified and/or expanded, then transfused back into the patient.

Research Areas

CAR T-cell Therapy

Chimeric Antigen Receptor (CAR) T-cell therapies involve the genetic modification of a patients T-cells, which play important roles in immune response organisation and killing of pathogenic cells, to express a CAR specific for a tumor antigen. The CAR protein is a fusion of a single chain fragment of a monoclonal antibody, and one or more T-cell receptor intracellular signalling domains. This protein, when expressed via viral transduction, CRISPR-Cas9 or direct transfer of mRNA, enables T-cells to recognise a specific protein on tumor cells. Once expanded ex vivo, T-cells are transfused back into the patient, where they recognize and kill cancer cells with high specificity.

Acute Lymphoblastic Leukemia (ALL) in children and young adults, is an example of where CAR T-cell therapy has shown success. A clinical trial using CD19-targeting CAR T-cells resulted in a complete response, with all signs of cancer abolished in 27 of 30 patients in the trial. Following larger and longer clinical trials, in which patients showed long-lasting remission, this therapy has now been approved by the FDA.

NK Cell Therapy

Natural Killer (NK) cells are immune cells with an inherent ability to kill cells without previous sensitization. Their activation is tightly controlled to prevent damage to 'self' tissues, through the integration of pro- and anti-inflammatory signalling pathways. Their role on the front line of immune response and rapid response make NK cells attractive for cell-based therapies. As with other cell therapies, NK cells can be extracted from a patient and the population expanded ex vivo using cytokines and feeder cells. NK cells for therapy can also be derived from stem cells, including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs).

Similar to CAR T-cell therapies, NK cells can be genetically modified prior to transfusion into a patient. The aim of this is to enable NK cells to detect a tumor specific antigen, increasing target specificity. NK cells are relatively resistant to retroviral transfer, although the efficiency of transfer can be enhanced with small molecules targeting the TBK1/IKKε complex, for example. Alternatively, electroporation can be used for gene transfer.

In cancer, both autologous and allogeneic NK cells are under investigation, with the most promising results shown in blood cancers such as leukemia and lymphoma. NK cell therapy is also being investigated for melanomas and other solid tumors.

Treg Cell Therapy

Regulatory T-cells (Treg) are peripheral blood lymphocytes that are involved in the control of 'self' tolerance, tissue inflammation and long-term immune system homeostasis. In autoimmune disorders, the number of Tregs is reduced, and their function in impaired, leading to misrecognition and immune response to 'self' tissues. Exogenous stabilizing factors, such as Rapamycin, can enhance Treg function in autoimmune diseases and Graft vs Host Disease (GvHD). The enhancement of Treg function is also the goal of Treg-based ACT therapies.

The first preclinical investigations into Treg cell therapies were performed with polyclonal Tregs cells that are not specific for a single antigen. These cells were isolated based on expression of multiple cell markers. Purified FOXP3+ Tregs have been investigated for the treatment of GvHD and type I diabetes. Cells were purified from blood, grown ex vivo in the presence of antibodies against CD3 and CD28 with high concentrations of IL-2 to expand a highly enriched population of Tregs.

Monoclonal Tregs, i.e. those that are specific for a particular antigen, are more likely to be effective in autoimmune disorders against a single cell type, for example Multiple Sclerosis (MS). They have also shown efficacy in the treatment of organ rejection. Tregs isolated from an organ transplant recipient are stimulated with antigen-presenting cells from the donor organ to expand a population of donor tissue specific Tregs. These cells have been shown to be more effective at suppressing organ rejection than polyclonal Tregs.