NAME Development of donor-derived Chimeric Antigen Receptor (CAR)T cell therapies for cancer
CANCER TYPE Blood Cancer
INSTITUTION Children's Cancer Institute
STATE New South Wales
GRANT TYPE $200,000
PROJECT TYPE Research
Adoptive cell therapy using immune cells genetically modified with chimeric antigen receptors (CAR) targeting tumour cells (Attachment, Figure 1), is a potentially curative treatment for leukaemia and lymphomas. Patient’s own T cells can successfully be redirected in the laboratory using synthetic molecules called Chimeric Antigen Receptors (CARs) to initiate an effective anti-tumour response, even in advanced stages of the disease (1-11). This strategy led to complete responses in 80% of patients with durable remissions lasting for 1-5 years. For comparison, the complete remission for the most recently FDA-approved drugs for acute B-cell lymphoblastic leukaemia (B-ALL) is less than 25% with median duration of response of 4-9 weeks. CART cells have recently been approved as therapy for relapsed or refractory B-ALL and diffuse large B cell lymphoma.
Currently, a patient’s own T cells are used for CART-cell therapy. The need to produce an individual product for each patient creates issues of prohibitive cost, feasibility in heavily pre-treated patients and delays in administering therapy. CART cells generated using healthy donor T-cells could provide an alternative for the administration of a patient’s own T-cells. Adoptively transferred donor T-cells, however, may recognise recipient tissue as foreign, leading to an immune reaction known as graft versus host disease (GVHD) (12). Eliminating the native T Cell Receptors (TCR) from donor T cells could overcome this limitation, with inexpensive “off-the-shelf” CART-cells readily available for administration at the time of patient need.
We are developing a new method for production of TCR-depleted CART-cells by co-expression of TCR-inhibiting short hairpin (sh)RNAs (Figure 2). The goal of the project is to demonstrate the feasibility, potency and safety of TCR-depleted CART-cells. The intended result is getting the evidence that TCR-depleted CART-cells can produce strong anti-tumour activity and do not induce GVHD.