Cellular immunotherapy – engineering “custom built” cells to treat cancer

This project is suited for a Master’s or PhD work and is flexible for clinical students.

BACKGROUND

Current standard approaches for the treatment of human cancers typically employ broad acting radiotherapeutic and chemotherapeutic approaches. There has been growing interest in approaches using immunotherapy with adoptive cell transfer (ACT): using patient’s immune cells to treat their cancer. A specific type of ACT uses chimeric antigen receptors (CARs). These are genetically engineered molecules, which are custom built to specifically target protein antigens expressed on malignant cells. There are three FDA-approved CAR T cell-based therapies targeting CD19 on certain B-cell malignancies. CAR19 treatment, of children with relapsed or refractory acute lymphoblastic leukaemia (ALL), and of adults with advanced lymphomas, has demonstrated remarkable success and complete remission in some patients. Although approved therapies are limited to blood cancers, a growing number of CAR T-cell therapies are being developed and tested in clinical studies in multiple solid tumours. There are promising clinical data targeting tumour-associated antigens in melanoma, lung, liver, breast, and brain cancers.

There are major differences between CAR therapies, mostly at the tumour-antigen recognition site, but CARs share similar components known as signalling domains that can affect the cells’ overall function, such as their ability to produce more cells after infusion into the patient (expansion), and to survive longer in circulation (persistence). The ability to manipulate these domains to custom build CAR T cells to specifically target certain tumours, and avoid toxicity, is critical for the success of CAR T cell therapy.

AIM

The CAR T cell program at the Tumour Immunology Laboratory aims to design and test novel CAR T cell therapies for virus-associated cancers. We have designed a CAR T cell, which targets a glioblastoma (GBM)-specific antigen A3 that is being tested for the treatment of GBM, an aggressive form of brain cancer. In our clinical trial of ACT to treat GBM (1) we identified a distinct T cell expression signature associated with potency and favourable long-term survival in GBM patients. This project will use this knowledge and expand the potential of the A3-specific CAR T cell product. We will customise the signalling domains to engineer a CAR with a similar expression signature to that of T cells with known GBM-killing potential. We will ultimately build a CAR better suited for the treatment of GBM.

METHODS

The student will learn in vitro molecular and cell biology techniques involving gene cloning, non-viral transfections, lentiviral transductions, cell phenotyping using flow cytometry and NanoString technology. For a PhD student the work will also involve in vivo study in murine xenograft models of GBM to test the efficacy of the custom-built CAR T cells.