This allows tumours to overcome the host’s inherent immune defences, and more importantly, cell-based immunotherapies that use non-engineered immune cells. By exploiting these immune cells, we have the exciting potential to create “living drugs”, sentinel-like cell-based therapies that patrol a patient’s body, seeking out malignant cells and eradicating them whilst leaving healthy tissues unharmed.ĭespite immune cells offering a certain degree of natural protection against cancer, tumours have evolved counter defence mechanisms that enable them to evade and/or suppress anti-tumour effector responses. In addition, they are capable of navigating the labyrinth of blood vessels that run throughout the human body, extravasating towards local inflammatory cues associated with tumours and squeezing through tight interstitial spaces in order to penetrate deep inside cancerous tissues. A particularly remarkable attribute of our immune system is that certain immune cells can detect malignantly transformed cells and use sophisticated cytotoxic machinery to deliver a death signal that is both potent and targeted. Harnessing the inherent anti-tumour properties of our immune system is a promising therapeutic strategy for cancer, not only as a last resort for patients that are refractory to standard treatments, but also as a stand-alone therapy in and of itself. We discuss here the novel concept of engineered immune cells as vessels for payload delivery into the tumour microenvironment, how these cells are better adapted to overcome the challenges faced in a solid tumour, and importantly, the novel gene engineering approaches required to deliver these more complex polycistronic gene constructs. Recent advances have involved gene constructs for membrane-bound and/or secretable proteins that provide added effector cell function over and above the benefits of classical CAR-mediated cytotoxicity, rendering immune cells not only as direct cytotoxic effectors against tumours, but also as vessels for payload delivery capable of both modulating the tumour microenvironment and orchestrating innate and adaptive anti-tumour immunity. Gene engineering approaches for generating immune cells capable of overcoming these hurdles remain an unmet therapeutic need and ongoing area of research. Solid tumours pose many additional challenges for CAR T cells that have severely blunted their potency, including homing to the sites of disease, survival and persistence within the adverse conditions of the tumour microenvironment, and above all, the highly immunosuppressive nature of the tumour milieu. Although chimeric antigen receptor (CAR) T cells have shown impressive clinical success against haematological malignancies such as B cell lymphoma and acute lymphoblastic leukaemia, their efficacy against non-haematological solid malignancies has been largely disappointing.

Bitburner infiltration exploit