Abstract
Simple SummaryCell-based therapies composed of genetically engineered immune cells have huge potential for treating cancer. T cells modified to express tumour-targeting receptors have been proven to be highly effective against blood cancers but not solid malignancies. Using innovative genetic modifications, we have the potential to enhance solid tumour targeting by cell-based therapies and fulfil this unmet clinical need. Different genetic engineering approaches have been proposed, each designed to overcome specific hurdles associated with solid tumours. In this review, we discuss the novel ways of engineering immune cells to enhance efficacy against solid tumours, and how this has led to a new era of cell-based therapies, capable of delivering immunotherapeutic payloads that disrupt the immunosuppressive tumour microenvironment and generate concerted anti-tumour immune responses.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. 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. Gene engineering approaches for generating immune cells capable of overcoming these hurdles remain an unmet therapeutic need and ongoing area of research. 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. 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.
Highlights
Harnessing the inherent anti-tumour properties of our immune system is a promising therapeutic strategy for cancer, as a last resort for patients that are refractory to standard treatments, and as a stand-alone therapy in and of itself
The abundant populations of TAMs, Tregs, and MDSCs often found in solid tumours are potent at suppressing immune cell function via multiple mechanisms of immunosuppression, including the following: (1) secretion of TGF-β, which inhibits effector cell proliferation, differentiation, and cytotoxicity [54]; (2) secretion of IL-10, an anti-inflammatory cytokine that downregulates major histocompatibility complex (MHC) II, blocks Th1 cytokine production, and inhibits NFκB signalling [55,56]; (3) expression of checkpoint ligands, which switch off activated effector cells [57]; (4) secretion of tissue remodelling matrix metalloproteinases (MMPs) that facilitate tumour metastasis and invasion [58]; and (5) secretion of chemokines such as CCL17 and CCL22, which recruit more immunosuppressive cells leading to the maintenance of the TME [59], as well as CXCL8, which further supports tumour metastasis and invasion [60]
T cells expressing chimeric antigen receptor (CAR) only were unable to kill all of the tumour, which resulted in an outgrowth of EGFRvIII-negative cells, whereas bispecific T cell engagers (BiTEs) co-expression resulted in complete tumour control
Summary
Harnessing the inherent anti-tumour properties of our immune system is a promising therapeutic strategy for cancer, as a last resort for patients that are refractory to standard treatments, and as a stand-alone therapy in and of itself. A 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 [1,2] 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 [3]. Engineering CAR T cells to stably express selected chemokine receptors has the potential to greatly enhance their tumour homing in vivo and subsequently improve their overall efficacy against solid malignancies. Data demonstrate the feasibility of a dual expression of genes for cytotoxicity and homing, paving the way for a new generation of CAR T cell therapies that are tailored for improved tumour infiltration, and better efficacy against solid cancers (Figure 1)
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