Payload Delivery: Engineering Immune Cells to Disrupt the Tumour Microenvironment

Abstract

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.

Newer generations of multi-target CAR and STAb-T immunotherapeutics: NEXT CART Consortium as a cooperative effort to overcome current limitations

“…The TRUCK concept is also suitable for other cells susceptible to carrying a CAR, such as NK cells and macrophages ( 62 ). New approaches include the use of payloads of a variety of immunomodulatory genes besides cytokines ( 63 ). For example, IL12 has been the subject of several studies addressing this issue, using distinct strategies to express IL12 in TILs or tumors ( 64 , 65 ).…”

Empowering the Potential of CAR-T Cell Immunotherapies by Epigenetic Reprogramming

“…Epigenetic modulation of TME-resistant CAR-Ts may hold the key to unleashing their true potential, even within hostile TMEs. To overcome the hurdle of localization to the tumor and facilitate T-cell migration towards the malignant milieu, the so-called armored CAR-Ts, which, in addition to targeting tumor antigens, constitutively secrete T-cell stimulating cytokines (such as IL-12,-15,-18, -21), have been generated to enhance the CAR-T cells’ homing to and activity against solid tumors (as reviewed in [ 184 , 185 , 186 ]).…”

Preclinical platforms to study therapeutic efficacy of human γδT‐cells for oncology indications

“…tumour‐associated myeloid cells), cancer‐associated fibroblasts and stroma. Depending on the type of immunotherapy modelled, further data can be gleaned from including cell types that are activated upon immunotherapy administration, such as when dealing with secreted therapeutic modules like cytokines or opsonins 7 . While ideally autologous to the tumour, bystander cells allogeneic to the tumour can be used for modelling non‐alloreactive therapeutics like γδT‐cells.…”

“…Depending on the type of immunotherapy modelled, further data can be gleaned from including cell types that are activated upon immunotherapy administration, such as when dealing with secreted therapeutic modules like cytokines or opsonins. 7 While ideally autologous to the tumour, bystander cells allogeneic to the tumour can be used for modelling non-alloreactive therapeutics like γδT-cells. Depending on availability and tolerance to various culture conditions, a mixture of primary and immortalized bystanders may be used, such as in colorectal carcinoma organoid modelling by Qin and colleagues.…”