Armored CAR T-Cells: The Next Chapter in T-Cell Cancer Immunotherapy

Abstract

Chimeric antigen receptor (CAR) T-cell therapy engineers T-cells to express a synthetic receptor which redirects effector function to the tumor, to improve efficacy and reduce toxicities associated with conventional treatments, such as radiotherapy and chemotherapy. This approach has proved effective in treating hematological malignancies; however, the same effects have not been observed in solid tumors. The immunosuppressive tumor microenvironment (TME) creates a significant barrier to solid tumor efficacy and reduces the anti-cancer activity of endogenous tumor-resident immune cells, enabling cancer progression. In recent years, researchers have attempted to enhance CAR T-cell function in the TME by engineering the cells to express various proteins alongside the CAR. Examples of this engineering include inducing CAR T-cells to secrete cytokines or express cytokine receptors to modulate the cytokine milieu of the TME. Alternatively, the CAR T-cell may secrete antibody-like proteins to target a range of tumor antigens. Collectively, these methods are termed armored CAR T-cell therapy, and in this review, we will discuss the range of armored CAR T-cell approaches which have been investigated to date.

Development of Stem Cell-Derived Immune Cells for Off-the-Shelf Cancer Immunotherapies

“…The next steps are to incorporate modifications that allow the adoptively transferred cells to persistent autonomously, maintain proliferative potential, outmaneuver the immunosuppressive tumor microenvironment, infiltrate tumor beds, and stimulate endogenous antitumor immunity. Each of these goals has been addressed extensively in preclinical T and NK cell studies [ 163 , 164 , 165 , 166 ], such as through the exogenous expression of IL-15, immune checkpoint inhibitors, chemokine receptors, or immunomodulatory proteins, but are usually targeted individually or in pairs due to the limited genetic pliability of mature immune cells. Stem cell engineering opens the door for increasingly complex designer cell products, and future research will need to reveal if the accumulated changes hinder immune cell antitumor efficacy.…”

Advances in Adoptive Cell Therapy Using Induced Pluripotent Stem Cell-Derived T Cells

“…Furthermore, in solid tumors, the immunosuppressive tumor microenvironments (TME) represent a significant barrier that impairs the function of CAR T cells. Several approaches have been applied to alter the TME from immunosuppressive to pro-inflammatory, including the use of a conditioning regimen prior to T cell infusion, small molecules to interfere with immunosuppressive cells, and blocking antibodies such as anti-PD-1 scFv to inhibit immune checkpoints (142,143) as well as engineering CAR to express cytokine receptor or to secrete cytokines such as IL-12, IL-18, IL-15 to increase T cell persistence and anti-tumor efficacy (141,(144)(145)(146)(147). To date, the CAR T cell therapy for solid tumors in clinical trials has not been effective since T cells cannot penetrate and survive in the TME.…”

Facing CAR T Cell Challenges on the Deadliest Paediatric Brain Tumours

“…These cytokines increase IFN-γ secretion, favouring T cell infiltration and persistence, as well as decrease the level of proangiogenic molecules, reactivating the endogenous immune system [ 132 ]. For CNS tumours, the local and the controlled administration of these immunomodulatory cytokines is paramount to minimise toxicities, since high toxicity has been related to their systemic application [ 133 ].…”

“…Although many preclinical studies have shown the feasibility of using TRUCKS, further research is warranted in paediatric CNS tumours. The selection of the appropriate interleukin(s) for each tumour type to produce a change in the immune state of the TME is essential to boost CAR T cell effector functions without increasing toxicities [ 123 , 133 ].…”