Optimizing Chimeric Artificial T Cell Receptor Therapy for Solid Tumour Targeting by Manipulating the Tumour Microenvironment: A Literature Review

Abstract

Introduction: Chimeric antigen receptor (CAR)-T cell therapy represents a breakthrough in cancer treatment by harnessing the power of genetically engineered T cells to target and eliminate tumour cells. This approach involves modifying a patient’s T cells to express CARs that recognize and bind to specific cancer antigens, bypassing conventional antigen presentation mechanisms. While CAR-T therapy has achieved notable success in treating ‘blood,’ or ‘liquid’ cancers, its application to solid tumours remains problematic due to the immunosuppressive tumour microenvironment (TME), which impairs T cell function and promotes tumour escape.

Methods: A comprehensive review was conducted using PubMed and Google Scholar, focusing on publications from March 2002 to March 2024. The search criteria included terms related to CAR-T therapy, solid tumours and TME modulation. Studies were selected based on their relevance to CAR-T therapy challenges, advancements in TME modulation and clinical applications. Research focusing exclusively on liquid tumours was excluded to ensure the review’s focus on solid tumour contexts.

Results: Analysis of lymphocyte densities revealed that hot tumours, characterized by high densities of CD3+ and CD8+ lymphocytes at both the tumour periphery and core, demonstrated the most favorable prognostic outcomes. Checkpoint blockades targeting CTLA-4 and PD-1/PD-L1 have been shown to prevent tumour escape. Additionally, engineering CAR-T cells to express immune checkpoint (IC) inhibitors counteracts the expression of IC ligands by immunosuppressive cells. T cells engineered to express IL-12 or IL-18 cytokines also allowed for better infiltration into the TME.

Discussion: Targeting inhibitory immune checkpoints and suppressive cells, as well as manipulating CAR-T cytokine expression, have all shown to be promising ways in which the TME can be modulated to improve patient outcomes. Future research may include looking into the development of strategies to ensure long-term immunological memory in CAR-T cells, particularly for chronic or recurring solid tumours.

Conclusion: Modulating the TME through various molecular and cellular avenues is crucial in improving the effectiveness of CAR-T cell therapy and therefore, optimizing antitumour immunity.