Promises and challenges of adoptive T-cell therapies for solid tumours

Abstract

Cancer is a leading cause of death worldwide and, despite new targeted therapies and immunotherapies, many patients with advanced-stage- or high-risk cancers still die, owing to metastatic disease. Adoptive T-cell therapy, involving the autologous or allogeneic transplant of tumour-infiltrating lymphocytes or genetically modified T cells expressing novel T-cell receptors or chimeric antigen receptors, has shown promise in the treatment of cancer patients, leading to durable responses and, in some cases, cure. Technological advances in genomics, computational biology, immunology and cell manufacturing have brought the aspiration of individualised therapies for cancer patients closer to reality. This new era of cell-based individualised therapeutics challenges the traditional standards of therapeutic interventions and provides opportunities for a paradigm shift in our approach to cancer therapy. Invited speakers at a 2020 symposium discussed three areas—cancer genomics, cancer immunology and cell-therapy manufacturing—that are essential to the effective translation of T-cell therapies in the treatment of solid malignancies. Key advances have been made in understanding genetic intratumour heterogeneity, and strategies to accurately identify neoantigens, overcome T-cell exhaustion and circumvent tumour immunosuppression after cell-therapy infusion are being developed. Advances are being made in cell-manufacturing approaches that have the potential to establish cell-therapies as credible therapeutic options. T-cell therapies face many challenges but hold great promise for improving clinical outcomes for patients with solid tumours.

Cancer Therapy Targeting CD47/SIRPα

“…By its nature, immune checkpoint inhibition works to overcome negative signals designed to protect “self” cells from immune attack. In addition to the currently approved molecular inhibitors of immune checkpoints, several other novel immunotherapy approaches are being investigated in preclinical and clinical settings, including CAR-T cells and TIL therapy, both of which are T cell products targeting specific proteins on the surface of malignant cells, aiming to augment adaptive immunity [ 7 , 14 ].…”

Development and Validation of a Good Manufacturing Process for IL-4-Driven Expansion of Chimeric Cytokine Receptor-Expressing CAR T-Cells

“…Manufacture of patient-specific cellular immunotherapies presents a series of unique challenges that add to costs and impose barriers to large scale production [ 17 ]. The complex nature of GMP manufacturing processes coupled with the lack of purity and stability of these living drug products constitute issues that are much less problematic with traditional chemical therapeutics [ 18 ], Moreover, marketing authorization requires consistent, robust and reproducible manufacture, supported by rigorous quality control, in addition to the demonstration of safety and efficacy [ 19 , 20 ].…”

T-cell receptor-based therapy: an innovative therapeutic approach for solid tumors

“…It is essential to conquer the obstacles associated with the manufacturing and administration of TCR therapy, including those challenges posed by the immunosuppressive microenvironment in solid tumors, as well as to develop next-generation strategies designed to improve the efficacy and safety of TCR therapies [ 107 ]. Although current TCR therapies have the potential to cure selected patients who meet the criteria to receive these treatments, given that MHC-I is downregulated/deficient in 40–90% of patients, these treatments may not be suitable or efficacious for the majority of patients with solid tumors.…”