Engineering Solutions for Mitigation of Chimeric Antigen Receptor T-Cell Dysfunction

Abstract

The clinical successes of chimeric antigen receptor (CAR)-T-cell therapy targeting cell surface antigens in B cell leukaemias and lymphomas has demonstrated the proof of concept that appropriately engineered T-cells have the capacity to destroy advanced cancer with long term remissions ensuing. Nevertheless, it has been significantly more problematic to effect long term clinical benefit in a solid tumour context. A major contributing factor to the clinical failure of CAR-T-cells in solid tumours has been named, almost interchangeably, as T-cell “dysfunction” or “exhaustion”. While unhelpful ambiguity surrounds the term “dysfunction”, “exhaustion” is canonically regarded as a pejorative term for T-cells. Recent understanding of T-cell developmental biology now identifies exhausted cells as vital for effective immune responses in the context of ongoing antigenic challenge. The purpose of this review is to explore the critical stages in the CAR-T-cell life-cycle and their various contributions to T-cell exhaustion. Through an appreciation of the predominant mechanisms of CAR-T-cell exhaustion and resultant dysfunction, we describe a range of engineering approaches to improve CAR-T-cell function.

Metformin sensitizes leukemic cells to cytotoxic lymphocytes by increasing expression of intercellular adhesion molecule-1 (ICAM-1)

“…This could be more relevant on hematological cancers in which effector immune cells are in close contact to malignant cells because they niche in the same tissues. Several clinical approaches such as CAR T 38 or CAR NK 39 cells have shown a relevant success to treat blood-borne cancers. However, roughly 50% of patients undergo relapse and new clinical protocols are required to improve the clinical activity of these genetically-modified cytotoxic lymphocytes.…”

Metformin Sensitizes Leukemic Cells to Cytotoxic Lymphocytes by Increasing Expression of Intercellular Adhesion Molecule-1 (ICAM-1)

“…This could be more relevant on hematological cancers in which effector immune cells are in close contact to malignant cells because they niche in the same tissues. Several clinical approaches such as CAR T [36] or CAR NK [37] cells have shown a relevant success to treat blood-borne cancers. However, roughly 50% of patients undergo relapse and new clinical protocols are required to improve the clinical activity of these genetically-modified cytotoxic lymphocytes.…”

A Simple and Robust Single-Step Method for CAR-Vδ1 γδT Cell Expansion and Transduction for Cancer Immunotherapy

“…An important area of ongoing research remains the identification of ‘optimal’ donors for allogeneic cell therapy products. It remains unclear whether high product yield during manufacture is a sure indicator of maximum therapeutic performance, or as recent data from the CAR-αβT field suggests ( 5 ) – that cell ‘quality’, including memory and exhaustion status, is a more predictive metric than quantity. The elucidation of the factors that govern γδT cell product ‘quality’ will be crucial to sustained clinical success.…”