Overcoming on-target, off-tumour toxicity of CAR T cell therapy for solid tumours

Abstract

Therapies with genetically modified T cells that express chimeric antigen receptors (CARs) specific for CD19 or B cell maturation antigen (BCMA) are approved to treat certain B cell malignancies. However, translating these successes into treatments for patients with solid tumours presents various challenges, including the risk of clinically serious on-target, off-tumour toxicity (OTOT) owing to CAR T cellmediated cytotoxicity against non-malignant tissues expressing the target antigen. Indeed, severe OTOT has been observed in various CAR Review articlewe examine the implications of OTOT on the development of CAR T cell therapies targeting solid tumours, summarize OTOT evidence in preclinical and clinical studies, and discuss advances in CAR T cell engineering that might help to overcome OTOT in the clinic. Risks and mechanisms of OTOTOTOT stems from CAR T cell-mediated recognition and lysis of nonmalignant tissues expressing the target antigen, potentially causing severe adverse events 23,26 . Upon recognition of a target antigen, CAR T cell activation leads to the formation of an immune synapse between the CAR and the target cell 27 , triggering effector functions (Fig. 2). The release of perforin and granzymes 28 is assumed to be a principal mechanism of CAR T cell-mediated cytotoxicity. However, other mechanisms, such as upregulation of T cell-surface molecules to induce target apoptosis (such as FAS ligand) 29 or secretion of cytokines, including IFNγ and/or TNF, may also contribute to tissue destruction [29][30][31] (Fig. 2).To generate CAR T cells that are both safe and effective in patients with solid tumours, target antigen selection is crucial. Optimal antigen candidates, referred to as neoantigens, should be exclusively expressed on malignant cells and not on non-malignant cells. Such antigens could arise from tumour-specific non-synonymous mutations, insertions or deletions that alter the amino acid sequence of cell-surface proteins, aberrant expression of oncofetal antigens, or tumour-specific posttranslational modifications [32][33][34][35][36][37] . However, cell-surface neoantigens are rare, particularly in tumours with a low mutational burden 38 . EGFRvIII, found in 24-67% of glioblastomas, is one of the few identified examples 39,40 . Consequently, the majority of CAR T cell therapy targets for solid tumours are tumour-associated antigens (TAAs) that are also expressed on non-malignant tissues (Fig. 3).

Drug-Mediated Control of Receptor Valency Enhances Immune Cell Potency

“…Additionally, dosing schedules could be tested to limit potential side-effects and increase safety by reducing or stopping drug treatment. Moreover, tumor localized drugs (e.g., conjugated to an antibody that binds to tumor antigens) could be explored to ensure T cells are only activated at the site of cancer, reducing the off-target effects often seen in solid tumor CAR T cells ( 58, 59 ). As our understanding deepens on how to induce VCR T cells in vivo , more complex dosing schedules could be leveraged such as oscillatory regiments that could help overcome T cell dysfunction ( 50, 60, 61 ).…”

CAR T Cell Therapy: A Versatile Living Drug

“…However, they are, more often than not, also coexpressed in low levels in non-malignant tissues, enabling dangerous cross-reactivity and on-target off-tumor toxicity [ 75 , 79 , 80 ]. This also means that CAR T cell therapies that end up proceeding to clinical trials, although deemed safe enough in preclinical testing, often spur cases of severe and sometimes deadly toxicity, leading to product failure [ 76 , 81 ]. Even when dealing with TAAs of very low expression in healthy cells, solid tumors are usually very heterogeneous, so wide antigen expression variability and antigen-loss events are quite common [ 80 ].…”

Deciphering and advancing CAR T-cell therapy with single-cell sequencing technologies

“…On-target, off-tumor effects refer to CAR T cell-mediated recognition and lysis of non-malignant tissues expressing the target antigens because the antigens recognized by CAR T-cells are mostly tumor-associated antigens (TAAs) expressed in both normal and malignant cells [ 115 ]. The development of single-cell sequencing technologies has improved the resolution of target antigen analysis, providing valuable guidance on on-target, off-tumor effects evaluation (Fig.…”