Abstract
Patient derived anti-CD19 chimeric antigen receptor-T (CAR-T) cells are a powerful tool in achieving a complete remission in a range of B-cell malignancies, most notably B-acute lymphoblastic leukaemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL). However, there are limitations, including inability to manufacture CAR-T cells from the patient’s own T cells, disease progression and death prior to return of engineered cells. T cell dysfunction is known to occur in cancer patients, and several groups have recently described differences in CAR-T cells generated from chronic lymphocytic leukaemia (CLL) patients compared with those from a healthy donor. This is thought to contribute to the low response rate in this disease group. Healthy donor, gene-edited CAR-T cells which do not require human leucocyte antigen (HLA) matching have the potential to provide an ‘off the shelf’ product, overcoming the manufacturing difficulties of producing CAR-T cells for each individual patient. They may also provide a more functional, potent product for malignancies such as CLL, where T cell dysfunction is common and frequently cannot be fully reversed during the manufacturing process. Here we review the potential benefits and obstacles for healthy donor, allogeneic CAR-T cells.
Highlights
Immune surveillance is the process by which the immune system is believed to detect and destroy cancerous cells before clinical malignancy develops
Torikai et al used zinc finger nucleases (ZFNs) to knock out the human leucocyte antigen (HLA)-A locus [37] but a more decisive approach was adopted by Ren et al to target Beta-2 microglobulin (B2M), which is required for HLA class I
T cell dysfunction can occur in cancer patients even in the absence of therapy as exemplified in chronic lymphocytic leukaemia (CLL)
Summary
Immune surveillance is the process by which the immune system is believed to detect and destroy cancerous cells before clinical malignancy develops. Chimeric antigen receptor-T (CAR-T) cells are one such emerging immunotherapy whereby T cells are genetically modified to recognise a particular antigen that the tumour cells are known to display. Transduced T cells are expanded ex vivo and infused back into patients following lymphodepleting chemotherapy This technology has overcome several strategies that malignant cells adopt to hide from the immune system and avoid immune destruction. USD per patient [8] and Novartis have matched this price when using their product in the setting of lymphoma This cost is purely for the T cell manufacture and excludes other aspects of patient care, which are likely to be high as patients frequently require admission to intensive care
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