Abstract
Simple SummaryCAR T cells are a type of immunotherapy whereby a patient’s own cells are genetically modified to recognise and kill the patient’s own cancer cells. Currently, each patient has CAR T cells made from their own blood cells. This type of therapy has had a big impact on the treatment of blood cancers, however making an individual treatment from each patient is expensive and labour intensive. This review discusses the potential of making CAR T cells more widely available by producing them in large numbers from healthy donors.CAR T cells have revolutionised the treatment of haematological malignancies. Despite this, several obstacles still prohibit their widespread use and efficacy. One of these barriers is the use of autologous T cells as the carrier of the CAR. The individual production of CAR T cells results in large variation in the product, greater wait times for treatment and higher costs. To overcome this several novel approaches have emerged that utilise allogeneic cells, so called “off the shelf” CAR T cells. In this Review, we describe the different approaches that have been used to produce allogeneic CAR T to date, as well as their current pre-clinical and clinical progress.
Highlights
It has long been recognised that the immune system plays a vital role in the establishment and progression of tumours [1,2,3]
chimeric antigen receptor (CAR) T cells have revolutionised the treatment of haematological malignancies, with three CD19 targeting CARs licenced for use [28,29,30]
In the ELIANA study of a CD19 targeting CAR for B-cell Acute Lymphoblastic Leukaemia (B-Acute Lymphoblastic Leukaemia (ALL)), 7.6% of patients did not receive the CAR T cells due to ‘product related issues’, whereby it was not possible to manufacture a sufficient number of CAR T cells for infusion [35]
Summary
It has long been recognised that the immune system plays a vital role in the establishment and progression of tumours [1,2,3]. The earliest studies from Steve Rosenberg investigated the systemic administration of lymphokine-activated killer cells (patient lymphocytes cultured ex-vivo in the presence of IL-2 re-infused) and IL-2 in patients with metastatic cancer This resulted in some partial responses and one patient with complete tumour regression [18]. The extracellular domain of the CAR contains antigen recognition domain that is able to bind to the target expressed on the cancer cells This binding domain is typically a single chain variable fragment (ScFv) against the target but can be derived from a ligand or peptide (such as the A20FMDV2 peptide that binds to αvβ6) that binds to the antigen [23,24]. Subsequent generations of CARs contain one or more co-stimulatory domains (usually 4–1BB or CD28) which provided pro-survival signals and improved persistence of the CAR T cells [27]
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