CAR T Cells: Engineering Immune Cells to Treat Cancers

For many years, surgery, chemotherapy and radiation therapy have been the foundations of cancer treatment. Over the last two decades, targeted therapies have cemented themselves as standard treatments for many cancers. Over the past several years, immunotherapy therapies that enlist and strengthen the power of a patient's immune system to attack tumours have emerged.

A rapidly progressing immunotherapy approach is called Adoptive Cell Transfer (ACT), where the patients' own immune cells are collected and used to treat their cancer. The one that has advanced the furthest in clinical development is called CAR T‑cell therapy.

T cells are harvested from a patient and by using a disarmed virus, the T cells are genetically engineered to produce receptors on their surface called Chimeric Antigen Receptors, or CARs. These special receptors allow T cells to recognise and attach to a specific protein or antigen on the tumour cells. Once the T cells have been engineered to express the antigen-specific CAR, they are "expanded" in the laboratory and infused back into the patient. The engineered cells further multiply in the patient's body and will, with guidance from their engineered receptor, recognise and kill cancer cells that harbour the antigen on their surfaces.

In 2017, two CAR T‑cell therapies were approved by the Food and Drug Administration (FDA), one for the treatment of children with Acute Lymphoblastic Leukaemia (ALL) and the other for adults with advanced lymphomas. A growing number of CAR T‑cell therapies are now being developed and tested in clinical studies/trials.

A recent paper by Petrov et al, 2018 in the Journal Leukemia has described a new CAR‑T therapy, compound CAR (cCAR), which targets both the CD123 and CD33 markers. Remission rates as high as 90% are seen with the single CAR CD19CAR therapy in B‑ALL patients, but almost all relapse prompting Petrov et al to develop a dual targeting approach, the CD123‑CD33cCAR for the treatment of AML.

This study used in vivo imaging and flow cytometry to analyse the effects of cCAR on cytotoxicity in AML cell lines and patient samples, its ability to eliminate one or both antigens in vitro and in vivo and the efficacy of the cCAR safety-switch process in vivo.

cCAR independently ablated CD123 and CD33‑expressing Jurkat cells in co-cultures and in mouse models.

Mice treated with cCAR demonstrated a lower disease burden during the study and an increased survival compared to control in MOLM13 and U937 xenograft models.

Haematological tissue from these models were relatively tumour-free with an expanded population of cCAR T‑cells present at the end of treatment.

CD123-CD33cCAR was rapidly depleted using an alemtuzumab safety switch resulting in 90% loss of cCAR within 6 hours, reducing the chances of off-target effects.

Currently anthracyclines, cytarabines and allogenic hematopoietic stem cell transplantation (HSCT) are standard of care for AML. There is a 50-70% relapse rate and only a five year survival of 27% meaning new therapies are urgently required. This paper describes the construction of a dual CD123/CD33 targeted cCAR that may have advanced efficacy over single target CAR‑T therapies and it has been given orphan drug designation for the treatment of AML by the FDA.

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Epistem's Oncology and Imaging Models

Epistem has extensive experience handling CAR T-cells and offers several pre-clinical human cancer models to assess the efficacy of CAR T-cell therapies. Epistem has in vivo optical imaging capabilities and can offer orthotopic imaging models of cancer to study the efficacy of CAR T-cell therapy in the same animal over time. We also have an in-house eight colour MACS quant which gives the opportunity to evaluate treatment effects and T cell function ex vivo.

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