Five areas of research advancing CAR T-cell therapy

This cutting-edge approach involves engineering a patient's T-cells to recognise and attack cancer cells. However, while CAR T-cell therapy has shown remarkable success, it is still in its infancy as a treatment. Malaghan Institute scientists Danielle Blud, Dr Patricia Rubio-Reyes, Dr Rachel Perret and Clinical Director Dr Robert Weinkove recently published a review article in Seminars in Hematology which outlines various strategies being implemented both here at the Malaghan and internationally to improve CAR T-cells to enhance therapeutic efficacy while minimising adverse effects.

Here are five areas being worked on by researchers across the globe to improve and expand the use of CAR T-cell therapy in the fight against cancer.

1. Overcoming antigen escape

Cancer cells can evade CAR T-cell therapy over time by losing the antigens (proteins) that CAR T-cells are designed to target. This is known as antigen escape. This means that although CAR T-cells may be effective initially, the cancer can evolve to escape targeting by CAR T-cells, leading to relapse in some patients.

Research approaches:

• Dual or multi-antigen targeting CARs: By engineering CAR T-cells to target multiple antigens simultaneously, the chances of cancer cells evading detection can be reduced. This means even if the cancer evolves to lose one antigen that is targeted by the CAR T-cells, there is still another antigen that can be used to recognise and destroy the cancer cell. The Malaghan Institute is currently working on developing dual CAR T-cells to target multiple myeloma, a cancer that has been shown to be particularly susceptible to antigen escape.

2. Targeting solid tumours

CAR T-cell therapy has been most effective in treating blood cancers like leukaemia and lymphoma, where the cancer cells are relatively easy to identify and access. However, solid tumours, such as lung, breast or colon cancer, present a more complex challenge. In solid tumours, cancerous cells are clumped together, often creating a hostile environment with limited resources for immune cells like CAR T-cells. This can suppress immune responses, making it difficult for CAR T-cells to infiltrate and attack the cancer effectively.

Research approaches:

• Cytotoxic pro-drugs: Researchers are investigating methods to enhance CAR T-cell activity by incorporating additional molecules to amplify the cancer-killing activity of CAR T-cells. These molecules activate only when the CAR T-cells bind to tumour cells, allowing the cell-killing activity to be concentrated around the tumour. This approach may provide the potency of treatment required to destroy solid tumours.

3. Enhancing safety

While the CAR T-cells used in the Malaghan Institute’s clinical trial have so far shown to have a good safety profile, one of the risks of CAR T-cell therapy is our immune system reacting adversely to CAR T-cells. CAR T-cells can sometimes generate a very strong immune response or may attack healthy cells that express proteins like those on cancer cells, leading to unintended side effects. 

Research approaches:

• CAR design: By tweaking the different structural components of the CAR T-cell to optimise for safety, it is possible to reduce the rate of adverse side effects. This is one of the approaches used in the Malaghan Institute’s CAR T-cell construct.
• Quality control: Researchers have developed methods to ensure that the CAR gene is inserted into a safe location within the T-cell genome during CAR T-cell production, reducing the risk of potential side effects. At the Malaghan Institute, researchers are refining and implementing further safety checks to CAR T-cells to incorporate into wider scale CAR T-cell production.
• Safety switches: To address the risks of severe side effects, scientists are integrating ‘safety switches’ or ‘suicide genes’ into CAR T-cells. These switches can be activated to quickly eliminate the CAR T-cells from the body if dangerous side effects begin to occur. The Malaghan Institute has created its own safety switch which could be used in future CAR T-cell constructs and other cell therapies.

4. Expanding access: off-the-shelf CAR T-cells

Currently, CAR T-cell therapy is a personalised treatment, requiring the modification of a patient’s own T-cells. This process is time-consuming and expensive, limiting the therapy's availability.

Research approaches:

• Pre-produced CAR T-cells: Scientists are exploring the development of CAR T-cells derived from healthy donors rather than from the patient. These CAR T-cells could be mass produced and stored, making the therapy more accessible and affordable.
• Gene editing: Techniques like CRISPR are being used to edit the genes of donor T-cells to reduce the risk of rejection and improve their safety and effectiveness in a broader range of patients.

5. Improving persistence and durability 

For CAR T-cell therapy to be effective in the long term, the engineered T-cells need to persist in the patient’s body and continue to fight any remaining or recurring cancer cells. However, in many cases, CAR T-cells lose their effectiveness over time which can lead to relapse.

Research approaches:

• Memory CAR T-cells: CAR T-cell therapy in usually a mixture of cytotoxic T-cells, which kill cancer cells, and memory T-cells which remain in the body after the cancer has initially been cleared, waiting for any reoccurrence of cells with the target protein. If the cancer cells resurface, these memory cells will convert to cytotoxic T-cells and rapidly proliferate to destroy the cancer cells. Part of optimising CAR T-cell therapy is determining the ideal proportion of cytotoxic and memory CAR T-cells to have the most effective outcome in patients.
• Enhanced metabolic programming: Scientists are identifying specific targets in the energy regulation pathways of CAR T-cells that reduce CAR T-cell effectiveness over time. After identifying these pathways, they can alter them to increase CAR T-cell longevity and efficacy within the body.