CAR-T is a powerful tool which is still evolving. Here we highlight what is new in CAR-T cell therapy
Cancer cells often play hide-and-seek with the immune system in an attempt to evade catastrophic death. But what gives them away? Many cancer cells express unique antigens (molecular markers) on their surface which can be recognised by specially designed chimeric antigen receptors (CAR).
Normally T cells, a type of white blood cell, do not express chimeric antigen receptors. But since the early 1990s, scientists have been developing ways to genetically modify T cells to do so. These turbocharged T cells can then seek and destroy cancer cells that would have otherwise escaped its wrath. This is the basis of CAR-T cell therapy, which has emerged as a revolutionary treatment for cancer, especially, blood cancers.
Allogeneic vs autologous CAR-T cell therapy
There are two ways of sourcing T cells for CAR-T cell therapy: autologous and allogeneic. In the autologous method, T cells are collected from the patient, genetically modified and then injected back into patients. In the allogeneic method, T cells sourced from a healthy donor are modified and injected into patients. The current standard is the autologous method, but several allogeneic methods are undergoing clinical trials. Each method presents distinct benefits and challenges.
A game of tug-of-war
A battle of wits is often at play between CAR-T cells and cancer cells, as even CAR-T cell therapy doesn’t guarantee total cancer cell elimination. For example, cancer cells can evolve tactics to evade death by reducing or stopping the production of the antigen that has been targeted by a CAR-T cell. Moreover, when a CAR-T cell binds to its target antigen, it triggers a cascade of events inside the cancer cell that leads to its death. The cancer cell may develop ways to become resistant to these triggers.
Another challenge to treating solid tumors with CAR-T cell therapy is presented by tumour microenvironments (TMEs). This complex network of tumour cells, normal cells, immune cells, blood vessels and the extracellular matrix – which provides structural support to cells and tissues – keeps tumours safe by repressing CAR-T activity.
Current research efforts broadly focus on:
- Identifying the right antigen targets for CAR-T cell therapy
- Developing CAR-T cells that can target multiple antigens across different cancer cells
- Designing CAR-T cells with an ON/OFF switch that activates only under specific conditions, minimising off-target effects where healthy cells that also express the target antigen are wrongly attacked.
Of these, two recent developments look promising.
New CAR-T therapy for a solid tumour
Solid tumours can be hard to treat as they are densely packed and often express more than one type of antigen. This makes it physically difficult for single-antigen-detecting CAR-T cells to infiltrate and kill all the cancer cells effectively. However, there has been promising progress in treating a type of solid tumour called gastro-oesophageal junction cancer.
Researchers have previously identified an antigen called Claudin-18 isoform 2 (CLDN18.2) which is present in moderate to high amounts in gastro-oesophageal junction cancer. Now, in a world first approach, a randomised controlled trial was conducted in China using CAR-T therapy targeting CLDN18.2.
Researchers found that 35% of the 156 trial participants with gastro-oesophageal junction cancer responded to CAR-T therapy which is a great improvement compared to the standard of care with a 4% response rate. A high rate of side effects was noted in these trials but the symptoms were mostly mild. Overall, the results indicate a promising application of CAR-T for treating solid tumours.
RNA: a new model for CAR-T therapy?
Side-effects are common in CAR-T cell therapy. Therefore, building ON/OFF switches to control CAR-T activity is of interest. For example, the drug dasatinib could be used as a reversible ON/OFF switch where the drug inactivates CAR-T activity, but once its dosage is stopped CAR-T activity is restored. Similarly, the potential of RNA to temporarily generate CAR-T activity is being explored.
Instead of permanently altering T cells to produce CAR by adding new DNA into their genomes, researchers are now exploring the delivery of CAR-producing RNA into T cells using lipid nanoparticles (LNP). Compared to viral vectors, usually used to genetically modify T cells, lipid nanoparticles are less likely to trigger the immune system. Also, as these RNAs degrade naturally over time, the T cells only temporarily express CARs.
The short-term nature of this RNA-based approach means that multiple doses of the treatment are needed to produce the desired effect in patients. However, this temporary effect offers the key advantage that should any serious side effects occur, the therapy can be halted, and the symptoms would resolve.
Several promising clinical trials are underway to assess the safety and efficacy of this RNA–LNP method. While early results suggest it may produce fewer side effects, there are still challenges to overcome. For example, lipid nanoparticles are not yet as efficient as viral vectors at delivering their cargo to specific cells and tissues, and improving their targeting remains a major area of active research.
CAR-T therapy patient in remission for 19 years
The potential of CAR-T is enormous. By equipping immune cells with the ability to selectively eliminate cancer cells, CAR-T offers a powerful and highly targeted treatment strategy. In some cases, the results have been remarkable, with a rare childhood cancer patient being in remission for 19 years.
The promise of CAR-T goes far beyond cancer. Researchers are also exploring its use in autoimmune diseases, where the immune system mistakenly attacks healthy tissues, as well as in chronic infections like HIV.
Overall, CAR-T is a powerful tool which is still evolving, but it is already reshaping the landscape of cell-based therapies.
