PhD Perspectives: Harnessing the immune system to tackle cancer

My name is Jared Darcy, and I am a third-year PhD student working on how we can optimise Chimeric Antigen Receptor (CAR)-T cell therapy for the treatment of blood cancers.

I accrued a lot of research experience leading up this PhD. As part of my bachelor’s degree, I completed a research studentship in Microbiology where I researched how genes found in budding yeast (Saccharomyces cerevisiae) could be used to study mitochondrial function and fitness. I presented my research findings at a conference and confirmed my wish to pursue a career in scientific research.

Following a Master’s in Immunology and Immunotherapy, I became fascinated with learning how the immune system works and leveraging this knowledge to tackle diseases such as cancer. CAR-T therapy is an excellent example of this, where we use the power of the immune system to make an impact in the clinic.

Under the bonnet of CAR-T cells: What my research is about

T cells are a type of white blood cell that act like security guards. They identify threats, coordinate immune responses, and eliminate dangerous pathogens using a T cell receptor (TCR). A T cell receptor acts like a molecular barcode scanner, which ‘beeps’ when it encounters a pathogen that it recognises, activating the T cell. CAR T cells are engineered cells and a step up from regular T cells. To make CAR-T cells, T cells are removed from patients with blood cancer and then genetically modified in a laboratory to give them an extra targeting device called a Chimeric Antigen Receptor (CAR). This receptor helps the T cells recognise specific markers found on cancer cells, making it easier for them to find and attack their target cancer cell when they are infused back into the patient’s blood stream.

However, while CAR-T therapy is effective in the short term, many patients relapse within a year and a key reason for this is that CAR T cells eventually die or become too exhausted to fight the cancer properly, leaving them ineffective. My work hopes to change that using viruses.

In health, regular T cells vary in their fitness and ability to function and kill cells. Sometimes the T cells can change to become more resistant to exhaustion and better equipped to eliminate certain pathogens. By studying and identifying these ‘fit’ T cells, it is hoped that we can produce CAR T cells that remain in the body for longer and unlock the potential for more durable remissions.

Shifting CARs into a higher gear: why this research matters

CAR T-cell therapy is expensive. At the time of writing this blog, the procedure costs approximately £300,000 per patient. With blood cancer becoming the 5th most common cancer in the UK, it is imperative that we maximise the potential for long term remission.

Since CAR T cell therapy uses a patient’s own T cells to fight cancer, the treatment is only as effective as the T cells used. If a patient has lots of exhausted T cells, then the CAR T cells won’t effectively control the cancer. Therefore, we need to be more selective, using only the best T cells in these patients to get the best CAR T cells.

In the driver’s seat: my research approach

I have used a plethora of techniques during my PhD. Primarily, I work with cells kindly donated by patients who have received CAR-T therapy for blood cancer. From here, I test how functional the CAR T cells are and compare with their original T cell donation material.

More recently, I have been looking deeper into these CAR T cells using RNA sequencing, a method that lets us “listen in” on individual cells and see which genes they are using to carry out their functions. This is particularly useful in CAR T therapy, where not all cells behave the same way — some are highly active, while others may become exhausted or less effective.

Overall, I am aiming to answer the question: What makes a good CAR T cell?

What has excited me most on my research journey

Perhaps the most exciting result that has come up in my PhD has come from my recent Single-cell analysis work.

So far, I have observed that some CAR T cells have a unique genetic profile and are highly cytotoxic. They have the potential anti-cancer function by expressing proteins such as interferons and granzymes.  Granzymes act like molecular scissors that enter the cancer cell and trigger a self-destruct program. Interferons are signalling molecules that warn nearby cells and help activate other parts of the immune system to join the fight. I am now comparing these findings to see if I can identify the same highly functional CAR-T cells in the patient’s original T cell collection that was used to manufacture the CAR-T product. If we can identify these cells when we collect the T cells at apheresis, we can potentially select them and enhance the generation of long-lived CAR-T cells in-vivo.

This work has the potential to drive long-lasting impact in the field of cancer therapy.

Life in the fast lane: My experience as a BRC student

Being part of the BRC has provided me with fantastic opportunities to develop my skills outside of the lab.

Working under the Cancer Inflammation theme, I have had the opportunity to network with researchers across Birmingham, who cover a wide range of specialties and techniques. The close location of the University Hospitals Birmingham and my laboratory at University of Birmingham, together with a BRC funded research nurse post has enabled me to recruit and analyse samples at speed.  

I was also fortunate to recently attend a workshop on grant writing hosted by the BRC, which has been instrumental in planning my next steps for the future.

The road ahead

With this research, I hope to change how we approach cancer therapy.  Cancer represents a significant on individuals, families, and society. The more research we do, the more we learn about what makes an effective therapy, and the more lives we can save.