Scientists explore new way to bring CAR-T cell therapy to pancreatic cancer
A new strategy to help powerful cancer-targeting immune cells, known as CAR-T cells, infiltrate pancreatic tumours has been developed by researchers at Barts Cancer Institute (BCI), Queen Mary University of London. The unique three-pronged approach could pave the way for making CAR-T cell therapy—a treatment that has transformed care for certain blood cancers—effective against pancreatic cancer, a disease that remains very difficult to treat.
Only around 5% of people with pancreatic cancer survive for ten years or more after diagnosis, and unlike most other cancers, survival has barely improved over the past few decades. There is an urgent need for better ways to detect and treat the disease to build a better future for people with this condition.
New research, published in Cancers, explores how combining a type of immunotherapy called CAR-T therapy with two other types of treatments could make it more effective for tackling pancreatic cancer. The work was supported by Pancreatic Cancer UK’s inaugural Grand Challenge award – funding allocated to research with the potential to dramatically improve the welfare and treatment of patients with pancreatic cancer. The project was led by led by senior authors Professor Nick Lemoine, Professor Yaohe Wang and Professor John F. Marshall, and first author Dr Zuoyi Zhao.
CAR-T therapy involves engineering a patient’s own T cells to recognise and kill cancer cells. It has shown remarkable success in certain types of leukaemia and lymphoma, but has not yet been successfully translated to solid tumours like pancreatic cancer.
“So far, I’m not aware of any trials that have successfully translated CAR-T therapy for solid tumours. We want to change that for pancreatic cancer.”
— Professor John F. Marshall
“The challenge is that solid tumours like pancreatic cancer create an environment that powerfully suppresses the immune system and blocks immune cells from entering,” explains Professor John F. Marshall. “So far, I’m not aware of any trials that have successfully translated CAR-T therapy for solid tumours. We want to change that for pancreatic cancer.”
The team tested a three-pronged approach. First, they equipped CAR-T cells with a molecule called A20, which helps the cells stick to integrin αvβ6 – a protein found at high levels on pancreatic cancer cells but largely absent from healthy pancreatic tissue. This targeting could allow the CAR-T cells to specifically seek out cancer cells while sparing normal cells.
Second, they used a virus designed to target and kill tumour cells, which was previously developed by Professor Yaohe Wang and his team at the BCI. The virus is armed with a protein called IL-21, which helps it to act like a beacon, drawing immune cells into the tumour site.
Third, they combined these treatments with an antibody that blocks TGFβ, a molecule that plays a key role in creating the tumour’s immunosuppressive environment. Blocking TGFβ may help lift some of the immune suppression, making it easier for the CAR-T cells to work.
Importantly, the team carried out this work in a mouse model of cancer with a fully functioning immune system. Most previous studies used mice with suppressed immune systems and so failed to address the challenge of designing CAR-T therapy to overcome pancreatic cancer’s anti-immune defences.
Together, the team’s trio of therapies improved the ability of T cells to enter the tumour. “Finding those T cells inside the tumours was such a fantastic observation,” says Professor Marshall. The approach also controlled tumour growth in mice and reduced the spread of cancer.
“Finding those T cells inside the tumours was such a fantastic observation...Any improvement we can make to the stubbornly low survival of pancreatic cancer is important, so these findings represent a promising first step. They set the scene for us to move forward.”
— Professor John F. Marshall
Overall survival was only modestly improved in the mice, but the results provide a valuable foundation to build on in further research. “Any improvement we can make to the stubbornly low survival of pancreatic cancer is important, so these findings represent a promising first step. They set the scene for us to move forward.” Professor Marshall comments.
The researchers are now considering how to translate the approach for use in people. One challenge will be simplifying the treatment so that it involves fewer components, reducing the potential side effects and making it quicker and easier for patients to receive. The team also plans to study what happens once the T cells are inside the tumour, to better understand how they interact with the cancer cells, supporting further efforts to make CAR-T cell therapy an effective option for pancreatic cancer.
This work was made possible thanks to funding from Pancreatic Cancer UK, the Medical Research Council and Cancer Research UK.
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