Next-generation autologous chimeric antigen receptor T cells targeting GPC3 for the treatment of hepatocellular carcinoma (HCC)

Context/Challenge: Cancer which originates from the liver (known as hepatocellular carcinoma/HCC) is the second commonest cause of cancer death worldwide and is becoming more common. The only curative treatment is surgery, but most patients are diagnosed with advanced disease which cannot be treated by surgery. Standard chemotherapy is ineffective, so patients are treated with immune-activating antibody drugs. However, most patients die within a year. Chimeric antigen receptor T-cell therapy (CAR-T for short) is a new kind of treatment where a patient’s immune cells (T-cells) are harvested from their blood and genetically engineered so that they recognize cancer cells. In blood cancers such as lymphoma, CAR-T is effective even in cancers resistant to chemotherapy. About 40% of patients have long-term complete remissions. Research efforts have recently focussed on replicating this success in solid cancers like HCC. CAR-T cells need a target on the cancer cell surface which can distinguish it from normal cells. HCC has a good target called Glypican-3(GPC3 for short). Early clinical studies of GPC3-CAR-T-cells have shown promising results: CAR-T appears safe, and some patients had a reduction in their tumours. However, unlike with lymphoma, patients did not have lasting responses. We wish to build on this work with a three-pronged strategy to generate an effective CAR-T-cell therapy for HCC. Aims and objectives: The aim of this application is to fully safety-check our HCC-targeting CAR-T approach to make it as safe and effective as possible before we apply for funding for an early-phase clinical trial. Our approach encompasses the following: Better targeting of GPC3: The target GPC3 is a protein found on the surface of HCC cancer cells. GPC3 gets partially digested, so part of this protein falls away becoming soluble in the blood and around the HCC. Current CARs target this part of the GPC3 which means CAR-T cells can be “blocked” by soluble fragments of GPC3. Our particular CAR targets the portion of GPC3 which remains attached to the cell after digestion so cannot be blocked by soluble GPC3. The outstanding task for our new CAR is to perform safety testing by a technique called 'tissue-cross' to ensure it only targets HCC and not other normal cells in the body. Tumour environment: Solid cancers like HCC surround themselves with cells and immune-hormones(cytokines) which shield the cancer from CAR-T. This is called the tumour microenvironment(TME for short). Two features of the HCC TME are the cytokine TGFß and immunoregulatory NK-cells. We will engineer CAR-T cells with two additional modifications(dTBRII & IL15) to protect them from being 'switched off' by the TME. Combining with Radiotherapy (X-ray-therapy): CAR-T works better with smaller amounts of disease. Radiotherapy can temporarily shrink HCC tumours and may also help CAR-T cells enter the tumour. We will test a number of new ways to use radiotherapy with CAR-T cells to find the best HCC cancer-targeting combination. Potential applications and benefits: If our project is successful, we will take our best CAR-T approach and apply for funding for an early-phase clinical trial in patients. If a future clinical study demonstrates safety and some patients respond, we will extend the study to better understand how well the treatment works. If a proportion of patients have complete and lasting remissions, we will work with pharmaceutical companies to bring this treatment to NHS patients.