Targeted cancer therapy using CAR-T cells

Reprogramming a person’s own immune system to target cancerous cells provides a truly individual approach to cancer treatment. Dr Julia Wolf and Dr James Griffin describe how a novel therapy was used to treat an aggressive form of leukaemia. 

CAR-T therapy is a novel and highly complex immune therapy that redirects the body’s own immune system to fight cancer. CAR-T cells are often described as ‘the living drug’ because they actively search and target malignant cells. It uses a type of immune cell called a T-cell, which is extracted from patients’ blood before being genetically altered to allow it to target surface proteins found on cancer cells.

CAR-T cells are often described as ‘the living drug’ because they actively search and target malignant cells.

The cell collection is performed by passing the blood through an apheresis machine that separates the white cells, including T-cells. The collected cells are then transported to manufacturing sites where the CAR-T cell drug is created by inserting a man-made gene, the chimeric antigen receptor (CAR), into the DNA of T-cells. As a result, the engineered cell can recognise and fight cancer cells. The CAR-T cells are then expanded and infused back into the patient after chemotherapy.

Since Food and Drug Administration approval in the USA in 2017, CART-T therapy has emerged as one of the biggest breakthroughs in cancer therapy in decades. Several products are now used routinely or in trials to treat a range of haematological and non-haematological malignancies.

The collection, processing and storage of patient cells that form the basis of CAR-T therapy depends on a multitude of clinical and laboratory processes, which are supported by NHS Blood and Transplant (NHSBT) and pathology services.

Prior to the emergence of CAR-T therapy, treatment options for relapsed ALL following stem cell transplant were extremely limited and outcomes sadly often extremely poor.

The first patient to receive CAR-T therapy at University Hospitals Bristol and Weston (UHBW) NHS Foundation Trust was Nitya. Nitya was diagnosed with acute lymphoblastic leukaemia (ALL), an aggressive form of blood cancer, at the age of 16. She received standard multiagent CAR-T cells are often described as ‘the living drug’ because they actively search and target malignant cells.Prior to the emergence of CAR-T therapy, treatment options for relapsed ALL following stem cell transplant were extremely limited and outcomes sadly often extremely poor. chemotherapy and achieved a good initial response but, unfortunately, her leukaemia relapsed only 23 months into treatment. Nitya required more chemotherapy, which achieved a complete remission from ALL. Despite her intensive treatment she also managed to complete her A-levels and received a place to study at University College London (UCL). However, these remissions are a fragile and temporary state and need to be consolidated with allogeneic (donor) stem cell transplant.

Nitya was accepted as one of the first NHS patients to receive CAR-T cells … What followed was a journey filled with anxious waiting.

The histocompatibility and immunogenetics laboratory in NHSBT Filton carried out tissue typing, which tests to see how closely a donor’s stem cells or tissue match your own, and found that Nitya’s sister was a full match for her. Her sister underwent successful apheresis stem cell collection. Nitya received more chemotherapy to prepare her body for transplant before having an infusion of her sister’s stem cells. She tolerated the treatment well despite developing graft versus host disease (GvHD). GvHD is a frequent complication of allogeneic stem cell transplant that occurs when the donated cells view the healthy cells of the person receiving the transplant as foreign and attack them. Unfortunately, three months after the transplant, Nitya had relapsed again.

Prior to the emergence of CAR-T therapy, treatment options for relapsed ALL following stem cell transplant were extremely limited and outcomes sadly often extremely poor. However, UHBW had set up its own CAR-T programme and was now offering this treatment as one of only six sites in the UK. As CAR-T therapy is associated with significant and complex adverse events, the decision of whether to offer CAR-T therapy to Nitya was not taken lightly. Specifically, there were concerns that Nitya’s GvHD could recur and be exacerbated through further immune therapy.

As other treatment options were inadequate, Nitya was accepted as one of the first NHS patients to receive CAR-T cells in December 2018. What followed was a journey filled with anxious waiting. Nitya received further chemotherapy, which again put her into a complete remission. She achieved a good apheresis collection but cells had to be cryopreserved and shipped to the USA for manufacture. The manufacturing process for CAR-T cells is complex and not always successful meaning some patients need further chemotherapy to hold their disease at bay. Some relapse despite this, making CAR-T treatment impossible. In Nitya’s case, the CAR-T cells were returned to the UK four weeks later. Nitya underwent yet more chemotherapy to prepare her body for the CAR-T cells before receiving the infusion.

Her treatment went well but was complicated by severe GvHD affecting her liver. While this was predicted as a possible complication, it had not been previously described in the literature. Nitya was very unwell and required treatment with extracorporeal photopheresis. This is an apheresis-based therapy that involves collecting the patient’s white blood cells, adding a chemical to the cells and exposing them to ultraviolet light outside of the body to cause programmed cell death. The dying cells are re-infused back to the patient where they affect how the patient’s immune system works. Nitya received this therapy regularly for a year after CAR-T treatment but has nowstopped after achieving a complete response.

And Nitya’s leukaemia? The CAR-T therapy appears to have cured the ALL with no detectable disease in her bone marrow within a month after treatment. This remains the case 18 months later. Despite her often tumultuous treatment course, Nitya managed to start her studies at UCL and is planning on spending a year abroad soon. This would have been impossible without the close collaboration between pathology and clinical haematology services at UHBW, NHSBT and international manufacturing sites, highlighting the need for teamwork and partnership when aiming to achieve the best outcomes for our patients