Drug development and discovery

TWO NEW FORMS OF THERAPY GIVE HOPE WHEN BLOOD CANCER RETURNS AND BOWEL CANCER SPREADS

Scientists trial new way to boost CAR T-cell therapy

Cancer Research UK is collaborating with Aleta Biotherapeutics to trial a new therapy that reboots a treatment for some people whose blood cancer starts to come back.

The new therapy, called ALETA-001, aims to boost a treatment called CAR T-cell therapy, which takes some of a patient’s immune cells and alters them to attack cancer. Cancer Research UK’s Centre for Drug Development will fund, sponsor and conduct the clinical trial of ALETA-001, which will involve people with B cell lymphoma and leukaemia.

REBOOTING CAR T-CELL THERAPY

Nigel Blackburn, Cancer Research UK’s director of drug development, said this is a landmark collaboration for Cancer Research UK.

“It’s the first-in-human trial for a new drug that reboots CAR T-cell therapy, and we look forward to progress its early clinical development with Aleta.” CAR T-cell therapy works by taking some of a patient’s T cells and altering them to recognise a particular protein found on lymphoma and leukaemia cells, called CD19. After a few weeks, these cells are then fed back into the bloodstream and attack cancer cells.

“CAR T-cell therapy has been transformative in treating patients with hard-to-treat blood cancers, but many will see their cancer return and treatment options begin to run out,” said Blackburn.

Around half of the patients treated with CAR T-cell therapy relapse, mostly because their cancer cells stop producing the CD19 protein that CAR T-cells are looking for. When this happens, patients have few other options. ALETA-001 acts as a reboot for CAR T-cell therapy, attaching to a different protein called CD20 and recoating the cancer cell with CD19. The CAR T cells can then recognise and attack the cancer cells again. “ALETA-001 uses a simple yet elegant method to redirect a patient’s circulating CD19 CAR T cells against cancer cells expressing CD20, and we hope this could be a new treatment avenue for blood cancer,” said Blackburn.

“There is an urgent need to develop new therapies that can help people with B cell cancers, such as lymphoma and leukaemia, whose cancer has progressed after treatment with CD19 CAR T-cell therapy.”

Paul Rennert, President, co-founder and chief scientific officer of Aleta Biotherapeutics

TAKING ALETA-001 TO THE CLINIC

The first trial will enrol patients with B cell lymphoma or leukaemia who have received CD19 CAR T-cell therapy but did not achieve a complete response or whose cancer has come back.

Led by a team at The Christie NHS Foundation Trust in Manchester, it will be the first time that this type of therapy has ever been tested in humans.

A key aim of the trial is to find out the right dosage of ALETA-001. After this, it will be move into a much bigger trial in the US involving people with diffuse large B cell lymphoma. This second trial will be designed to support potential accelerated approval of ALETA-001 for cancer patients. Paul Rennert, President, co-founder and chief scientific officer of Aleta Biotherapeutics, said: “There is an urgent need to develop new therapies that can help people with B cell cancers, such as lymphoma and leukaemia, whose cancer has progressed after treatment with CD19 CAR T-cell therapy.” “We look forward to working with Cancer Research UK’s exceptional network of experienced clinical trial investigators and researchers to conduct the trial.”

Combination immunotherapy for advanced bowel cancer approved for NHS in England

People who have previously been treated for a type of bowel cancer that’s spread to other parts of their body will now have another treatment option in England, following the approval of nivolumab (Opdivo) and ipilimumab (Yervoy).

The National Institute of Health and Care Excellence (NICE) has approved this combination of immunotherapy drugs for use in adults with bowel cancer that has spread to other parts of the body (metastatic bowel cancer) and has a lot of errors (mutations) in its DNA.

Ben Chiu, policy manager at Cancer Research UK, said that this decision is “excellent news” for people with this type of cancer. “Even though some uncertainty remains, clinical evidence suggests that nivolumab plus ipilimumab can improve patients’ survival and help maintain their quality of life.”

AN UNMET NEED

Around 4 in 100 metastatic bowel cancers have a lot more DNA mutations than others, as they’re unable to repair any mistakes that are made in their DNA.

These cancers are said to have high ‘microsatellite instability’ (MSI) or ‘mismatch repair (MMR) deficiency’, which can make them more aggressive, and are associated with a poorer outlook and greater risk of death. Despite this, there aren’t specific treatments for this type of bowel cancer, so people are offered the same treatment whether or not their cancer has this inability to fix mistakes in its DNA.

Patient experts explained to the NICE committee that this kind of diagnosis affects the quality of life both physically and psychologically, and that new treatments like the newly approved immunotherapy drugs are needed. People with previously treated metastatic bowel cancer are currently offered combination chemotherapy as their second-line treatment.

But following the NICE decision, patients with bowel cancer that has high MSI or an MMR deficiency will now have an option of a combination of immunotherapies.

WHY DOES IMMUNOTHERAPY WORK BETTER FOR THESE PATIENTS?

Immunotherapies harness the body’s immune system to fight cancer. Researchers have found that bowel cancer tumours with high MSI or MMR deficiency have a lot of immune cells within them, but the cancer stops them from working. Nivolumab and ipilimumab block the cancer’s ability to do this, allowing the immune cells to attack the tumours.

Experts commented that having the immunotherapy combo rather than combination chemotherapy may mean less debilitating side effects. The absence of side effects like nausea, stomach pain and fatigue could give people a better quality of life. The clinical evidence for the effectiveness of this treatment came from the single-arm, phase 2 CheckMate 142 study. The trial included 119 people with metastatic colorectal cancer with high MSI or MMR deficiency, previously treated with combination therapies. As a single-arm trial, the study did not directly compare the use of nivolumab plus ipilimumab with other treatments, so the data had to be compared indirectly with data about current treatments.

The NICE committee concluded that despite this uncertainty, the trial showed that the benefits of the treatment, measured by overall survival for patients and the amount of time where their cancer didn’t get worse, was likely to be greater than current standard care. Overall, the treatment was considered cost-effective for use in the NHS by NICE and will now be an option on the NHS in England. NICE decisions are usually adopted in Wales and Northern Ireland as well, so the decision is likely to affect patients in all 3 nations. Scotland has a separate process for reviewing drugs.