Next-generation immunotherapy against cancer enters clinical trials

Next-generation immunotherapy against cancer enters clinical trials

Scientists have developed a new experimental drug that aims to use the body’s immune system in a response against cancer, which is now entering early phase clinical trials.

The experimental drug has been developed by Cancer Research UK scientists and targets suppressive ‘regulatory’ immune cells inside a tumour, significantly improving long-term survival in animal models even when used without other drugs. The potent effect of the drug was observed across multiple mouse models of cancer, with some models showing a near 100% response.

If this clinical trial, which aims to determine the drug’s safety in people with advanced cancer, and larger follow-up trials are successful, it could lead to new immunotherapy treatment for people with high numbers of a certain type of immune cell that is found in cancers such as melanoma, certain lung cancers, and head and neck cancer.

The study has been published in the journal Nature.

How does the drug work?

Regulatory T cells, or ‘Tregs’, usually act as brakes on our immune system, preventing it from becoming overactive, and previous work has shown that these cells are often found in high numbers in tumours. They are thought to prevent other immune cells from eradicating cancer. A hallmark of Treg immune cells is a protein called CD25, which is present in large amounts on the cells’ surfaces.

Drugs that target the CD25 protein have previously been used to kill regulatory T cells, to try to release these brakes that dampen down the immune system, however, these drugs have been ineffective. This new study reveals why they have not been effective so far, leading to the development of the new immunotherapy drug.

Led by Professor Sergio Quezada and Professor Karl Peggs, the Cancer Research UK team discovered that previous CD25 drugs inadvertently affected cancer-killing ‘effector’ T cells in the tumour, which reduced the effectiveness of their immune response against the disease.

Professor Sergio Quezada, co-lead author from University College London, said: “For many years it’s been a complex mystery; why targeting CD25 with other drugs has not been as effective as anticipated. Now, by going back to basic biology and unpicking the mechanism behind this protein we have found that targeting CD25 was absolutely the right approach, but we needed to target a different part of the protein.”

The team were able to invent the new drug, an antibody which binds to a different part of the CD25 protein to other currently available drugs.

Professor Sergio Quezada said: “This drug not only eliminates the regulatory immune cells that dampen down the immune response to cancer, but also activates the cancer-killing immune cells. This two-pronged approach is a huge opportunity to significantly alter the tumour network of cells in and around the tumour, so they no longer protect the cancer cells, but start to turn against the tumour.”

Professor Karen Vousden, Cancer Research UK’s chief scientist, said: “This is a stand-out example of how studying cancer in the laboratory can lead directly to experimental treatments for people with the disease. Therapies that activate an immune response against cancers have already been a game changer for many tumour types, but they only work for a minority of patients. One approach to try to make them more effective has been to try to target immune cells called regulatory T cells, which normally limit the immune response. However, attempts to do this have been unsuccessful.

“In this study, Cancer Research UK scientists at UCL have worked out why these previous attempts have failed, and, in doing so, have invented a new antibody that lacks these unwanted additional activities, and shown that it produces potent anti-tumour responses in mice. It is now being tested in clinical trials against several types of cancer.”

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