Ovarian cancer immunotherapy reactivates immune cells: Study
Experimental treatment shows promise for overcoming immune suppression
An experimental immunotherapy known as MOv18 IgE showed promise in overcoming the immune suppression caused by ovarian cancer cells, potentially enabling the immune system to mount a stronger attack against tumors, a study found.
Preliminary evidence from animal models and an early clinical trial have shown the therapy can help promote an immune response against cancer cells. Now, researchers investigated how MOv18 IgE interacts with the immune system to promote this response, showing that it mainly involves two types of immune cells — macrophages and T cells — which are normally suppressed by tumor cells.
“Understanding the biology of how a treatment works is essential for bringing treatments closer to patients,” senior author Sophia Karagiannis, PhD, a professor of translational cancer immunology and immunotherapy at King’s College London, said in a university press release. “We found that immune cells which are otherwise inhibited in the ‘microenvironment’ of the tumour, are directed by [MOv18] IgE to target the cancer cells.”
The study, “Hyperinflammatory repolarisation of ovarian cancer patient macrophages by anti-tumour IgE antibody, MOv18, restricts an immunosuppressive macrophage:Treg cell interaction,” was published in Nature Communications.
Targeting ovarian cancer immune cells in tissue
Cancer cells frequently evade the immune system by suppressing its natural defenses, making it difficult for the body to recognize and destroy tumors. Immunotherapies such as MOv18 IgE are engineered to overcome this immune suppression, enhancing the body’s ability to detect and attack cancer cells.
Most cancer immunotherapies on the market use an antibody called immunoglobulin G (IgG). IgG binds to immune cells in the bloodstream, helping them identify and attack cancer cells. However, IgG antibody therapies have had limited success in targeting ovarian cancers.
The research team developed MOv18 using an alternative antibody, immunoglobulin E (IgE), which targets immune cells in tissues rather than blood. IgE antibodies also bind more tightly to immune cells than IgG antibodies do.
Previous work in animal models has suggested that IgE antibodies target a specific type of immune cell called a macrophage. Under normal conditions, macrophages help defend the body by destroying harmful microorganisms. Cancer cells can hijack and reprogram these immune cells, turning them into allies that fail to attack, and may even support, tumor growth.
The team studied MOv18 IgE to see if it could activate immune cells in ovarian cancer patients and affect the tumor environment. First, they collected macrophages from healthy donors and exposed them to cancerous fluid samples taken from patients who participated in a Phase 1a clinical trial (NCT02546921) in which low doses of MOv18 IgE shrank an ovarian tumor in a patient who did not respond to conventional therapies. They also directly isolated macrophages from these patient-derived fluid samples.
In both cases, they found that ovarian cancer weakened the macrophages’ immune activity.
The researchers then exposed the suppressed macrophage samples to MOv18 IgE. They found that MOv18 IgE could bind to the suppressed macrophages and reactivate them to attack ovarian cancer cells. This activation also helped lift the suppression on T-cells, which are crucial immune cells that help maintain a long-term defense against cancer, allowing them to function more effectively.
“This study adds important patient-level information to support what we previously observed for MOv18 IgE in the laboratory and reveals, for the first time, that IgE-driven macrophage stimulation can activate the wider tumour immune system,” said Gabriel Osborn, PhD, a research fellow at University College London who worked on the project as a graduate student.
Macrophages, T-cells
The team further investigated the therapy’s mechanisms using tumor biopsies from two patients who participated in the Phase 1a trial. Compared with initial samples taken before MOv18 IgE treatment, those taken after therapy had more macrophages and T-cells. These T-cells had a pro-inflammatory profile, which is associated with improved patient prognosis, rather than an immune-suppressing one.
This signature immune reaction suggests that macrophages and T-cells are important parts of the mechanisms that MOv18 IgE uses to fight cancer.
‘This study sheds light on the anti-tumoural macrophage-mediated mechanism of IgE [antibodies], indicating how, in addition to tumour killing, IgE may promote a tumour immunity reorganisation,’ the researchers wrote.
“Clear progress is being made by studying the immune system and the environment in which the cancer grows,” said study co-author James Spicer, PhD, a professor of experimental cancer medicine at King’s College London and chief clinical investigator of the Phase 1a clinical trial. “In our ongoing research we are striving to understand how we can capitalise on the power of IgE to develop novel effective treatments, which will complement established IgG antibody drugs used in the clinic.”
A Phase 1b trial (NCT06547840) testing MOv18 IgE’s safety is ongoing in patients with ovarian cancer that is resistant to platinum-based chemotherapy. The trial is enrolling patients at several sites in the U.K.
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