How zalifrelimab works
Zalifrelimab is a type of immunotherapy, a treatment that acts to improve the immune system’s ability to target and kill cancer cells.
The immune system is capable of targeting damaged or infected cells by directing a type of immune cell, called a T-cell, to recognize and kill them. But to protect healthy tissues from accidental damage, immune system checkpoints work to inhibit their cell-killing ability when T-cells come in contact with a healthy cell.
Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) is involved in one of these immune system checkpoints. CTLA4 is a protein normally only produced by healthy cells, and it can interact with the proteins CD80 and CD86 found on the surface of T-cells and some other immune cells. When CTLA4 binds to CD80 or CD86, it inhibits the T-cells and can prevent the production of proteins, such as IL-2, that stimulate the proliferation and activation of surrounding T-cells. Many types of cancer can take advantage of this checkpoint, masking themselves to evade immune system detection and continue to grow unchecked.
Zalifrelimab is an antibody, a protein designed to interact with a specific target, that binds to and blocks CTLA4. This prevents CTL4 from binding to its targets, which reduces the CTLA-4-mediated inhibition of T-cells. It is hoped that through this mechanism, zalifrelimab will cause an increase in the number of activated T-cells in the tumor environment, allowing the immune system to effectively target and kill the cancer’s cells.
Zalifrelimab in clinical trials
An ongoing Phase 1 clinical trial (NCT02694822) is currently recruiting about 48 people with advanced solid tumors across the U.S. Its aim is to evaluate the safety, pharmacokinetics (movement in the body), and pharmacodynamics (effect on the body) of zalifrelimab. It will also determine the maximum tolerated dose of zalifrelimab. The study is expected to conclude in October 2018.
Preliminary results from the first 11 patients were presented at the American Society of Clinical Oncology (ASCO) 2017 annual meeting, and suggested that zalifrelimab is safe and well-tolerated at lower doses. Recruitment and dose escalation is ongoing at several U.S. sites.
A Phase 2a clinical trial (ACTRN12617001061325) is enrolling in Australia and New Zealand to assess the safety and tolerability of zalifrelimab in combination with Keytruda (pembrolizumab) as a first-line treatment in NSCLC patients whose cancer has spread. Keytruda is an inhibitor of a different immune system checkpoint, the PD-1 pathway. A total of 26 people will be treated with two different doses of zalifrelimab plus Keytruda. The study’s first part will determine the dose of zalifrelimab to be used in the second part. Zalifrelimab will be administered every six weeks and Keytruda every three weeks by intravenous infusion. The study is expected to run through February 2021.
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