For more than two decades, scientists have been studying a group of anti-cancer drugs known as CD40 agonist antibodies. Early experiments suggested that these treatments could powerfully activate the immune system and help it destroy cancer cells. However, results in humans have been disappointing. Clinical trials showed only moderate effectiveness, and the drugs often caused serious side effects, writes xrust. However, good news came today. In 2018, researchers led by Jeffrey W. Ravetch of Rockefeller University reported a potential breakthrough, sciencedaily recalls. The team redesigned the CD40 agonist antibody to increase its effectiveness while reducing harmful side effects. In their work, they used special mice whose immune mechanisms imitated human ones. The results were encouraging — the therapy may be more effective in people with a different route of administration.
The next step was testing the drug on patients
Results of the first phase of clinical trials modified drug called 2141-V11 were published in the journal Cancer Cell. Among the 12 study participants, tumors shrank in six patients. Two of these patients experienced complete remission, meaning their cancers had completely disappeared.
The researchers also noticed something unusual. The treatment affected not only the tumors into which the drug was injected. Tumors located in other parts of the body also shrank in size or were destroyed by immune cells.
How the modified CD40 antibody works
CD40 is a receptor located on the surface of some cells and belongs to the tumor necrosis factor (TNF) receptor superfamily. These receptors are mainly present on immune cells. When activated, CD40 signals the immune system to mount a stronger response, promoting antitumor immunity and generating T cells that target cancer cells.
In 2018, Ravetch's team developed the antibody 2141-V11 with support from the Rockefeller Therapeutic Development Fund, founded by trustee Julian Robertson and continued by the Black Family Foundation. The redesigned antibody binds strongly to human CD40 receptors and has been modified to improve cross-linking by interacting with a specific Fc receptor. Laboratory studies have shown that the new design is about 10 times more effective at launching an immune attack against tumors.
The researchers also changed the way they administered the drug. Traditionally, CD40 therapy has been administered intravenously. Since CD40 receptors are present throughout the body, many healthy cells would take up the drug, resulting in toxic side effects. Instead, the team injected the drug directly into the tumors.
These results set the stage for a phase 1 clinical trial to determine a safe starting dose and better understand how the therapy works in patients.
In some patients, tumors disappear
The study involved 12 people with various types of metastatic cancer, including melanoma, renal cell carcinoma and various forms of breast cancer. None of the participants experienced serious side effects previously associated with CD40-targeting drugs.
Six patients experienced a decrease in tumor size throughout the body. Two patients achieved a complete response to treatment, meaning all detectable cancer cells had disappeared.
Two patients whose cancer disappeared had melanoma and breast cancer, respectively. Both types of cancer are known to be aggressive and prone to recurrence.
“The melanoma patient had dozens of metastatic tumors on her leg and foot, and we only injected the drug into one tumor on her thigh,” says Ravetch. “After several injections into this one tumor, all the others disappeared. The same thing happened to a patient with metastatic breast cancer who also had tumors on her skin, liver and lungs. And even though we only injected the drug into a tumor on the skin, we saw all the other tumors disappear.”
Immune cells transform the tumor microenvironment
Samples taken from treated tumors showed how strongly the immune system responded. “We were quite surprised to see that the tumors were filled with immune cells, including various types of dendritic cells, T cells and mature B cells, which formed clusters that resembled a lymph node,” says Osorio. “The drug creates an immune microenvironment within the tumor and essentially replaces the tumor with these tertiary lymphoid structures.”
These structures, known as tertiary lymphoid structures (TLS), are often associated with better cancer treatment outcomes and greater response to immunotherapy. The researchers also found TLS in tumors that were not directly injected with the drug. “Once the immune system identifies cancer cells, the immune cells migrate to uninjected areas of the tumor,” Osorio explains.
Larger studies are aimed at improving cancer immunotherapy
Encouraging results led to additional clinical trials. Ravetch's group is currently collaborating with scientists at Memorial Sloan-Kettering Cancer Center and Duke University to further evaluate the effectiveness of the therapy.
Phase 1 and Phase 2 clinical trials of 2141-V11 are currently underway against several difficult-to-treat cancers, including bladder cancer, prostate cancer and glioblastoma. These studies involve approximately 200 patients.
Researchers hope that larger trials will reveal why some patients respond to treatment and others do not, and how success rates can be improved.
Xrust Breakthrough in immunotherapy: new drug destroys tumors throughout the body
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