Breakthrough: Investigating cancer drug toxicity leads to key discovery
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Breakthrough: Investigating cancer drug toxicity leads to key discovery
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Scientific breakthrough in failed clinical trial: Investigating cancer drug toxicity leads to key discovery.
It is not uncommon for a failed clinical trial to lead to a scientific breakthrough. Researchers have discovered a new strategy to avoid the side effects of cancer immunotherapy.
When patients in the UK started experiencing negative side effects in a cancer immunotherapy trial, researchers from the La Jolla Institute for Immunology (LJI) Cancer Immunotherapy Centre and the University of Liverpool went back, examined the data, and used the patient’s sample to determine the cause of the error.
3D rendering of T cells attacking cancer cells. Source: La Jolla Institute for Immunology
Their findings, published today (May 4, 2022) in the journal Nature, provide key clues to why many immunotherapies cause dangerous side effects — and point to more effective strategies for treating patients with solid tumors.
La Jolla Institute of Immunology (LJI) Professor Vijayanand and University of Liverpool’s Ottensmeier, an attending oncologist who treats patients with solid tumors, are both physicians and scientists.
Just over the past decade, he has seen more and more patients thrive because of advances in immunotherapy, which works with the immune system to kill cancer.
In oncology, immunotherapy has revolutionized the way we think about treatment. It’s a shocking change that we can give patients immunotherapy, even for metastatic and spreading disease, and even tell them that their cancer is cured if it goes well.
Unfortunately, only about 20 to 30 percent of patients with solid cancers who receive immunotherapy experience long-term remission.
Some people saw no change after immunotherapy, but some developed serious problems with their lungs, intestines, and even skin during treatment.
These side effects can be debilitating and even fatal, and these patients are forced to stop receiving immunotherapy.
Important lessons from clinical trials
Researchers at LJI and the University of Liverpool used samples from a recent UK clinical trial in head and neck cancer patients.
The patients received an oral cancer immunotherapy called a PI3Kd inhibitor. At the time, PI3Kd inhibitors had been shown to be effective in B-cell lymphomas, but had not been tested in solid tumors.
PI3Kd inhibitors are new to the field of cancer immunotherapy, but they hold promise in their ability to suppress “regulatory” T cells (Tregs).
Tregs typically try to prevent other T cells, called effector T cells, from targeting the body’s own tissues. Oncologists suppress Tregs within tumors so that effector T cells can release and generate cancer-killing CD8+ T cells.
“It would be a huge asset for oncologists if there was an oral tablet that could relieve Tregs,” Vijayanand said.
Unfortunately, 12 of the 21 patients in the trial had to stop treatment early because they developed inflammation of the colon, a condition known as colitis. “We don’t think the drug would be toxic, so why is this happening?” Vijayanand said.
LJI lecturer Dr. Simon Eschweiler took the lead to look back at how treatment with PI3Kd inhibitors might actually affect the immune cells of these patients. Using single-cell genome sequencing, he showed that in increasing tumor-fighting T cells in tumors, PI3Kd inhibitors also prevented a specific subset of Treg cells from protecting the colon.
Without the work of Tregs, pathogenic T cells called Th17 and Tc17 cells can come in and cause inflammation and colitis.
Clearly, the patients in these cancer trials were being given higher doses of PI3Kd inhibitors than they needed, and the immunotherapy had thrown the delicate makeup of immune cells in the gut out of balance.
The pathway leading to the toxicity seen in the new study could be broadly applicable to other organs that house similar Treg cells, as well as other Treg-targeted immunotherapies, such as anti-CTLA-4, Eschweiler said.
New dosing strategy could save lives The team found that intermittent dosing could be an effective treatment strategy that combines sustained anti-tumor immunity with reduced toxicity.
The researchers are now designing a human clinical trial to test the intermittent dosing strategy in humans.
“This study illustrates how you can go from clinical studies to mouse studies and see what’s behind the toxicity in these patients,” said LJI professor and chief scientific officer Dr. Mitchell Kronenberg, whose lab led the research on the new study. Most mouse models work.
How can the lack of toxicity in the B-cell lymphoma test be explained? In previous studies, patients with lymphoma had previously received several treatments that resulted in a decline in overall immunity, Eschweiler said.
This means that lymphoma patients do not have the same type or degree of immune response after receiving PI3Kd inhibition.
Meanwhile, head and neck cancer patients are untreated. Their immune systems were not compromised, so immune-related adverse events occurred faster and were more pronounced.
Overall, the new study shows that it is not just individualized therapy that needs to be studied, but also individualized treatment doses and schedules.
As Ottensmeier explains, a decade ago doctors offered only one type of immunotherapy. It either helps the patient or it doesn’t. Today, physicians have a rapidly growing arsenal of immunotherapies to choose from.
Vijayanand and Ottensmeier were among the first researchers to use single-cell genome sequencing tools to determine which treatment combinations work best for individual patients, and the optimal schedule for administering those treatments.
In a 2021 study in Nature Immunology, the pair showed the potential importance of giving immunotherapies in a specific order.
“If you design your clinical trials well and apply sophisticated genomics, you have a lot to learn,” Vijayanand said. “You can figure out what’s going on and get back to the patient.”
Breakthrough: Investigating cancer drug toxicity leads to key discovery
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