A recent failed clinical trial by British and American researchers resulted in a breakthrough in cancer immunotherapy research. The team of researchers from the University of Liverpool and the La Jolla Institute for Immunology in California believe their findings could improve immunotherapy treatments for some cancer patients.
These findings address an issue that has perplexed immunotherapy researchers for years: why do so many immunotherapies cause dangerous side effects in certain patients? Here is a detailed look at what these researchers discovered and how their findings could be used to build stronger immunotherapy treatment plans.
Side Effects of Immunotherapy
Immunotherapy has allowed the oncology field to make major strides in cancer treatment, but there are still several issues that need to be addressed. For instance, only about 20 percent to 30 percent of patients with solid cancers see long-term improvements after immunotherapy.
In addition, many patients suffer severe side effects that can affect their lungs, bowels, and skin. If these side effects are severe enough, physicians discontinue the immunotherapy treatment.
These recent findings on immunotherapy side effects were discovered during a clinical trial for head and neck cancer patients. Many patients showed adverse side effects during the immunotherapy trial, prompting researchers to analyze data and samples to determine the cause.
Trial participants were given a new oral cancer immunotherapy drug called a PI3Kδ inhibitor, which is designed to inhibit T cells. Of the 21 patients, 12 were forced to stop treatment early after developing colitis, or inflammation of the colon. This surprised the researchers, who did not expect the inhibitor to be toxic.
Why Did the Patients Respond This Way?
Following the adverse response of these 12 patients, the researchers shifted their focus to what was causing these side effects. They used a new single-cell genomic sequencing technology to analyze human and mouse tissue. This team of researchers is among the first to use single-cell genomic sequencing tools to reveal which therapeutic combinations are most effective in specific patients. In a previous study published in Nature Immunology in 2021, the same researchers showed how immunotherapies could be more effective when administered in a specific sequence.
The genome sequencing analysis in this study revealed that during the process of boosting T-cell levels, the PI3Kδ inhibitor also prevented a specific regulatory T cell (Treg) subset from protecting the colon. This allowed pathogenic T-cells to enter the bowel and cause inflammation.
The researchers concluded that the immunotherapy trial patients had been given excessive doses of the inhibitor, which interfered with the function of immune cells in the bowels.
Developing a New Dosage Strategy
Next, researchers analyzed a mouse model to determine how to properly adjust their dosing. They found that an intermittent dosing strategy could be more effective. This type of dosing schedule could potentially provide anti-tumor immunity and reduce the toxic effects observed in the failed clinical trial.
The study’s authors plan to continue investigating this issue and are in the process of designing a human clinical trial that will test this intermittent dosing strategy. If successful, this new dosing strategy has the potential to save lives.
Lack of Toxicity in B-cell Lymphoma Immunotherapy Trials
Before this clinical trial, PI3Kδ inhibitors had also been tested in clinical trials for B-cell lymphoma patients. The patients in this trial did not show any signs of toxicity, which is why the researchers in the head and neck cancer trial were surprised to see these effects.
The lymphoma patients from these previous studies had received several prior immunotherapies, which created an overall immunocompromised state. Thus, these patients did not have the same type or severity of immune response to PI3Kδ inhibitors.
Conversely, the head and neck cancer patients had not received any prior treatments before taking the PI3Kδ inhibitors. This means that they were not immunocompromised, and their adverse immune-related responses happened more quickly and were stronger.
Takeaways from This Study
Beyond the direct observations of this study, several important lessons can be gleaned from the trial.
According to La Jolla Institute instructor Simon Eschweiler, PhD, the toxicity pathway observed in this study could be applied to other organs that contain similar Treg cells, as well as other Treg cell-targeting immunotherapies, such as anti-CTLA-4.
Additionally, this study shows that researchers can pivot from a clinical study to a mouse sample study to investigate the cause of toxicity in human patients.
Finally, the study illustrates the importance of researching personalized therapies, along with dosage strategies and schedules. Just a decade ago, there was only one available type of immunotherapy. Today, doctors have access to a wide array of immunotherapies—and their selection is growing quickly.
Thus, special attention must be given to which immunotherapies and dosages work best for which patients and why. As further studies answer these questions, the overall effectiveness of immunotherapy could improve significantly.