Combined immunotherapy produces different waves of cancer-fighting T cells with each dose

A new tool for long-term monitoring of healthy immune patterns has shown how two checkpoint inhibitor therapies work together to recruit new cancer-fighting T cells with each infusion.

Results from the use of the new tool, developed by researchers at the Perelman School of Medicine of the University of Pennsylvania and the Abramson Cancer Center (ACC) of Penn Medicine, were published in Cancer cell.

The study challenges fundamental assumptions about how a common combination of immunotherapy drugs activates different types of T cells to defeat cancer and could help researchers measure the immune response more precisely in future clinical trials.

Immunotherapy has made tremendous progress in improving survival in advanced melanoma over the past decade, although researchers are still working to understand why some cancers respond better than others and to develop therapies that have fewer side effects. This study focused on a particular immunotherapy combination that has become a mainstay of melanoma treatment: PD-1 and CTLA-4 checkpoint inhibitors.

A new understanding of the T cell response

Immune checkpoint inhibitors work by releasing T cells to find and kill cancer cells. This type of combination immunotherapy was thought to work by equipping an army of T cells to recognize and fight cancer over the course of treatment.

The idea was that this group of T cells could defeat the cancer if they stayed strong long enough, but would lose the fight if their numbers dropped too much.

The study analyzed data from 36 patients treated with immunotherapy for advanced melanoma. The finding is that the combination therapy generates waves of new T cells – a so-called clonal response – with each dose, rather than continually strengthening the same pool of T cells.

“We found that after each infusion, a new immune response occurs with a new group of T cells fighting the cancer,” explained the study's lead author, Dr. Alexander Huang, assistant professor of hematology and oncology and research investigator at the ACC's Tara Miller Melanoma Center.

“Think of these T cells as an army: In many cancer patients, even as tumors grow, experienced T cell fighters try to slow the advance of enemy cancer cells. We call them 'exhausted T cells' because they have been fighting for so long, but they are elite because they can survive in a hostile environment and know how to recognize and fight the cancer cells.”

It was previously thought that certain immune checkpoint blockade therapies would boost exhausted T cells and thus directly rejuvenate them. However, these new data suggest that immune checkpoint blockade actually brings new recruits out of the barracks to fight cancer.

Conversely, there comes a time when all new T cell recruits have been sent out and the barracks are empty. Then the immune checkpoint blockade may lose its effectiveness.

Previous research has shown that exhausted T cells, the elite fighters, come from a source called progenitor cells. Anti-PD-1 immunotherapy taps into this source and eventually depletes the supply. In the current study, researchers discovered that anti-CTLA-4 therapy complements PD-1 checkpoint inhibitors by replenishing the supply of exhausted progenitor T cells, adding more elite fighters to the ranks.

Assessment of the immune response over time

To make these discoveries, the team developed a new algorithm called Cyclone to track immune responses and patterns over time by tracking the unique receptors of individual T cells.

Using blood samples from the same patients taken at different times during treatment, the researchers were able to determine which T cells moved, remained or disappeared over the course of each patient's nine-week treatment.

This approach also allows researchers to assess the magnitude of the response, including the number and type of immune cells that are activated over the course of patients' treatment. Other current single-cell methods for studying immune response provide more of a temporally limited “snapshot” by comparison.

“We envision that this more precise method of immune monitoring could be used in a variety of ways in clinical trials,” Huang said.

“For example, researchers could better understand how new drugs affect the immune system or what dosage is appropriate for the desired biological effect without having to search for the 'maximum tolerated dose' and potentially exposing patients to unnecessary toxicity.”

The research team plans to use Cyclone in upcoming clinical trials for new approaches to cancer immunotherapy, including neoadjuvant studies that can track T cells in both blood and tumor samples, as well as new immunotherapy combinations such as drugs that target PD-1 and LAG-3, a new type of checkpoint inhibitor therapy.

The lead author of the study was Kevin Wang, a medical student in Huang's lab.