Meet Cyclone: ​​a monitoring tool that tracks immune response waves

wWhen a patient persistently fights an aggressive cancer, the T cells gradually lose their ability to kill. Identifying when T cells are depleted and when to use additional treatments remains a significant challenge for clinicians. But as patients undergoing long-term treatments or those with advanced cancer often suffer from weakness, it becomes increasingly difficult to obtain samples. So researchers lack longitudinal data on T-cell dynamics after administration of immunotherapies.

Recently, a team of researchers at the University of Pennsylvania Perelman School of Medicine (Penn Medicine) reported a solution in the form of a new immunotherapy monitoring tool called Cyclone. When testing this tool on immune checkpoint therapeutic regimens, the team found that a combination of checkpoint inhibitors triggers large waves of immune response in patients with stage IV melanoma. These findings, published in Cancer cellprovides new insights into drug efficacy and may lead to better treatment monitoring strategies in cancer medicine.¹

“We wanted to create a monitoring tool that would help clinicians understand what’s happening in the patient at a precise level, rather than looking at serial CT scans to see if the tumor has grown or shrunk” , he said. Kevin Wanga medical student at Penn Medicine and co-author of the study. “Clinicians could use these algorithms to personalize therapy and tailor it to each patient.”

Although each patient’s cancer is unique, one common feature is that their cancer T cells become exhausted and peppered with checkpoint protein.² These proteins shut down the immune system and prevent it from killing cancer cells. Anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4) and anti-programmed death-1 (anti-PD-1) drugs work by blocking surface checkpoint proteins on T cells. Blocking these drugs at their control is like taking a foot off the brake, which helps immune cells to better destroy cancer cells.

Anti-PD-1 and anti-CTLA-4 are common drugs used to treat cancers such as melanoma. However, timing is critical when deciding whether to use one or both. The research team collected blood and tissue samples from 36 melanoma patients every three weeks before and after checkpoint blockades were administered. The team constructed reference maps of expression levels from single-cell RNA and T-cell receptor sequencing to confirm T-cell states and track T-cell dynamics from week zero to week nine of the treatment program. These confirmed differentiated cells and migration patterns were then analyzed on the Cyclone to observe T-cell responses over time, Wang said.

Patients were divided into subsets and treated with either single or combined checkpoint blockades. From this data, the researchers found that patients in the PD-1 blockade group, who had been treated with a CTLA-4 blockade in their previous off-study cancer therapy, had a weakened immune response compared to patients in the same group without no therapy. In fact, Cyclone identified more diverse T cell states in the anti-PD-1 naïve group.

The research team suspected these results based on the reported characteristics of checkpoint inhibitors and team previous findings on PD-1 blockade in 2017.³ Anti-PD-1 recruits T cells to the tumor site until they are no longer available. With anti-CTLA-4 drugs, progenitor T cells are renewed in tissues and lymph nodes, and those cells can differentiate into battle-ready T cells. It is called the accumulation of new progenitor T cells and replenished T cells clonal replacement and has been important in turning the tide on many other cancers.⁴

For patients given the combination block, Cyclone measured large and diverse waves of T-cell responses after six and nine weeks of combination treatment. Dual checkpoint blockades also demonstrated that blocking CTLA-4 checkpoints maintained a pool of progenitor T cells that consistently contributed to the fight against cancer.

“Anytime you can get a real, mathematical synergy between drugs that is biologically explainable, that’s a wonderful discovery,” said Panna Sharmapresident and chief executive officer of Lantern Pharmawho was not involved in this study. “That means you can give less medicine, have more effective medicine, and everybody can be a winner.”

Sharma and his team are testing immunotherapies, such as checkpoint inhibitors, with other classes of drugs such as Molecules that damage DNA to safely and effectively fight cancers.⁵ Sharma hopes that unique combination treatments and tools like Cyclone will gain more traction among clinicians, who have intimate knowledge of patients’ individual treatment journeys.

Wang and Sharma share a similar list of cancers they think Cyclone could look at next: non-small cell lung cancer, Merkel cell carcinoma, head and neck squamous cell cancer, and kidney cancer. “We wanted to develop an immune monitoring tool that could be widely applicable in many other contexts,” Wang said. “So we can certainly apply the Cyclone assays to different types of cancer.”

The research team’s future goals are to test Cyclone in neoadjuvant trials, investigate epigenetic states, and evaluate new drug combinations, such as targets for PD-1 and the lymphocyte activation gene-3. “There is a lot of room to expand Cyclone to precisely observe the immune response from multiple angles,” Wang said.