SIRPα: A New Chapter in Cancer Immunology Research

It’s a summer afternoon and a patient is waiting in a clinic in Belgium to receive their first treatment in a clinical trial. Little do they know that thousands of miles away, scientists in the USA are holding their collective breath as they wait for news. This is the first time a patient will receive the potential new cancer treatment that they have spent years researching and refining in collaboration with scientists at OSE Immunotherapeutics.

Sergio Trombetta and Kerry Ralph, scientists at Boehringer Ingelheim, are two of those researchers. Sergio is leading a team of scientists working on a completely novel approach to treat cancers, pursuing a new target and trying to awaken a different part of the immune system that no approved drugs are currently targeting.

“The first time a patient receives the medicine we have been working on is such an important milestone. We wonder how they’re doing in the first 10 minutes, the first hour, the rest of the day, that first night... This is the reason we come to work every day.”

That’s why Boehringer Ingelheim is taking cancer on by working on innovative approaches to fight cancer on two fronts – boosting the body’s immune response against cancer at the same time as developing drugs that target cancer cells directly.

Sergio’s team is looking at ways to mobilize the immune system as part of Boehringer Ingelheim’s cancer immunology research strategy. This is complex work, as the immune system has two different branches. Innate immunity – or natural immunity – is what we are born with and is the body’s first line of defence. Adaptive – or acquired immunity – is immunity that builds over time in response to specific threats. While several of the more notable cancer immunotherapy treatments activate adaptive immunity pathways, Sergio and his team are exploring a research path scientifically less travelled by investigating a new target in the innate immune system – signal-regulating protein alpha or SIRPα.

Developed in collaboration with OSE Immunotherapeutics, Boehringer Ingelheim’s potential first-in-class SIRPα monoclonal antibody BI 765063 selectively blocks the SIRPα/CD47 interaction pathway. This restores the capacity of macrophages to attack tumor cells directly and enhances anti-tumor immunity.

“SIRPα offers patients a completely different approach to what’s already being used in the clinic in oncology. It’s a target that only a few research groups are working on and mobilizes a different part of the immune system. It’s a completely fresh angle and may have great potential to enhance treatment options in cancer as part of a combination treatment approach.” 

SIRPα is found on macrophages and dendritic cells, some of the key myeloid cells of the innate immune system. Macrophages are large, specialized cells that recognize, engulf and destroy target cells. In fact, the term macrophage is derived from the Greek words "makro" meaning big and "phagein" meaning eat. Dendritic cells play a central role in controlling the immune response and act as messengers between innate and adaptive immunity. The distinct properties of these cells have led researchers to consider them an important new class of targets for cancer immunology research.

SIRPα is part of the CD47/SIRPα pathway that controls the activation of macrophages and dendritic cells. CD47 is a surface molecule on numerous cell types including tumor cells and is often associated with poor prognosis. In many cancer types, CD47 forms a potent ‘don’t eat me’ signaling complex with SIRPα that triggers a cascade of events that enables cancer cells to avoid detection by the innate immune system and inhibits the ability of macrophage cells to fight cancer.

Early clinical results recently presented at the American Society for Clinical Oncology Annual Meeting (ASCO) are encouraging. BI 765063 was well tolerated with no dose-limiting toxicities and showed preliminary anti-tumor activity, with clinical benefit observed in 45% of patients, and one patient with liver cancer demonstrating a maintained tumor shrinkage of 55% after 9 months.¹

This is another milestone that Sergio and his colleagues have been working towards.

“It’s quite encouraging when clinicians have something good to report, and we have been fortunate to have this case presented at ASCO. It’s still very early to draw conclusions from this, but nevertheless, when it happens, it’s exciting for us.”

If all goes according to plan, Sergio believes SIRPα is a target that offers enormous promise for patients, not only through clinical benefits, but also by opening the door to more and better treatments. “If we can show that targeting this type of cell in this fashion could be beneficial, maybe we can improve on this and go for other targets of a similar nature. By doing things that have not been done before and targeting a branch of the immune system that has not been targeted before, it could teach us a lot and supports our ambition to be first4patients.”

References

1. Champiat et al. Safety, pharmacokinetics, efficacy, and preliminary biomarker data of first-in class BI 765063, a selective SIRPα inhibitor: results of monotherapy dose escalation in phase 1 study in patients with advanced solid tumors. Poster Presentation #2623, American Society of Clinical Oncology Annual Meeting, June 4-8, 2021.