Immuno-oncology (IO) is at a plateau, with myriad technologies experiencing success in limited patient populations and tumor types. “It’s nowhere near bursting its bubble,” stresses Jeffrey M. Bockman, VP, Defined Health, moderating the IO panel discussion at Biotech Showcase™ 2017.
Tito Serafini, President and CEO, Atreca
“This is the very beginnings of the field,” Ira Mellman, VP, cancer immunology, Genentech, points out. “Immunologists haven’t paid much attention to cancer. They focused on infectious agents. Cancer biologists focused on genetics. IO fell between the cracks. Now that it’s showing results, there’s a backlog of understanding. We are, essentially, trying to build the plane while we’re flying it.” Nonetheless, he says, “Using the immune system is one of the most important modalities we have to combat cancer.”
Tito A. Serafini, president and CEO, Atreca, concurs. “This is a 20-year endeavor to understand how to use the immune system. The sector is trying to develop an autoimmune attack that targets tissue the patient doesn’t want.” While much remains unknown about autoimmune disease, the IO sector is focused on using characteristics of that discipline to drive clinical efficacy for oncology. “It’s challenging, but there are opportunities.”
Many IO advances are discovered in the clinic. “The models we have to interrogate preclinically are extremely limited in their utility,” John Haurum, CEO, F-star GmbH points out, “so we go to the clinic without robust knowledge of what will work.” When effective approaches are identified, they are examined in the laboratory to determine the reason for those results and to identify the best model for that situation for future research. Model refinement is continual.
Given that reality, Robert Coffin, CEO of Replimune interjects, “There is every justification to taking logical, rational therapies to human trials early.”
Robert Coffin, CEO, Replimune
An embarrassment of riches
“IO has a diversity of molecular targets, cell types and pathways as well as a wide range of therapeutics that include antibodies, cell and gene therapies and oncolytic viruses. It’s almost an embarrassment of riches,” Bockman says. To optimize results, drug developers and clinicians must have a way to identify the most efficacious agents for individual situations and patient populations.
T cells are the foundation of IO. “There’s more to getting T cells to work better than just targeting them directly,” Mellman says. They have a complex biology that requires a series of events before they can be successfully combined with other therapeutics and delivered to tumors. “There’s a lot of immunology work involved, and a small body of knowledge. The next major breakthrough will be in that area,” he predicts.
“Oncolytic viruses can be a cornerstone for IO,” says Coffin, whose company develops oncolytic virus therapeutics. “They are active alone, but early data shows that using oncolytic viruses strategically, with immunomodulators, makes the tumor environment more susceptible to other drugs. Therefore, they may be a natural partner to other approaches, like checkpoint inhibitors, to create the environment those therapeutics need to elicit good responses.”
Haurum focuses on bispecifics. “This isn’t just combining drugs A and B. This technology offers a novel mechanism that preferentially agonizes T cells depending on the presence of a second signal, thereby eliciting activity beyond the additive effects of the two.” He predicts triplet combinations will emerge in the near future. Currently, his company is introducing new antigen binding sites to make bivalent antibodies that can inhibit or stimulate checkpoint inhibitors or agonists.
Consider fresh spaces
IO is extremely trendy now, which helps companies attract investors and partners. But, rather than being one of many companies in an existing niche, finding novel approaches that, hopefully, will capture imaginations in about eight years’ time, hundreds of companies are conducting combination trials with existing modalities, contributing to a crowded market with, often, little meaningful differential. Few of those compounds are likely to be commercialized. “Proof of concept isn’t the same as proof of relevance,” Bockman says.
For new approaches, Mellman encourages researchers to investigate the intercellular space. It’s only in the past two years that scientists clarified that T cells are attracted to mutant epitopes, he says. “Those mutants probably have other types of covalent mutations, and we know that neoantigens are protective in humans. The question, then, becomes what controls T cell response?”
He suggests that within five years researchers will be talking about immune set points for individual patients. Emerging data suggests those set points will be controlled by a few key things. Host genetics of the patient—not just the tumor—appear to play a role in regulating the immune response to cancer. “There’s a complement of genes that predispose individuals to certain conditions, changing their immune set points based on a combination of factors that include the microbiota and the environment. “Today, however, we don’t know how, or what to do about it. That’s where innovation and scientific courage are needed.”
Ultimately, the question isn’t whether very personalized or broad spectrum approaches are most effective. The immune system can eradicate tumors if it is harnessed properly. Today, researchers are working to determine exactly how, to allow more broadly applicable solutions that the plethora of approaches being advanced today may suggest.