Advances in the cancer-immunity cycle

By Laura Fraser, New York Times bestselling author

“The interest in cancer immunotherapy came long before there was a detailed scientific understanding of what was going on,” says Ira Mellman, Ph.D., Vice President, Cancer Immunology at Genentech. “Now, pairing our own scientific expertise with some of the brightest scientists outside our walls, our understanding of the cancer immune environment has totally transformed the way we think about cancer and cancer therapy.”

With the aim of creating new treatments, scientists have recently begun to unlock the mysteries of the immune system to discover the proteins, biomarkers, antigens, and T-cell receptors involved in cancer immunity. Initially, biotechnology companies have focused primarily on checkpoint inhibitors, molecules that block the proteins that jam the immune systems’ ability to recognize intruders. But while many patients have benefited from these medicines, others don’t, and scientists have begun to research why that is.

The key to this question may lie in a breakthrough intellectual framework for understanding the immune response to cancer, created by Mellman and Dan Chen, former Head of Development for Cancer Immunotherapies at Roche and Genentech. Their “cancer-immunity cycle” is an elegant, seven-step visualization of how cancer and the immune system interact with each other. “We came up with something that seems incredibly profound but was actually based on simple, obvious logic,” says Mellman.

“Creating a simple framework of the cancer-immunity cycle allowed scientists in the field to think about which parts of the cycle were important for mounting an immune response,” says Jane Grogan, Head of Adaptive Tumor Immunity and Cell Therapy at Genentech. “It gave us therapeutic targets.”

Genentech and Roche are working with partners along each step of the cancer-immunity cycle to find potential new treatments for various types of cancers. “It’s impossible for us to try to do all of this ourselves,” says Mellman, who came to Genentech after 20 years of teaching and research at Yale University School of Medicine. “Partnering allows you to identify, evaluate, and collaborate with individuals and companies that may have solved the problem you know you need to solve.”

Some partners’ technologies are designed to fit anywhere in the immunity cycle. Other approaches are specific to a particular step. Here are a few examples of partners working with Roche or Genentech to attack the cancer-immunity cycle at various steps.

It’s difficult for the human immune system to recognize cancers as invaders since cancer cells arise from the body’s own tissues. But in recent years, scientists have discovered that there are mutations in genes coding for proteins, called “neoantigens,” that set cancer cells apart from normal cells, even if only slightly. Neoantigens are as unique to an individual tumor as a fingerprint. By sequencing the genome of a tumor, it’s possible to identify those neoantigens and create an individualized neoantigen specific therapy – otherwise known as an individualized cancer vaccine – which is designed to deliver the neoantigen proteins back to the patient to educate and prime the immune system so the T–cells can precisely recognize and attack the cancer cells.

In 2016, Genentech partnered with BioNTech, a company that has pioneered the concept of truly individualized cancer vaccines and developed the technology to identify the right neoantigens for each patient and to generate specific vaccines against them. “We believe neoantigens may be the best approach to effectively harness the immune system against cancer,” says Don O'Sullivan, Global Head of Oncology Partnering, Roche Pharma Partnering.

Working together, BioNTech and Genentech’s approach is to treat cancer recognizing that each tumor is as unique as each patient. BioNTech analyzes the genomic sequence of each individual patient’s tumor to identify the most promising neoantigens to fight it. They insert the genetic information encoding these neoantigens into mRNA–a messenger molecule of the body, that BioNTech has specifically optimized to effectively provide that information to the immune system and activate it against the cancer. “The mRNA therapy is tailor-made to the patient because the mutations that cause cancer are random events, generating a specific tumor within each patient,” says Sean Marett, BioNTech’s Chief Business and Commercial officer. “The probability of matching, for example, two breast cancer tumors from two different patients is vanishingly small.”

According to Marett, BioNTech was attracted to working with Genentech partly because they have precision and experience in everything from manufacturing to clinical trials. “As a leading oncology company, they have a lot of know-how around developing and commercializing medicines,” says Marett. BioNTech also sought Genentech as a partner, he says, as they saw a chance to develop therapies that may be more effective when used together with other standard of care medicines. “Genentech and Roche have checkpoint inhibitors that decloak the cancer cells which could work synergistically with a cancer vaccine.” Already, the combination of these approaches is in early clinical trials.

Another way to enhance neoantigen-specific T–cells to target and kill tumor cells is to generate them in a dish and then infuse them into a patient. The challenge with “neoantigen-directed T-cell therapies,” as this approach is called, is being able to identify T-cell receptors (TCRs) that specifically recognize unique neoantigens within a patient’s own immune system and then engineer those receptors back into a patient’s own T-cells to fight the cancer. This requires actually sequencing the patient’s entire immune repertoire, not just the cancer. Genentech recently partnered with Adaptive Biotechnologies to develop these neoantigen-directed T-cell therapies.

“Adaptive Biotechnologies truly are the leaders in the identification of T-cell receptors specific to neoantigens,” says O’Sullivan. “Adaptive’s technologies are essential in making neoantigen-directed T-cell therapies a possibility.”

Harlan Robins, Ph.D., Co-founder and Chief Scientific Officer of Adaptive Biotechnologies, says that his company specializes in revealing how the immune system works. “We’re not studying cancer, we’re studying the immune response to cancer,” he says. The Adaptive team has built an immune medicine platform that allows them to take the genetic code of a tumor, identify the complementary T-cell receptors, and then map those receptors to the disease-related antigens. “We find the TCRs that bind to the cancer-related antigens, then funnel them down to the ones that enable strong binding, target killing and have minimal off-target effects, which can potentially be turned into medicines that might treat cancer,” Robins says.

“There are trillions of T-cell receptors, and the challenge is to pair a neoantigen on a tumor cell with a specific receptor,” says Jane Grogan. “Adaptive Biotechnologies is the only company that allows us to screen a patient’s tumor and T-cell repertoire so that we can work to create an individualized therapy.”

The partnership with Genentech marks Adaptive’s first foray into making medicines. “We created this technology, and after having discussions with multiple potential partners, we resonated with the team at Genentech because it’s a science-driven company,” says Robins.

He says that the Genentech and Adaptive scientists had a shared vision. “We’re committed to being able to develop personalized therapies for cancer patients, in real time. Hopefully in the not-too-distant future, we’ll be making a real difference in patients’ lives.”

For Genentech, this partnership also marks a new way of creating medicines for the long run. Genentech and Adaptive will have to work closely together to sequence tumors and T-cells in order to get personalized medicines to patients in a timely fashion. “We’re moving into a new frontier together,” says Grogan. “We have a meeting of the minds when it comes to science, and a shared excitement about the promise of this approach.”

Roche recently acquired Tusk Therapeutics, which has developed an antibody aimed at reducing regulatory T-cells (Tregs). These Tregs usually suppress immune responses, including those aimed at cancer cells. The antibody was engineered to reduce the harmful Tregs while limiting interference with other immune cells that act against the tumor.

The antibody targets CD25, which is a marker for the types of Tregs that block the immune system from attacking cancer. “We take away the brakes and push on the gas pedal with the aim of creating a specific immune response that is local to the tumor,” says Luc Dochez, who developed the medicine as CEO at Tusk Therapeutics.

“Developing new medicines is a lengthy, costly, and risky process, and as a small company you have limitations,” says Luc. “By partnering with Roche, we felt we could push the science faster, and our chances of ultimately succeeding in helping patients with cancer will significantly increase.” Luc says that the molecule may also work synergistically with other Roche medicines to hopefully make the treatment more effective.

Pablo Umaña, Head of Oncology Discovery, Cancer Immunotherapies at Roche, says that before he tested the Tusk molecule himself, he wasn’t sure it would live up to the claims. “We used a stringent test with the best clinical models at hand, and I was positively surprised to see the compound really targeted the regulatory T–cells, and by doing so, unleashed the conventional t-cell attack on the tumor,” he says. “We have a full project team dedicated to bringing this molecule as soon as possible to the clinic, and to identify which cancer patients will benefit from it best.”

“Many of these approaches are in the early stages, but they have the promise to fundamentally change the way we treat cancer,” Pablo says.

Genentech’s Mellman says that his group is currently studying more than two dozen cancer immunology agents. “The rate of discovery is shocking,” he says. Partnerships with other companies and scientists are critical to this progress. “We view our partners as colleagues, and they work really closely with us to understand and advance the science. Their goals are our goals, and our goals are theirs.” The result is a type of collaboration that is both unusual and essential in the quest to find more effective immunotherapies to treat cancer.