Progress in medicine requires going beyond what’s known in order to reveal new fundamental truths about human biology. Today, no area encapsulates this search better than cancer immunotherapy.
“The rate of discovery in this space is shocking,” says Ira Mellman, Ph.D., Vice President, Cancer Immunology. “In just the last year the number of immunotherapy targets has increased by 30 percent, and there are now more than 3,300 agents under clinical or pre-clinical investigation.”
Within this enormous body of research, Genentech scientists have zeroed in on one particular area — neoantigens, proteins generated by tumor-specific mutations — that could have significant potential in treating cancer. Tumor cells share a majority of their DNA with healthy cells, but looking deeper, there are areas where tumor DNA is distinct. It’s these differences, which manifest as neoantigens, that offer a ‘seek-and-destroy’ signal for our immune systems to home in on.
“The concept of using neoantigens to elicit an immune response is well known and has been used to predict responses to checkpoint inhibitor therapy, as well as in the design of our personalized cancer vaccines,” says Jane Grogan, Ph.D., Principal Scientist, Cancer Immunology. “Personalized cancer vaccines, which we’re currently testing in clinical studies, work by training our immune systems to recognize the unique neoantigens associated with a person’s cancer.”
To further explore the science of neoantigens, Genentech will partner with Adaptive Biotechnologies, a leader in immune-driven medicine, to develop a new type of cell therapy that targets an individual’s tumor-specific proteins*.
“The cell-based approach — what we’re calling neoantigen-directed T-cell therapies — builds perfectly on what we’re doing with cancer immunotherapy. But instead of training the immune system, we’re synthetically rewiring it by engineering a person’s own T-cells with receptors that recognize their cancer’s neoantigens,” says Mellman.
A “Neo” Partnership
Cell therapies vary in their specifics, but the general concept is the same: a specific subset of a person’s immune cells, called T-cells, are extracted, modified, multiplied and reintroduced into the body to attack and destroy tumor cells. For neoantigen-directed T-cell therapies, this means genetically engineering a person’s T-cells with receptors that recognize their own tumor-specific neoantigens. The big challenge, though, is choosing the right neoantigen to target for each patient, and the right receptor to target those specific neoantigens. Each person’s T-cells carry an incredibly diverse and unique collection of receptor types that are generated to recognize foreign cells.
“This is the reason we are looking to partner with Adaptive Biotechnologies,” says Don O’Sullivan, Ph.D., Global Head of Oncology Business Development. “They truly are the leaders in the identification of T-cell receptors (TCRs) specific to neoantigens. Their proprietary sequencing platforms and neoantigen-TCR matching technology are essential in making neoantigen-directed T-cell therapies a possibility.”
Adaptive Biotechnologies has focused on a number of “shared” neoantigens that have been found in the cancers of more than one person, and have built a complementary library of TCRs. This library offers a starting point to begin developing neoantigen-directed T-cell therapies that could be tested in small groups of people, with more individualized TCR identification to come.
“When it comes to immunosequencing, there isn’t anyone that can identify TCRs with the breadth, depth and speed at which Adaptive Biotechnologies is able to. Combine that with our rich experience and expertise in cancer immunotherapy and you could have a really effective partnership,” says Anna Williamson, Ph.D., Director, Oncology Business Development.
The partnership’s focus on neoantigens will also have a potential advantage in that these targets exist universally across cancer types. That means neoantigen-directed T-cell therapies could possibly be used in many different cases, including in solid tumors. This approach represents a natural progression in the personalization of cancer immunotherapy, says Mellman. “We know how critical neoantigens are, and we think neoantigen-directed T-cell therapies have the potential to be an incredibly effective way of reshaping a person’s immune system to fight cancer.”
*The completion of this agreement is subject to customary closing conditions, including clearance under the Hart-Scott-Rodino Antitrust Improvements Act, and is expected to occur in the first quarter of 2019.