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February 10, 2017

All Antigens Are Not Created Equal

Unique Tumor Mutations Called Neoantigens Could Hold the Key to Personalized Cancer Therapies

All Antigens Are Not Created Equal

A generalized strategy for neoantigen identification, isolation, and therapeutic use. [NIH]

  • Imagine that you’re groping around wildly in a pitch-black room. You grab hold of what feels like a foot, and you decide to investigate further. Your findings: Toe-like shapes that include what seem to be hard-surfaced toenails. A soft, curving arch. A roughened, callused knob-like prominence—a heel, surely. All these sensations lead you to conclude that what you’re holding is most certainly a foot. But whose?

    You wonder if any barefooted people might be nearby. Suddenly, the overhead lights burst on and you see that you are sitting in the middle of an empty room, holding your own foot, like some sort of giant infant that has just discovered it has appendages. “How can this be?” you think to yourself. “How could I not recognize my own body?”

    This Serling-esque anecdote is meant to highlight the complex nature of the human immune system’s ability to recognize its own cells and tissues from foreign or diseased ones. Now, the immune system does not recognize objects quite the way we do. It achieves nothing like consciousness. But it does process sensations, after a fashion.

    The immune system dispatches marauding cells that can quickly determine if an encountered cell is something harmful that needs to be eliminated, or if it is something that contributes to the greater collective good. While these cells have evolved to be efficient and discriminating, biological scenarios often emerge causing these “immuno-bouncers” to become lax in their ID-checking prowess—cancer being the most notable of these circumstances.

    If immune cells were able to identify every aberrant cell type from healthy ones, cancer would be nothing to dread. It would be, at best, a minor annoyance, like a wart or a pimple. However, cancer can disguise itself from the immune system.

    The immune system not only tries to recognize cancer, it also attempts to subject cancer to adverse selective pressure. To cope, cancer doesn’t entertain fundamentalist arguments about whether or not selective pressure—an evolutionary mechanism—exists. Instead, in the game of survival, cancer is in it to win it. Cancer exploits evolutionary mechanisms of its own.

    Cancer uses mutational processes to deceive the immune system. Many cancers have become so adept at camouflage that they overexpress surface proteins that convince search-and-destroy immune cells to “stand down.” Such immune-evasion techniques underlie the development of cancer drug resistance and add to the difficulties in treating various tumors.

  • My Name is Neoantigen

    Unlike microbial pathogens, which present cell-surface antigens that are readily recognizable by the human immune system as foreign, tumors present antigens that reflect tumor cells’ origins as normal cells. Consequently, tumors may not appear to be a threat.

    Yet T cells do often recognize tumor-associated antigens (TAAs), which are typically overexpressed in malignant tissues. Since these TAAs have been identified as the targets of reactive T cells from isolated lymphocyte samples, researchers have become extremely interested in their potential as a source for the development of new cancer therapies. Unfortunately, attempts at either targeting TAAs with high-affinity T cell receptors (TCRs) or expression of these antigens in normal cells has led to unproductive outcomes, and in some instances, severely toxic side-effects.

    TAAs of another class have existed that are exclusive to tumors but have remained just outside the reach of scientists. These TAAs are the so-called neoantigens. They represent high-value therapeutic targets, but their uniqueness within individual patients has previously hampered the development of personalized TCR-based treatments. In this post-genome, precision-medicine age, however, advancements such as massive parallel sequencing—or next generation sequencing (NGS)—are making personalized treatments a reality and allowing scientist to another look at neoantigens as a legitimate treatment option.

    Neoantigens typically arise from somatic mutations in tumor cells, thus preventing them from undergoing thymic tolerance, giving researchers an exploitable advantage over other TAAs. For instance, as mentioned previously, when self-TAAs are expressed in normal cells, they often trigger central and peripheral tolerance mechanisms that lead to the selection of T cells with low-affinity TCRs. In fact, T-cell reactivity to self-TAAs is achieved only when the tolerance mechanisms are not fully developed—representing a very minute fraction of occurrences. Moreover, it is the lack of thymic tolerance that allows cancer patients to mount an immune response when they are treated with immunotherapy checkpoint inhibitor molecules against CTLA-4 and PD-1.

    With the rapid advances and plummeting costs of genomic analyses by NGS technologies, the true goals of precision medicine are beginning to be realized. NGS allows researchers to quickly scan the mutational range of individual tumors—the so-called mutanome—for neoepitopes that have high antigenicity potential. Interestingly, research in this area has revealed that solid tumors can contain thousands of somatic mutations, many of which can serve as neoantigen targets for personalized immunotherapy development.

    NGS analysis, however, isn’t the only technique that can be employed to determine neoantigen targets. As sequencing technology has advanced, so too have the computational tools used to assemble and accurately identify the somatic mutations leading to potential target neoepitopes. Neural networks such as NetMHC or entire workflow programs such as pVacSeq are used in silico to analyze the acquired mutanome sequence and predict neoepitopes that should bind to the patient’s own HLA class I molecules and elicit, potentially, a specific immune response. Continuing with this reverse identification approach, the identified peptides are synthesized and could potentially be used therapeutically, analogous to a vaccine. Direct identification of potential neoantigens is also a possible strategy, through the identification of antigenic peptides bound to HLA molecules from patient-derived tumor tissue. This approach, however, requires numerous additional steps, typically incorporating fractionation by high-performance liquid chromatography and identification by mass spectrometry.

  • Collaboration Breeds Innovation and Success

    Current research into neoantigen detection and identification has not gone unnoticed by the biopharmaceutical industry. With immunotherapy compounds seeing continued clinical success in recent years, and with estimates of the cancer immunotherapy market alone approaching $120 billion by 2021, companies are looking for improved or complementary drug targets that will enhance patient care and secure them a footing in this burgeoning field.

    FDA-approved immuno-oncology compounds have primarily targeted immune checkpoint molecules (PD-1 and CTL4). These compounds have enjoyed some success under specific circumstances, but seldom as first-line drugs. Neoantigen targeting, however, represents truly personalized medicine and potential aid for many patients who would otherwise have little to no therapeutic options.

    Recent announcements by various companies show the level of commitment these organizations have toward the development of neoantigen identification technology for personalized cancer care. For example, Aduro Biotech recently entered an exclusive license agreement with Stanford University for state-of-the-art neoantigen identification technology developed by Hanlee Ji, Ph.D., associate professor of medicine at Stanford.

    The company explained that it would leverage its proprietary live, attenuated double-deleted Listeria (LADD) immunotherapy platform to engineer personalized LADD (pLADD) cancer therapies encoding multiple neoantigens identified through this technology. The company plans to initially evaluate pLADD for the treatment of cancers of the gastrointestinal tract, including colorectal cancer, with a Phase I clinical trial expected to be initiated in 2017.

    Additionally, Neon Therapeutics, which has already been developing neoantigen-based therapeutic vaccines and T-cell therapies to treat cancer, just announced the successful completion of a $70 million Series B financing—the proceeds from which will be used to advance its lead program NEO-PV-01, a personalized neoantigen vaccine, through an ongoing Phase Ib clinical trial. In addition, this investment will support preclinical development of NEO-PTC-01, a personalized adoptive T-cell program, and the company’s Shared Neoantigen Program.

    Finally, this past December, the Parker Institute for Cancer Immunotherapy and the Cancer Research Institute launched a new collaboration on cancer neoantigens, entitled TESLA for tumor neoantigen selection alliance. TESLA is set to include 30 of the world’s leading cancer neoantigen research groups from both academia and industry to test algorithms that predict tumor markers from DNA in the hunt for new personalized cancer treatments.

    Industry participants include Advaxis, Agenus, Amgen, BioNTech, Bristol-Myers Squibb, Genentech, a member of the Roche Group, ISA Pharmaceuticals, MedImmune, the global biologics research and development arm of AstraZeneca, Neon Therapeutics, and Personalis. Research institutes involved include the Broad Institute, Caltech, the Dana-Farber Cancer Institute, the La Jolla Institute for Allergy and Immunology, the Ludwig Institute for Cancer Research, the Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, the University of California, Santa Cruz, the University of Connecticut, and Washington University School of Medicine.

    These collaborations represent only a small fraction of the neoantigen projects currently underway, but they reflect the widespread belief in the neoantigen-based approach to personalized medicine. This approach, once brushed aside by many scientists and organizations, used to be fraught with technical and developmental difficulties. Now, however, with the availability of advanced technology, it is becoming a reality.

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