Neoantigen vaccines are being touted by some as the next big cancer treatment breakthrough. Here, we explore how these vaccines work and the companies looking to bring them to market.
Immunotherapy has taken center stage in the fight against cancer.
Broadly, this type of treatment directs a patient’s immune system to attack cancer cells. Some immunotherapies target the disease by going after antigens, which are substances (usually made up of proteins) present on a cancer cell’s surface.
But sometimes, normal cells also express certain antigens — so destroying them en masse poses a big health risk.
WHAT ARE NEOANTIGENS?
Neoantigens are protein fragments found only on cancer cells. Due to their unique nature, targeting them would allow a patient’s immune systems to find and attack cancer cells, while leaving healthy cells alone.
Since the first human clinical trial using such neoantigen vaccines was conducted in 2015, interest in the space has climbed.
Cancer cells are difficult to trace, due to their uncanny ability to continuously adapt to different environments. Neoantigens present a new, sophisticated way to go after the disease.
While this is still a new area of research, with only early data available, we’re already beginning to see both incumbents and upstarts invest in the space.
Below, we dive into how neoantigen vaccines work and why this technology may hold the key to curing cancer.
TABLE OF CONTENTS
- Neoantigen vaccines lead to more personalized medicine
- How neoantigen vaccines work
- Where the research is now
- First clinical trials
- Companies developing neoantigen vaccines
- What’s next?
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Neoantigen vaccines lead to more personalized medicine
Cancer is tricky, in that rapid growth of abnormal cells can often bypass many defense mechanisms, going undetected by the immune system. Moreover, antigens are often expressed on normal cells as well as cancerous cells, making the body vulnerable to attacks in the wrong places.
This is where neoantigens step in.
NEOANTIGENS ARE CANCER-SPECIFIC MUTATIONS
Imagine neoantigens as radio antennas sitting on the surface of cancer cells.
The goal is to find these antennas and trigger white blood cells known as T cells, which fight virus-infected cells, to attack cancer cells.
Since only cancer cells express neoantigens, they are ideal targets for the immune system to attack without harming normal cells. If researchers can predict which antigens are on a patient’s tumor, they could nudge the immune system to go after them.
A general cancer immunity cycle. Source: Bioorganic & Medicinal Chemistry
There are two subtypes of neoantigen:
Shared neoantigens, which are not unique to an individual or tumor type. Two different people may present with the same neoantigens.
Personalized neoantigens, which are highly specific to an individual’s tumor.
Certain cancers see higher rates of mutation, which result in more neoantigens being created. This is actually preferable, since more neoantigens means more targets for the immune system to go after.
This happens with cancers such as melanoma (skin cancer) and lung cancer, which is why new clinical trials exploring the use of neoantigen vaccines are targeting these cancers. In fact, all 3 key clinical trials using neoantigen vaccines since 2015 have targeted melanoma.
NEOANTIGEN VACCINE DELIVERY PLATFORMS
Vaccines often consist of weakened or dead forms of the germs they are trying to target. In this case, researchers are looking to develop personalized neoantigen-based vaccines that can be injected into patients to help stimulate an immune response.
In addition to selecting which neoantigens mount the strongest immune response, researchers are also currently conducting studies to assess which neoantigen delivery platforms are the most effective.
Each vaccine platform presents its own set of benefits and drawbacks, due to the different biological properties of each type, but all seek to leverage neoantigens to elicit anti-tumor responses.
Below are the main vaccine platforms being used in neoantigen vaccine research. There are several early clinical trials in progress that employ these various vehicles.
Synthetic long peptide (SLP) vaccine: The peptide vaccine tends to be the most commonly used in clinical trials. This type can call on both types of T cells (the body’s defender cells) to elicit an immune response.
However, unlike other platforms, the SLP vaccine requires an extra ingredient in the vaccine: an adjuvant, which must be administered with the neoantigens for the vaccine to work properly and activate an immune response.
RNA vaccine: RNA molecules (DNA’s cousin) that result in neoantigen peptides can also be used as a vaccine platform to target cancer cells.
These are beneficial in that they don’t need an additional molecule (adjuvant) to stimulate an immune response — because RNA is the genetic material of many pathogens, our immune systems are already on alert for these molecules. However, this delivery platform can be harder to manufacture.
Dendritic cell vaccine: Dendritic cells play an important role in immunity as Antigen Presenting Cells (APCs): they process antigens and present them on cells’ surfaces, which then stimulates a response from T cells. Drawbacks include high costs and the labor-intensive process to create them.
Virus or bacteria-based delivery platforms (aka vectors) are also being manipulated to carry neoantigens in these vaccines. A type of bacteria called Listeria monocytogenes has emerged as a potential promising option.
How neoantigen vaccines work
Since neoantigen vaccines are personalized to a patient’s specific tumor profile, there are several steps that have to be taken before they can be administered.
Most researchers use the in silico approach, which uses algorithms to predict which neoantigens will cause the immune system to act most effectively according to a patient’s tumor profile.
Conversely, some opt for an ex-vivo approach, where tumor cells are extracted and experimented on to identify which neoantigens create which effects.
Although there is some variability among different companies developing these vaccines, these are the general steps that go into making a neoantigen vaccine:
Take a biopsy of the tumor. A sample of the tumor is taken surgically from the patient for further laboratory testing. This allows more detailed insights to be deduced about the tumor’s profile.
Conduct sequencing & computational analysis. Researchers then sequence the exomes (the part of the genome that ends up actually creating proteins) of both the tumor and normal cells. This allows researchers to look for unique mutations in tumor cells, such as extra DNA base pairs being inserted or deleted.
Predict and select the specific neoantigens to target. This step involves identifying the neoantigens (the patient’s specific tumor mutations) that are more likely to cause the patient’s immune system to react and attract T cells to go after cancer cells. Many companies are training their data and developing their own predictive algorithms for doing this with a higher degree of precision.
Develop the personalized vaccine. Based on the predicted neoantigens that can stimulate one’s immune system to mount an attack on the cancer cells, a personalized vaccine is engineered using a delivery vehicle (e.g. peptide, RNA, etc.).
Administer the neoantigen vaccine. After the vaccine is created and manufactured, it is administered to the patient.
CHECKPOINT INHIBITORS CAN BOOST NEOANTIGEN VACCINES’ EFFICIENCY
Some companies couple these vaccines with another class of immunotherapy treatments — checkpoint inhibitors — in order to strengthen the immune system’s attack on cancer cells that may still escape.
“The neoantigen vaccine is like the steering wheel, to guide the immune response … the checkpoint blockade is removal of the brakes.” — Nir Hacohen, Director of the Center for Cancer Immunotherapy, Massachusetts General Hospital in Charlestown
Normally, the immune system uses T cells to hunt down foreign pathogens like bacteria or viruses, then deploy other immune cells to attack.
But cancer cells are unique in that they are able to avoid detection by immune cells.
In fact, cancer cells can hide behind a “shield” on their cells’ surface and trick T cells. This allows cancer cells to blend in with normal cells and avoid triggering an immune attack.
This is where checkpoint inhibitors come in.
Checkpoint inhibitors can stop cancer cells from “tricking” T cells, allowing the T cell to properly identify and attack the cancer cell.
Source: National Cancer Institute
Checkpoint inhibitors make up a core class of immunotherapies that have seen approved drugs enter the market since 2011. They’re usually administered intravenously.
Using this treatment with neoantigen vaccines in a combination therapy could result in a higher rate of efficacy in eradicating cancer cells.
Where the research is now
Neoantigen vaccines are still new in the cancer immunotherapy space compared to veteran therapies like checkpoint inhibitors.
And while there were studies done in the 2000s that demonstrated the relationship between the immune system and neoantigens, human studies are just starting to take off.
FIRST CLINICAL TRIALS USING NEOANTIGEN VACCINES
The first human clinical trial using a neoantigen vaccine published its results in 2015.
The study enrolled 3 melanoma patients, who each patient received a vaccine with dendritic cells as the vaccine platform. The results showed that the delivery of these neoantigens stimulated more T cells to be produced. This indicated that the vaccine essentially reminded the immune system to react to the cancer cells that needed to be attacked.
In 2017, two additional studies published results on examining the efficacy of neoantigen vaccines in humans.
Two co-founders of neoantigen company Neon Therapeutics — Nir Hacohen and Catherine Wu — helped conduct one of those studies. In the study, a peptide-based neoantigen vaccine composed of up to 20 neoantigens was administered in 6 melanoma patients. Within 2.5 years, 4 of those patients were cancer-free. The remaining 2 patients became cancer-free after receiving an additional treatment with checkpoint inhibitors.
The study design is described in the image below:
In the other 2017 study, Ugur Sahin at Johannes Gutenberg University of Mainz in Germany used RNA molecules to create the vaccines, each with a mix of 10 neoantigens.
These vaccines were given to 13 patients with melanoma. Within 12 — 23 months, 8 patients became cancer-free with an additional patient seeing a complete regression after treatment with a checkpoint inhibitor.
Sahin is the founder & CEO of the Germany-based cancer therapeutics company BioNTech.
As mentioned above, melanoma (an aggressive type of skin cancer) was the key target for all 3 of these clinical trials, due to the high mutation rate that makes it easier to attack the cancer using neoantigens.
COMPANIES CREATING NEOANTIGEN VACCINES
Drug companies are using different techniques and platforms to develop their own proprietary neoantigen vaccines. Below, we take a look at some of the main players in the space and the progress they’ve made.
As mentioned above, Germany-based BioNTech is a key player in the neoantigen vaccine space.
Its Individualized Vaccines Against Cancer (IVAC) Mutanome platform engineers RNA molecules to make custom neoantigen vaccines, while its FixVAC treatments target shared antigens among cancer patients.
BioNTech has pending clinical trials using its IVAC Mutanome platform targeting triple negative breast cancer, melanoma, and multiple tumor types. According to the company’s pipeline, one of the trials is in partnership with pharma company Genentech.
BioNTech has raised a total disclosed funding of $270M from investors such as Fidelity Investments and Redmile Group. It also announced a $120M mRNA-based flu vaccine partnership with Pfizer this August.
Genocea Biosciences‘ ATLAS platform uses an ex-vivo method to create personalized neoantigen vaccines — a unique method among other companies in the space that use in silico, or algorithmic-based methods.
Before going public in 2014, Genocea had raised $91M from key healthcare investors such as Polaris Partners, GlaxoSmithKline, and Johnson & Johnson Innovation.
Its lead neoantigen cancer vaccine, GEN-009, is currently recruiting for patients in a Phase 1a/2 clinical trial targeting cancers including melanoma, lung cancer, and carcinomas.
Genocea’s latest data, presented at Society for Immunotherapy of Cancer’s (SITC) 33rd Annual Meeting last month, showed the possibility of “inhibitory” neoantigens that increase tumor growth being present in mice models. This new data suggests that immune system responses could also be manipulated by this new class of neoantigens that promote tumor proliferation.
Neon Therapeutics has also been a prominent player in the neoantigen space, with two of its co-founders (Nir Hacohen and Catherine Wu) having conducted a key clinical trial, mentioned above. In fact, Neon’s drug pipeline is the result of continued research efforts from the Broad Institute of MIT and Harvard, along with the Dana-Farber Cancer Institute.
Like others in the space, Neon’s drug pipeline includes a personalized vaccine (NEO-PV-01) and with a shared antigen vaccine (NEO-SV-01) to administer in multiple patients.
Phase 1 clinical trials started in 2016, consisting of a neoantigen vaccine made out of a synthetic peptide with the addition of the checkpoint inhibitor Nivolumab. The trial is targeting melanoma, smoking related non-small cell lung cancer (NSCLC), and bladder cancer.
Neon raised $161M in total disclosed funding before going public this August. Investors have included Third Rock Ventures, Nextech Invest, Access Industries, and Wellington Management.
Gritstone Oncology approaches the neoantigen vaccines with an in silico approach, using its proprietary AI platform EDGE to predict which neoantigens will result in a higher likelihood of deploying immune cells.
It has two neoantigen products: GRANITE-001 is an individual treatment based on each patient’s specific tumor profile, while SLATE-001 is used for multiple patients that have certain neoantigens in common.
Currently, Gritstone has one international Phase 1/2 clinical trial targeting advanced solid tumors (lung, gastro-esophageal, bladder, and colorectal cancers). The trial is slated to begin in October 2018 but has not started recruiting for patients yet.
Gritstone recently went public in September after raising $195M from investors such as Versant Ventures, Clarus, and Google Ventures.
Biotech company Agenus is developing its AutoSynVax (ASV) neoantigen vaccine, which is administered with an adjuvant in solid tumor patients. It is currently conducting a Phase 1 trial.
Since 2016, mRNA-focused cancer therapeutic company Moderna Therapeutics has partnered with pharma giant Merck to create mRNA-based personalized cancer vaccines with Keytruda, an antibody that helps the immune system detect cancer cells.
What’s next for neoantigens?
Current challenges with neoantigens include the lag time involved in the formulation and manufacturing of personalized vaccines.
Because each vaccine is specific to a patient’s tumor profile, it takes time to extract the tumor sample, predict which neoantigens will stimulate the ideal immune response, create the vaccine, and then administer it. But as these processes get more refined in the future, these timelines could possibly be shortened.
For now, neoantigen vaccines are still relatively new methods in fighting cancer.
So far, only small-scale Phase 1 clinical trials have been conducted, mostly focusing on high mutation cancers like melanoma or non-small cell lung cancer. As drug companies ramp up more Phase 2 trials and are able to demonstrate the efficacy of their respective vaccines, we could see this area becoming a larger focus of research.
In particular, combination therapies using checkpoint inhibitors or chemotherapy could be more prevalent as researchers learn more about neoantigens.
We’re also seeing different ways to manipulate immune cells to go after neoantigens. So far, research has largely focused on the injection of neoantigens to stimulate T cells to attack tumor cells — but there’s also emerging research looking at other tactics as well.
For example, Ziopharm Oncology‘s Sleeping Beauty neoantigen product aims to engineer T cell receptors (TCRs), which sit on the surface of T cells and can identify neoantigens and kill the tumor cells.
This transfer of genetically-modified T cells presents another way to target neoantigens and could potentially be used as a dual therapy along with neoantigen vaccines.
As more scientific data reveals the efficacy of neoantigen therapies and how it affects different cancer types (with both low and high mutation rates), the neoantigen space is shaping up to be a promising area of cancer research.