Cary Pfeffer M.D. is a Partner at Third Rock Ventures and the Chair of Neon Therapeutics, a biotech startup company that deploys the most cutting-edge sequencing technology and neoantigen prediction methods to develop personalized cancer vaccines. The Pulse had a chance to discuss with Dr. Cary Pfeffer about the opportunities and challenges with personalized cancer vaccine.

Pulse: Could you briefly introduce the concept of personalized cancer vaccine and the history of its development?

CP: I am not sure I know the full history of personalized cancer vaccine but I could certainly tell you about Neon and how it is developed there. First of all, the concept of cancer vaccine has been around for a long time. People have tried to develop cancer vaccines for 30 years or longer. In most cases before the last 5 years, people used tumor associated antigens, different types of cytokines, and in some cases cell type specific markers to go against cancer. I think one of the issues with these approaches is the lack of efficacy. One of the most recent large trial failures was GSK’s MAGE-A3 cancer vaccine. It targets a tumor associated antigen that is found commonly on other tissues, but more prevalently on tumors. The common issue with all the previously developed cancer vaccine is, first of all, they haven’t shown much efficacy. Even if they were to show efficacy, the issue is that all the tumor associated antigens are also on normal tissues. Because of these issues, two things can happen. On one hand, if you were to get significant immune reaction, you’d also get immune reaction to normal tissues, which obviously will cause a lot of toxicity. On the other hand, one could argue that you don’t get that strong an immune reaction, because given that these antigens are also on normal tissue, they go through a process called immune tolerance. This is a process that the immune cells are specifically trained to not target normal tissue antigens. so, it would be very unlikely for you to get a very significant immune response against the normal tissue antigen. All the antigens that we have tried until several years ago, even if they are tumor associated antigens, they would still exist on normal tissues. So, you would not get a very significant immune response. That gets to what is different about personalized cancer vaccines that Neon is developing. The whole new area of neoantigens has taken hold in the vaccine space. A neoantigen is an antigen that specifically and only exists on the tumor tissues. In most cases, that specific neoantigen only exists on that specific patient’s tumor tissue and not other people’s tumor. Hence, it needs to be personalized. The reason for why that becomes exciting for us and creates a new surge of interests in cancer vaccines is because now you have an antigen that has not gone through normal human immune tolerance process. This means that just like a viral antigen or other types of foreign antigens to the body, you should be able to generate robust immune response with the neoantigen. In fact, that has been shown in some of the trials. So far, Neon as well as other people have shown that if you target these neoantigens that only exist on the tumors, in fact you can produce a robust immune response, similar to the level of immune response that one might get with a viral antigen. The other exciting fact is that you only go against the antigens that only exist on the tumors, so, at least in theory, you should significantly eliminate that issue of toxicity where your immune system might also attack normal tissue. These antigens don’t exist on normal tissues, so that should not be an issue.

The other thing that has happened in the last few years and that has made personalized cancer vaccines more feasible is the capability of measuring immune response, which does not exist before. Today, we can actually look at the T Cell Receptors that are created on the surface of T cells that you need to bind to these neoantigens, and you could assay for them. So after we inject neoantigens into a patient, we could then very clearly test to see whether any of the T cells are created in that patient’s body that has specific TCRs against the neoantigen that we injected. That capability has only recently been invented in the last 5 years or so and it was not possible to do before. Our ability to measure immune response, to target neoantigens that don’t exist on normal tissue to reduce toxicity, and to allow robust immune response with neoantigens are the three key things that have changed in the last few years, which have made personalized neoantigen cancer vaccines more feasible. That’s why a bunch of companies are going after neoantigen based cancer vaccine.

Pulse: What are the major technology advancements in the past few years that support and enable these scientific breakthroughs for personalized cancer vaccine?

CP: The sequencing ability has been an important factor, because to create the vaccine we have to be able to quickly sequence patients’ tumors. Then, there are algorithms that have been created to predict the neoantigens that we think would be most immunogenic. Neon has its own unique algorithm platform to do these predictions. That predictive capability on the bioinformatics side is the technical capability that is still being developed and improved, and the capability to measure the immune responses didn’t exist until recently.

Another important piece of technical advancement is the capability of making the vaccines. Most pharma companies make products that are ‘one size fits all”. For its personalized cancer vaccine, Neon uses peptides as vaccines, and some other companies use mRNA. But in either case, in order to produce the cancer vaccine, you have to get the tumor biopsy from the patient, followed by sequencing and then perform algorithm predictions to identify the right neoantigens. Then, you have to make the personalized vaccine by peptide synthesis or mRNA synthesis for each individual patient. All these steps need to be finished in a reasonable amount of time and at a reasonable cost, otherwise it is not commercially viable. That is why a lot of pharma companies do not want to bother with, because you have to go through the whole process with every single patient. Typically, when you make the drug, you make grams of the drug. With personalized cancer vaccine, you have to make very small amounts but you have to make it separately for each patient. That is very challenging because it is an on-going manufacturing process, and for each patient you have to go through the whole manufacturing process to make the vaccine specifically for that patient.

Pulse: As a personalized therapy, what would be the pricing strategy for cancer vaccine, compared to other current immunotherapies or other personalized medicine on the market?

CP: Current immunotherapies are not personalized and it is used as sort of a chronic treatment. It is not clear yet to us what the dosing requirement is for personalized cancer vaccine. Right now, the standard way that vaccines are given, in general, is that it is given a few times, including an initial dose, and then there are multiple boosting doses. When patient get fully vaccinated, no more dose will be given. For personalized cancer vaccine, we don’t know yet whether you have to give more often or to give every three months to continue to maintain the immune response. Without knowing that, it is hard to know what the price strategy will be at this point. For gene therapy, you just give one dose and cure the disease, but with cancer vaccine, you might have to give multiple does or continue the doses depends on how well the immune responses are maintained. We just don’t know yet. Nevertheless, the pricing strategy has to be carefully considered in order to reveal the value for the medicine.

Pulse: How would you expect payer to respond to personalized cancer vaccine?

CP: We don’t know yet. If it brings similar benefit as other cancer therapies, then we’d expect the payers to pay a price that is in line with those therapies. If it is highly effective and almost curative in a lot of cases, then the payers are more willing to pay a higher price. In the end of the day, I think cancer vaccines are not going to be used unless they are very effective. The hope is that the Pharma/Biotech companies charge what make sense given the efficacy of the cancer vaccine.

Pulse: When we talk about ‘vaccine’, we usually think it as preventive. Here, with cancer vaccine, we are talking about therapeutic vaccines. Do you think cancer vaccine can become preventive someday? If so, what are the major technical hurdles we need to overcome?

CP: It is an interesting point. Yes, today cancer vaccines are mostly viewed as therapeutic not preventive. It is probably more likely that cancer vaccines are going to be most effective in the setting where the tumor burden is relatively low. Most experts would say that a cancer vaccine by itself is not going to have the ability to significantly reduce large tumor burdens in the body. We could either use the cancer vaccine in combination with another therapy that does reduce tumor burden, in which case the vaccine acts as a cleanup mechanism, or use the cancer vaccine in adjuvant with surgery treatment. Using cancer vaccines as preventive is challenging, because for personalized vaccine, you need to know what the neoantigens are from the tumor in order to make the personalized vaccine. If you don’t have tumor, then you cannot really make the vaccine.

Pulse: For tumor types that are more common, would you expect shared neoantigens among a group of people so that you could develop preventive cancer vaccines?

CP: That is possible if you could identify shared neoantigens that exist in the tumors across many patients. It turns out that we have done a lot of related work at Neon. There are some shared neoantigens that do exist across small patient populations, but they don’t exist across large patient populations. That is the issue— the neoantigens across large patient populations just don’t exist. It is less likely to be able to find a vaccine which you could immunize people against many cancers with that one vaccine.

There are neoantigens that exist in 10% of the breast cancer patients or 8% of the prostate cancer patients—those are the sizes of patient populations that we have been able to find shared neoantigens for. We are working to create vaccines against those antigens. These vaccines are not personalized, and the vaccine can be used in that group of patients with shared antigen. But once again, we don’t know how effective those vaccines are going to be in those patients, and that is something we just have not tested yet but we will.

Pulse: Could you describe the patient journey for personalized cancer vaccine treatment?

CP: I don’t think the patient journey will be very different from current standard care. In our current clinical trial, after patient get diagnosed, they get biopsy for their tumor and started with immunotherapy treatment or whatever therapy that makes sense. Based on the neoantigen information we get from the biopsy, the cancer vaccine will be created. Eight weeks later, the patients will come back to the doctor, assuming things are still going ok, and they will get the vaccine over a course of two weeks with about 5-10 injections. Patients will continue to take the other standard care treatments and the vaccine will be there for the patient. We will continue to monitor the patient’s progress. It is not all that different except that they will get the biopsy and then come back to get the vaccine eight weeks later.

Pulse: Would you expect personalized cancer vaccine becomes the first-line treatment for cancer someday?

CP: One challenge with personalized cancer vaccine is that it takes time to make the vaccine. They cannot be made in a couple of days. Right now, the best we can do is in a time period of probably eight weeks. The mRNA based vaccine may be made more quickly, but it is still not within couple of days. It still at least takes a few weeks to make these cancer vaccines. The time-consuming feature of making cancer vaccine is the fundamental challenge. The reason why cancer vaccines are not given right away is because they are not ready right away. Once diagnosed, patients need to be put on some treatments that is effective right away, otherwise it is not ethical. The vaccine will then be added to the initial therapy once it is ready.

Pulse: Besides what you have mentioned above, what are the other challenges with personalized cancer vaccine?

CP: There are couple of challenges. First, we are trying to figure out what is going to work the best in combination with the other current treatments and which combinations work the best and make sense. Addressing these questions is a challenge. We are in the process of trying to do that in Neon right now. Second, the cost of these therapies is going to be a challenge– it is not going to be cheap. The general paradigm in pharma industry is the same drug for every patient. Personalized cancer vaccine is completely different. We need different drug for every single patient. That whole paradigm of personalized manufacturing and personalized delivery is a challenge because it is not following the way that the system is conventionally set up to work. It is a huge challenge for personalized medicine. I do think that it is going to be possible if the drug works—I think we will figure it out. In fact, any personalized medicine in the industry will face that same challenge, and there are many other companies working on the exactly same problems as Neon.