April 15-21 is the National Cancer Prevention Awareness Week. At the 2023 American Association for Cancer Research (AACR) annual meeting held recently, the American pharmaceutical company Moderna and MSD announced the positive results of the mid-term clinical trial of the cancer vaccine they cooperated with, announcing that they will conduct a phase III clinical trial.

Now we see mRNA cancer vaccines have positive effects in early clinical trials, and the focus is often on mRNA technology. The development of mRNA cancer vaccines is based on the development of next-generation sequencing-based bioinformatics and tumor precision medicine. Cancer vaccines are not fighting alone, but in combination with other immunotherapies, most notably with PD-1 or PD-L1 monoclonal antibodies.

Almost three years ago, mRNA vaccines were a never-before-proven heresy in the pharmaceutical industry. At that time, the main direction of mRNA technology and even mRNA vaccines was not the treatment of infectious diseases, but the treatment of cancer. It’s just that the cancer vaccine itself has not made a breakthrough for many years, and the combination of two unproven concepts really makes people dare not say how much confidence they have.

With the great success of the mRNA COVID-19 vaccine, mRNA technology is no longer a illusory castle in the air, but has been proven to be a very efficient drug delivery platform. With the support of mRNA technology, cancer vaccines have also become the focus of much attention. Many people are thinking: Is the next stop of mRNA vaccines to conquer cancer through cancer vaccines?

What is a cancer vaccine? How far is it from being practical? Let’s talk about these topics.

This vaccine is not that vaccine

When the public heard again that mRNA tumor vaccines are being made, many people wondered: If it is done, will this vaccine prevent cancer? Are cancers going to be eradicated by us?

This is actually a misunderstanding brought to us by common infectious disease vaccines. In infectious diseases, which is also the most important application scenario of vaccines at present, the role of vaccines is to induce an immune response against a certain pathogen. With this immune response and the subsequent immune memory, when the human body encounters a pathogen, it will Can respond in time to avoid disease. It can be seen that vaccines are disease-preventive here.

There are indeed vaccines that can prevent cancer in the world, such as HPV vaccine and hepatitis B vaccine, which can prevent the occurrence of certain cancers by blocking the infection of pathogens that can cause specific cancers. But that’s not what the cancer vaccines that are getting a lot of attention these days are trying to do.

The formation mechanism of cancer is that cells become uncontrolled and constantly dividing cancer cells due to gene mutation, that is, canceration. Although a few pathogens such as HPV and hepatitis B virus can cause specific cells to become cancerous after being infected, there are no clear pathogens behind most cancers. The source of cancer cells is the healthy cells of the human body, which belong to “our own people”. Naturally, it is impossible to block the occurrence of cancer by inoculating a certain vaccine.

However, if we focus on the mechanism of action of the vaccine – stimulating an immune response, then this mechanism of action can theoretically be used to kill cancer cells. No matter how healthy the source of cancer cells is, they are no longer the same as healthy cells after they become cancerous. The biggest feature of the immune system is that it can distinguish between “same” and “different”. The immune system will turn a blind eye to the cells belonging to one’s own people – “the same kind”, while the “non-kind” will be attacked by the immune system.

In fact, in order for cancer cells to survive and truly form cancer, a very important step is to achieve immune escape and get rid of the checks of the immune system. Theoretically, many cells in the human body may experience DNA damage and mutation due to various reasons every day, and are on the road to “cancerous transformation”. But most of them will be detected by the immune system and eliminated at the “emergent” stage, making the incidence of cancer far lower than the probability of cell mutation.

However, there is always one thing in every secret. Even with a perfect immune system, there will be cancers that get rid of immune surveillance and successfully grow. However, the immune system is not a static diehard, and the immune response can be induced and changed. Since cancer cells are different from healthy cells, based on the principles of immunology, we can theoretically stimulate the human immune system, allowing immune cells to learn to recognize these cancer cells, so that immune cells can kill cancer cells.

Vaccines are precisely a tool to stimulate the immune system. Therefore, in theory, we can use vaccines to “educate” and “induce” the immune system, what are the characteristics of a patient’s cancer cells, and let immune cells attack cancer cells with these characteristics. This vaccine can be used to treat cancer, that is, a therapeutic vaccine that is different from a general preventive vaccine. This is also the main form of cancer vaccines today.

Cancer Vaccines: Not a New Immunotherapy Attempt

Stimulate the human immune system and allow your own immune cells to eliminate cancer cells. From this principle, it is not difficult to see that mRNA cancer vaccines are not only mRNA drugs, but also a kind of immunotherapy.

Yes, cancer vaccines are a form of tumor immunotherapy. Tumor immunotherapy represented by PD-1 antibody and CAR-T cells is the biggest breakthrough in the field of cancer in the past 10 years. But cancer vaccines actually started earlier than these two star drugs. The earliest tumor immunotherapy drug approved by the US Food and Drug Administration (FDA), Sipuleucel-T (common name: Provenge, trade name: Provenge), is a cancer vaccine in disguise.

Sipuleucel-T, which was approved for the treatment of advanced prostate cancer in 2010, separates the patient’s own white blood cells and mainly enriches a type of white blood cells called dendritic cells. Dendritic cells are the main antigen-presenting cells. Sipuleucel-T is a patient’s dendritic cells cultured in the laboratory, and added an antigen present in 95% of prostate cancer: prostatic acid phosphatase. During in vitro culture, dendritic cells were activated and also acquired prostatic acid phosphate, an antigen against the prostate. Infusing these cells back into the body allows them to present antigens to the body’s T cells and other immune cells, thereby activating the T cells to kill cancer cells that express the relevant antigens.

In terms of treatment, Sipuleucel-T is a cell therapy similar to CAR-T—the finished product is cells. In principle, delivering cancer antigens to immune cells and activating the immune system to kill tumor cells expressing related cancer antigens is exactly the idea of cancer vaccines. In fact, the process of cancer vaccine effectiveness is to deliver tumor antigens to dendritic cells, and then dendritic cells present antigens to activate effective killer cells such as T cells.

However, Sipuleucel-T is cumbersome to produce, has mediocre effectiveness, and has not been commercially successful. Moreover, it is not easy to deal with highly heterogeneous tumors that are prone to produce drug-resistant mutations with just one antigen.

Cancer vaccines are like the entire field of tumor immunity. For a long time, the theory is very beautiful, but the reality is very skinny. All this did not change until the success of PD-1 and CAR-T. While the success of these two classes of drugs puts cancer vaccines in the dark by comparison, their success demonstrates that activating the immune system can be extremely effective against cancer. This is equivalent to proving that the basic idea of ​​cancer vaccines is correct, and what we need to overcome may just be how to improve the specific implementation methods.

Combination of mRNA technology, bioinformatics and immunotherapy

Now we see news that mRNA cancer vaccines have positive effects in early clinical trials, and the focus is often on mRNA technology. But behind today’s mRNA tumor vaccines is not just mRNA technology.

The development of mRNA cancer vaccines is based on the development of next-generation sequencing-based bioinformatics and tumor precision medicine. Tumor heterogeneity is extremely high, and it is not easy to find a cancer antigen that spreads in most patients with a certain type of tumor, and as shown by Sipuleucel-T, even if there is such an antigen, the effectiveness may not be so high. So the researchers began to think about whether they could tailor a personalized set of cancer antigens based on each patient’s tumor.

The heterogeneity of tumors means that it is not easy to find universal cancer antigens that are universally applicable. But cancer cells are different from healthy cells after all, so it is more feasible in theory to find personalized cancer antigens. However, this means that based on the genome sequencing of each patient’s tumor, and then through bioinformatics methods, to find potential available antigens. Fortunately, with the rapid development of next-generation sequencing in recent years, it has become practical to search for cancer antigens and design targeted cancer vaccines for each patient.

But this personalized cancer vaccine design also has new requirements for vaccine production: it must be flexible and fast. Cancer patients are facing the threat of disease progression, and customized cancer vaccines cannot be waited for months or years. The vaccine customized for each patient is different, and the vaccine must be very flexible during production, and it is best to be able to change it at any time.

The above requirements and mRNA technology have become a match made in heaven. When mRNA delivers antigens, it only needs to change the sequence to deliver different antigens; production, especially small-scale production for a small number of patients, is extremely fast. It is also for these reasons that the pioneers of mRNA technology such as Moderna and BioNTech (a German biotechnology company) have not long since been established, and have included cancer vaccines as key development targets.

In addition, cancer vaccines do not fight alone, but are combined with other immunotherapies, most notably with PD-1 or PD-L1 monoclonal antibodies. Although PD-1 antibody drugs are the reality of the current mainstream tumor immunotherapy, the complexity of the tumor microenvironment also makes researchers realize that it is necessary to use multiple mechanisms to activate the immune system. Stimulating the immune system with cancer vaccines is one aspect. On the other hand, PD-1 monoclonal antibodies must be used to break through the inhibitory effect of the tumor microenvironment itself on immune cells.

Therefore, today’s cancer vaccine is not only the hope brought by mRNA technology, but also the product of multiple high-tech combinations such as mRNA platform, precision tumor treatment, and immunotherapy.

Moderna headquarters in Massachusetts, USA. Visual China Map

Companies such as Moderna and BioNTech have been developing cancer vaccines and have previously announced relatively positive results in some early clinical trials. But what really makes everyone think that the mRNA cancer vaccine may be coming soon is the KEYNOTE-942 phase II clinical trial announced in December 2022.

This is Moderna’s personalized cancer vaccine mRNA-4157/V940, combined with Merck’s anti-Pembrolizumab PD-1 monoclonal antibody in patients with advanced skin cancer, compared with Pembrolizumab monotherapy. At the AACR annual meeting just held, the two companies also provided more information about the trial.
mRNA-4157/V940 is a cancer vaccine that is customized according to the sequencing results of each patient’s tumor. According to the sequencing results, Moderna will design a vaccine containing up to 34 antigens. It is hoped that by inoculating this vaccine against the patient’s tumor , to stimulate the body’s immune system to kill cancer cells.

In this clinical trial with a total of 157 people, 107 patients used both mRNA-4157/V940 and Pemboli beads, and 50 patients only used Pemboli beads. After 18 months of follow-up, the tumor recurrence-free survival rate was 78.6% in the combined drug group, and 62.2% in the pembrolizumab single drug group. Compared with single drug, the combined drug reduced the risk of tumor recurrence or patient death by 44%.

This is the first time a cancer vaccine has shown efficacy in a randomized clinical trial. It is precisely because of this that this result has attracted widespread attention, and many people have seen the hope that cancer vaccines are finally about to succeed.

In addition to Moderna, BioNTech is also vigorously promoting cancer vaccines. For example, it is cooperating with Genentech (Genentech, an American biotechnology company) to develop a personalized vaccine BNT122. It has just announced the first phase of clinical trials in pancreatic cancer. Increased T-cell responses against tumor cells were observed in about half of the subjects, arguably resulting in a decent immune response. Now BNT122 is also undergoing clinical trials for colon cancer and skin cancer. In addition to personalized cancer vaccines, BioNTech is also working with Regeneron Pharmaceuticals (a US pharmaceutical company) to develop a fixed multi-antigen cancer vaccine based on antigens that often appear in some cancers.

With the development of these studies, perhaps in the next few years, there may be cancer vaccines that break through the finish line of Phase III clinical trials and meet patients in the real world outside of clinical trials.

It is important to note, however, that even with the positive results of some recent early trials, there is uncertainty about the success of mRNA cancer vaccines.

Moderna and Merck’s skin cancer trial is the first and only one to show effectiveness in a randomized clinical trial. However, the number of subjects in this study was small and the follow-up time was short. Larger phase III clinical trials are needed to confirm the true effectiveness. Moreover, skin cancer has the highest mutation rate in the tumor genome. A high mutation rate means that it is easier to find the antigens required for cancer vaccine design. Some tumors, such as bladder cancer, have a low genome mutation rate. Whether this kind of cancer vaccine can be applied is very important. of uncertainty. In addition, previous trials of mRNA-4157/V940 in colon cancer had mediocre results. Why this difference occurs in skin and colon cancers remains a mystery.

Like CAR-T, personalized cancer vaccines also have high costs, and patients need to wait for technical challenges such as drug production.

But just like the current mRNA cancer vaccine is the crystallization of continuous development in many fields over the years, it is believed that with the further development of technology, cancer vaccines will eventually usher in their own breakthroughs and bring hope to cancer patients.

Reference materials:

1.https://www.cancer.net/navigating-cancer-care/how-cancer-treated/immunotherapy-and-vaccines/what-are-cancer-vaccines

2.https://www.nejm.org/doi/full/10.1056/NEJMoa1001294

3.https://www.cancer.gov/publications/dictionaries/cancer-drug/def/mrna-based-personalized-cancer-vaccine-mrna-4157

4.https://www.merck.com/news/moderna-and-merck-announce-mrna-4157-v940-an-investigational-personalized-mrna-cancer-vaccine-in-combination-with-keytruda-pembrolizumab-met-primary-efficacy-endpoint-in-phase-2b-keynote-94/

5.https://www.aacr.org/about-the-aacr/newsroom/news-releases/adding-a-personalized-mrna-cancer-vaccine-to-immunotherapy-may-prolong-recurrence-free-survival-in-patients-with-high-risk-melanoma/

6.https://www.fiercebiotech.com/biotech/bristol-myers-cmo-still-skeptical-about-cancer-vaccine-biontech-moderna-march-ahead-i-o

7.https://endpts.com/biontech-touts-differences-with-moderna-in-race-for-cancer-vaccines/