From "textbook" to "exclusive secret", how hard is it to develop tumor vaccines?

Author: Ye Tong (Institute of Process Engineering, Chinese Academy of Sciences)

The article comes from the Science Academy official account (ID: kexuedayuan)

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To protect human health, researchers and medical workers, like teachers, often use various "teaching materials" such as vaccines to enhance the immune system's knowledge and allow it to calmly face various challenges from "bad guys."

Generally speaking, vaccines used as "teaching materials" can be divided into two categories: preventive vaccines and therapeutic vaccines. The former mainly use pathogen antigens to induce humoral immunity, such as hepatitis B vaccine and COVID-19 vaccine, which are mostly used in healthy people; the latter mainly use antigens to induce cellular immunity, such as tumor vaccines, which are suitable for cancer patients.

If the use of preventive vaccines is to "teach" the immune system to recognize the "appearance" of bad elements and then launch antibody missiles to intercept the bad guys, then therapeutic vaccines are more about teaching the immune system to recognize the bad guys and then taking the initiative to attack through decapitation operations to achieve the purpose of killing.

So, as a typical representative of therapeutic vaccines, how do tumor vaccines work? How will the new achievements of the Institute of Process Engineering of the Chinese Academy of Sciences better play the "teaching resource" advantage of tumor vaccines?

(Image source: pixabay)

A general textbook for the immune system

Before further explaining whether tumor vaccines are effective, we must first understand how tumor cells are formed.

Under normal physiological conditions, the growth and proliferation of cells are strictly managed and controlled. However, it is inevitable that some "small mistakes" will occur. In most cases, these small mistakes will be discovered and corrected. Among the few errors that are not corrected, a large part is insignificant. Only those critical errors that continue to accumulate will lead to the emergence of completely out-of-control tumor cells. The division and proliferation of these tumor cells are not controlled by the body, nor do they have biological functions. They can affect the operation of normal cells by competing for blood and nutrients, and even run around everywhere, which can be called a complete bad guy.

Is our immune system being lazy when it comes to fighting tumor cells?

Normally, mutations that alert the immune system are discovered and eliminated, but hidden mutations can survive. After a period of accumulation of mutations, the bad habits of tumor cells have become irreversible, but their cell surface proteins are still highly similar to those of normal cells. This allows them to hide among normal cells and escape recognition by the immune system. This process is also called tumor immunoediting.

In order to teach the immune system to accurately identify tumor cells, people began to analyze a large amount of clinical data and tried to "manually" find the differences between tumor cells and normal cells. With unremitting efforts, some common mutations of tumor cells were finally found, namely tumor-associated antigens (TAA), such as oncofetal protein CEA and melanoma-associated antigen MAGE, which are highly expressed in tumor cells. After encapsulating them in the form of peptides or nucleic acids, vaccines can be produced to guide the immune system to recognize and kill tumor cells.

Unlike preventive vaccines such as the hepatitis B vaccine and the COVID-19 vaccine, tumor vaccines are therapeutic vaccines that train the immune system to recognize tumor cells and activate the patient's own specific cellular immunity to kill tumors. This TAA-based tumor vaccine describes the prominent features of most tumors, similar to a widely applicable textbook. In principle, it can teach the immune systems of many tumor patients to recognize tumor-associated antigens and eliminate tumors while distinguishing between tumor cells and normal cells.

A general textbook on the immune system (Image source: self-made by the author)

Private customization, exclusive tips

However, "ideals are full, but reality is skinny." A basin of cold water was soon poured on the heads of researchers - a large number of clinical trials of tumor therapeutic vaccines based on TAA ended in failure.

In 2010, Provenge®, the first therapeutic tumor vaccine for prostate cancer, was launched abroad. Later, it was forced to withdraw from the market due to the mismatch between its effectiveness and high cost, and the limitations of TAA tumor vaccines also became apparent. In addition, TAA is expressed at low levels in normal cells. Due to central immune tolerance (tolerance to self-antigens formed during the development of T and B cells during the embryonic period and after birth is an indispensable protective mechanism), the immune response caused by the vaccine is not too strong. At the same time, the expression levels of TAA in different tumor patients are not consistent, and the effects of their immunotherapy will also be uneven. People began to realize that the closer the tumor cell characteristics described by the vaccine are to the expression of the patient's actual tumor characteristic molecules, the better the treatment effect. "Teaching students in accordance with their aptitude" is very important.

With the continuous development of gene sequencing technology and computer algorithms, a new and more accurate tumor vaccine has emerged.

They are produced like this:

First, the patient's tumor tissue and normal tissue must be compared through gene sequencing technology to draw a complete mutation map for the individual;

Secondly, computer algorithms, combined with immunological knowledge, comprehensively consider 20-25 factors such as major histocompatibility complex (MHC) affinity, peptide-MHC binding stability and human leukocyte antigen phenotype to predict the vaccine components that can induce the best immune effect;

Finally, the corresponding vaccine production and packaging are carried out in the clean workshop.

This type of vaccine, which is customized to the individual and in which the antigen is expressed only in tumor cells, is also called a tumor neoantigen vaccine.

Compared with general textbooks with a wide range of applications and uniform formats, tumor neoantigen vaccines are a "special recipe" tailored for tumor patients. Based on a comprehensive understanding of tumor cells, vaccines are prepared for several or dozens of antigens. In this way, although the vaccine components of each person are different, they are definitely the most suitable for him or her.

Exclusive secret recipe tailored for the immune system (Image source: self-made by the author)

A good lesson for the immune system

With the secret recipe, how can we better pass on the "magic skills" to the immune system? Should we just leave it to the immune system and let it learn on its own?

What most teachers believe is that they should not trust students' ability to learn on their own. Similarly, letting the immune system "learn on its own" is often just wishful thinking. Too fast tumor vaccine metabolism and insufficient antigen uptake will lead to "poor learning effect" of the immune system, and easily produce immune tolerance and aversion to learning.

In addition, the components of tumor neoantigen vaccines vary in nature, and there are a thousand different formulations for a thousand vaccines, which makes vaccine delivery extremely difficult. Improper teaching plans not only affect the immune effect, but also waste precious treatment time for tumor patients. This requires a set of convenient and efficient "teaching plans" that integrate multiple factors and have strong compatibility.

To address this issue, Researchers Ma Guanghui and Wei Wei from the State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, used polylactic acid materials approved by the U.S. Food and Drug Administration (FDA) and combined more than ten years of research experience in vaccine adjuvants and tumor immunity to build a multi-effect synergistic vaccine platform loaded with diverse neoantigens, and designed teaching routes such as "unified teaching", "continuous learning", and "appropriate learning atmosphere".

This platform can gather the "sentinels" in the immune system, that is, antigen-presenting cells, to the vaccine injection site for "unified teaching". When the antigen-presenting cells gather to a certain number, they release antigens for a longer period of time to enable them to "continue to learn". At the same time, the local acid environment generated by the degradation of the carrier is used, supplemented by appropriate adjuvant stimulation, to create a "suitable learning atmosphere", and multiple aspects work synergistically to ultimately improve the immune effect.

The experimental results show that after a single injection of the tumor vaccine, a sustained and strong T cell immune response can be induced, which significantly inhibits the progression of lymphoma, melanoma, breast cancer and other tumors in mouse models. At the same time, the system can also be combined with the immune checkpoint inhibitor PD-1 antibody to treat leukemia, and it has also shown good therapeutic effects in mouse models. (Click here to learn useful knowledge about PD-1 antibodies)

Personalized tumor microsphere vaccine (Image source: self-made by the author)

Conclusion

In the spectrum of diseases in China, the mortality rate of malignant tumors ranks first and is higher than the world average. In 2020 alone, there were 4.57 million new cases of cancer in China, and each case means great pain for the patient and his family.

In the near future, the results of tumor vaccines may help to defeat cancer and bring hope to patients. But in any case, remediation is always worse than prevention. I want to remind everyone that no matter how busy you are, you should still maintain good living habits. While you are busy and hardworking, you should also cherish the "learning energy" of your immune system.

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