Are cancer vaccines not reliable due to too many failures?

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Are cancer vaccines not reliable due to too many failures?

Are cancer vaccines not reliable due to too many failures? In fact, this is a history of repeated struggles.

Guide

Whether it is from the first cancer vaccine approved by the US FDA, or from the failures of Nobel Prize winner Ralph Steinman who saved himself through a tumor vaccine and the active anti-cancer Macia, the history of cancer vaccine development is full of tragic and tragic s story.

In the end, cancer vaccines are not reliable, and can they be a good way to treat diseases and save people? What are the shortcomings in the design of cancer vaccines before? This article will be interpreted one by one. In the opinion of the author of this article, there is nothing wrong with the scientific nature of cancer vaccines, but it is still far from being widely used in clinical practice.

In today’s hot cancer immunotherapy rankings, in addition to the highly visible immune checkpoint PD-(L)1 inhibitors and cellular immunotherapy (CAR-T, etc.), therapeutic cancer vaccines are not only on the list, but also enjoy cancer. The reputation of the holy grail of immunotherapy.

Preventive cancer vaccines are widely known along with the popularity of HPV vaccines. Does cancer vaccine have a therapeutic function? This is so fascinating that it looks like a fairy tale.

More paradoxically, on the one hand, clinical good news is coming frequently, such as cancer vaccines to help advanced ovarian cancer to get rid of cancer for up to 5 years [1], and for melanoma patients, the tumor disappears completely after receiving the vaccine, and there is no recurrence within 25 months. [2].

The performance of treating mice is even more alarming: in 2018, it was reported that the cure rate of cancer vaccine was as high as 97% [3], and the heat-transmitted cancer vaccine recently increased the treatment rate by 275% [4]. Although some media reports are suspected of having the title party, the cited data are all published in academic journals that are serious.

On the other hand, the development of therapeutic cancer vaccines has been difficult for decades. Only one product has been approved in the United States, and it is not very popular after it goes on the market.

In addition, because of the “Wei Zexi Incident”, the cancer therapy DC-CIK, which was known to the public, has similar principles with cancer vaccines. It uses intelligence agents-dendritic cells to collect tumor information (antigens) and send it to the pole. The main force of lethal T cells. After receiving the information, T cells can accurately encircle cancer cells.

What is puzzling is that, unlike the tragedy of Wei Zexi’s loss of wealth and wealth, Nobel Prize winner Ralph Steinman used his own dendritic cell cancer vaccine to save himself after he was diagnosed with advanced pancreatic cancer. Successfully survived for more than 4 years, and most similar patients often do not survive for a year.

Does the cancer vaccine still depend on others? If this is the case, the aura of the Holy Grail would be uncoordinated. So what is the truth, whether the cancer vaccine is reliable or not?

01.  A history of repeated defeats and struggles

The history of cancer vaccine development can be described as a thorny one, and the following anecdotes show the hardships here.

01) “Black Wednesday” in the history of cancer immunotherapy

As the first and so far only approved therapeutic cancer vaccine in the United States, the situation of Provenge is hard to say.

In 2007, Provenge relied on optimistic clinical trial data (compared to the control group, the life span of patients was extended by 4.5 months; 25.9 months VS. 21.4 months; p=0.01) [5], and got the vote of most members of the US FDA Yes (13:4).

However, the few who voted against it are very influential in the cancer field and questioned the clinical effectiveness of Provenge: the survival rate has improved, but the tumor size has not changed significantly.

As a result, opponents launched a massive public relations campaign, accusing those who voted for being completely ignorant of cancer drugs, and they would be easily deceived by this ancient concept of stimulating the immune system to treat cancer. The safety of Provenge vaccine is not a big problem, that is, there is a high probability that the patient will not die, but this cannot whitewash its “lack of good results” in terms of efficacy [6].

Provenge Phase III clinical data, data source: [5]

Due to the pressure of the situation and public opinion, the FDA can only declare the Provenge vote abolished and request more clinical data to support it. One stone caused a thousand waves of waves. In the indignation of former FDA officials, the Wall Street Journal called this incident “Black Wednesday” in the history of cancer immunotherapy, and sighed that this would make immunotherapy return to the pre-liberation period overnight. of a new era in cancer immunotherapy was driven back into thenight)[7]. Provenge opponents later received threatening emails.

Basic principles of Provenge tumor vaccine

After going around for three years, it was not until 2010 that Provenge was approved by the FDA, creating a new era of cancer immunotherapy. However, the good times did not last long. Dendreon, the developer of Provenge, was overconfident. He tore up the cooperation agreement with the giant GSK in 2011 and found himself unable to do the Provenge production work alone. Furthermore, the high price (US$93,000) and complicated treatment plans have dissuaded many doctors and patients. Provenge’s sales in 2011 were only US$214 million, which is far from the 350-400 million that Haikou originally boasted. By 2014, Dendreon was declared bankrupt due to his inability to repay huge debts, and his fate was shocking.

To make matters worse, abiraterone and enzalutamide, which are also treatments for prostate cancer, were launched in 2011 and 2012, respectively, and they are selling well with the affordable price (about 40,000 US dollars) and the advantages of oral drugs. Abiraterone’s sales in the second year after its approval rushed to US$960 million. Provenge could only look forward to it. Later, it had to be strategically bundled. Abiraterone/enzalutamide plus Provenge reduced the risk of death by 45%. The survival time was extended by 14.5 months (35.2 months vs 20.7 months; p<0.0001) [8].

Provenge’s performance is mediocre in terms of efficacy and lack of convenience. It is natural to be abandoned by the market after competing products are on the market. It is envisaged that if Provenge is on the market for 10 years in the morning, it should be able to achieve good results without too much competition. Since the market reacts positively to stimulate greater enthusiasm for cancer vaccines, the entire field can form a virtuous circle to accelerate development.

Unfortunately, history cannot be rewritten after all.

02) Is it madness or conviction to try medicine by oneself?

Tom Marsilje (Tom Marsilje), like Steinman, is a scientist who studies cancer and suffers from cancer. He also hopes for cancer vaccines in desperation.

Although Marcia is active in fighting cancer, she did not escape bad luck in the end

Marcia seems to have been fighting cancer all her life. In 1999, before Marcia graduated from graduate school, her mother Tess was diagnosed with advanced pancreatic cancer. The unfortunate death of his mother strengthened Macia’s determination to become a cancer drug research and development scientist, and then resolutely moved to San Diego to join Novartis.

June 4, 2012 was a dramatic day for Malaysia. On the one hand, his cancer drug Zykadia made a major breakthrough. This day was officially released to the public. However, on the same day, Tom was diagnosed. He had stage III colon cancer.

Tom knows too well that chemotherapy cannot change his destiny. Sooner or later, tumors in the body will erupt, and before it is too late,

He will do everything possible to overcome cancer and buy himself more time with his wife and two daughters.

Tom Marcia and his wife and children, photo source: StatNews

After the diagnosis, Marcia put on running shoes, boosted immunity by running six miles every other day, and managed to complete a half marathon. He has also become an advocate for the colon cancer patient community, sharing his insights on treatment options and clinical opportunities, and helping other patients.

After investigating various clinical opportunities, Marcia believes that immunotherapy is the most promising. Unfortunately, most clinical trials do not accept patients with secondary cancer, because they are worried that they will confuse the test results, and Marcia was found to have melanoma after bowel cancer, so it did not meet the requirements [9].

Marcia did not give up. After several twists and turns, after striving to participate in the personalized vaccine clinical trial, Marcia said excitedly: “I am willing to pin my hopes on a 10% or 20% chance, because this is definitely better than zero.” If the vaccine works, it may turn the cancer of Malaysia into a controllable chronic disease or even eliminate it.

Unfortunately, after analyzing the data of Masian cancer cells and screening and designing vaccine antigens, his condition deteriorated and eventually he could not participate in clinical trials. He died in 2017. It also left an unknowable answer: Can cancer vaccines work miracles in Marcia?

Both Steinman and Marcia chose cancer vaccines, but the latter added a tailor-made element called a personalized vaccine. The so-called personalized vaccine is to study the cancer cells in the patient’s body (sequencing), identify the characteristics of each patient’s cancer cells (specific antigens), and then design the vaccine based on the characteristic information. The vaccine can provide cancer characteristics to the intelligence agent’s dendritic cells in the patient’s body. The dendritic cells then express the information to the T cells, so the T cells take a picture of the cancer cells and find the cancer cells that are good at camouflage. Annihilate.

Cancer cell antigen presentation. Image source: [10]

The milestone breakthrough for personalized vaccines comes from two studies published in the journal Nature in 2017 [2, 11], one from the Dana-Farber Cancer Institute, and the other from the University of Johannesburg/BioNTech. The vaccine designs of the two independent teams across the Atlantic Ocean are not the same, but they have the same goal: after receiving cancer vaccine treatment, more than half of the patients’ tumors completely disappeared, and the tumors of relapsed patients combined with immune checkpoint inhibitors also completely disappeared. Even after 4 years of cancer vaccine treatment, the immune response triggered by the vaccine is still strong and can effectively control cancer cells [12].

The development of personalized vaccines is inseparable from an important hero: neoantigens.

02. Promising neoantigens

For many years, sharing tumor antigens has been the focus of cancer vaccines. After all, sharing means that it can be mass-produced, and the cost is lower than tailor-made. To this end, the United States has also set up a working group to formulate a priority list of shared tumor antigens [13], the top ones include the familiar WT1, MUC1, HER-2 and so on in the industry.

Prioritization of tumor antigens, data source: [13]

These officially certified antigens do have good early clinical manifestations. One of the most concerned is the birth of a vaccine called GP2 (a polypeptide of HER2 protein) at the 2020 San Antonio Breast Cancer Symposium. After breast cancer patients receive treatment , The disease-free survival rate (DFS) of the 5-year follow-up was 100%, and the recurrence rate was 0%. Therefore, the stock of GLSI, the owner of the GP2 vaccine, rose more than 20 times that day, because the volatility was too fierce and the trading was suspended for no less than 20 times.

GP2 vaccine clinical DFS data. Data source: GLSI official website.

Of course, there are endless cases of failure. For example, the cancer vaccine Prostvac against the antigen PSA can prolong the survival of prostate patients by 8.5 months in the second clinical phase, and it will lose the chain at the critical time of the third clinical phase. It has no effect on the survival time. It can terminate the clinic early [14].

Regardless of whether it is HER2 or PSA, although it presents the important characteristics of cancer cells, it is also implicitly expressed on normal cells (relatively low levels), which lays two hidden dangers: first, the immune response triggered by these antigens may accidentally harm the normal Cells produce side effects. Secondly, as self-derived antigens, the immune system tends to tolerate them to a certain extent, that is, treating them as their own people may not be able to initiate an immune response.

With the deepening of the understanding of tumors, scientists have discovered that after mutations in cancer cells, they will produce uniquely expressed neoantigens (neoantigen). This means that the development of vaccines based on neoantigens can perfectly solve the above two hidden dangers. It can not only fight tolerance and trigger a real tumor-specific immune response, but also prevent normal cells from lying down innocently. Following this line of thinking, next-generation sequencing and bioinformatics tools provide technical support at the practical level, and personalized vaccines for neoantigens are no longer out of reach [15].

To treat different cancers, using the sharp sword of neoantigens has its own troubles. “Hot tumors” such as melanoma and lung cancer are too keen on mutations, so there are hundreds of new antigens, but only a small part of them can smoothly fall into the eyes of immune cells, and then stimulate tumor-specific immune responses. In other words, each neoantigen is like a lottery ticket. If it is selected at random, the chance of winning the final prize is not very high.

Therefore, the most important step when designing a vaccine is to determine the antigen priority. How to identify the neoantigens that are most likely to win a prize requires the use of cutting-edge deep machine learning and AI technology. In the end, who can stand out is useless, technology is the last word.

Of course, whether the antigen is strong or weak is not always a black eye. Scientists have found some clues. For example, clonal mutations are more likely to trigger immunity than subclonal mutations[16]( If cancer cell mutations are an evolutionary tree, clonal mutations are the backbone, and subclones are side branches), for example, more violent mutations (frameshift insertions and deletions, etc.) may be more effective than mild single-point mutations.

Contrary to “hot tumors”, “cold tumors” that do not enter into oil and salt (T cells) have very few neoantigens. Typical representatives include glioblastoma, pancreatic cancer and ovarian cancer.

Too many choices are easy to pick, but it is better than nothing. Therefore, the key clinical practice of neoantigen vaccines in recent years has been for melanoma. A large number of mutations give vaccine researchers a lot of space to choose antigens. For cold tumors, is the development based on new antigens a dead end?

Soldiers came to cover up the water and earth. Although these cold cancer cells are difficult to deal with, they are not indestructible. Even the most deadly glioblastoma has a vaccine called AV-GBM-1 that works well: the 15-month overall survival rate of patients treated with AV-GBM-1 is 76%, and only 48%[ 17].

In addition, cancer vaccines can also induce an immune response in “cold” tumors, which may turn them into “hot” tumors, creating conditions for PD-1 inhibitors and others to make a difference.

03.  Looking for an ideal cancer vaccine

If you want to give an ideal cancer vaccine portrait, at least the following items must be met:

• 1) Reducing the tumor and eradicating the residual as much as possible;
• 2) Establishing a lasting anti-tumor memory;
• 3) Avoiding non-specific or adverse reactions.

Looking back at history, the successful cases are similar, and the failure cases are different. Some selected antigens from the very beginning with weak combat effectiveness and lost directly at the starting line. Some selected antigens were right in this move, but lacked an effective helper (adjuvant) to help the vaccine. Some antigens and dendrites. The cells cannot fit together, and the dendrites are unwilling to give them a place, let alone recruit T cells to help.The currently ongoing personalized clinical trials can be roughly divided into three categories according to vaccine delivery methods: peptides, RNA/DNA, and dendritic cells.

As can be seen from the figure below, all changes are inseparable. In the final analysis, these three types allow cancer cell antigens to settle on dendritic cells smoothly. If dendritic cells are used as the delivery method, it is equivalent to most of the installation engineering has to be completed in vitro. If you choose RNA/DNA, it is more tricky (lazy). After simple synthesis in vitro, it is thrown into the human body and the somatic cell itself Complete the remaining work, but there is a risk that the antigen will not be accepted by the dendritic cells smoothly.

Different types of cancer vaccines, source of pictures: [18]

DNA and RNA production processes are relatively simple, but after RNA vaccines are delivered to cells, they can be immediately used as templates for protein production, and RNA can also be engineered to achieve self-amplification (such as the Ziphius Vaccines platform that has recently attracted attention). It is important to avoid the risk of DNA integration into the patient’s genome (note: only theoretically possible, there is no conclusive clinical evidence), so relatively speaking, RNA has received more attention.

The ideal cancer vaccine also has an excellent quality, that is, it is willing to make friends. After all, it is never a wise choice to fight alone. In addition to combined therapy with PD-1 inhibitors and other double swords, more intimate partners (adjuvants) include GM-CSF, TLR agonists, etc., whose purpose is to enhance the body’s immune response to antigens. For example, the listed Provenge has received strong support from GM-CSF.

04.  Conclusion

Although personalized cancer vaccines have made some progress, they have not fully awakened the body’s own anti-cancer weapons[19-21]: Among 108 solid tumor patients, only 9 have responded to cancer vaccines (ORR 8.3%) [20]; In another study called NT-001, ORR was up to 59%, but patient survival did not improve significantly [19]. After all, how long the patient can live is the gold standard for consideration.

In addition, the long production cycle and high cost of personalized cancer vaccines cannot be ignored. In the already very crowded immunotherapy clinical trials, the competition for patients is very fierce (emphasis: patient resources are very precious, and fees for participating in clinical trials are fraudulent behaviors), which may limit the development of personalized vaccines, and tend to be more suitable for mass production. A universal vaccine at a lower cost.

Fortunately, with the more accurate prediction of neoantigens, interdisciplinary cooperation, such as California Institute of Technology chemist James Heath, has convened talents in various fields to jointly design a microfluidic device for neoantigen prediction [22]. I believe that as long as there is enough imagination, personalized vaccines will go farther and farther. Since computers can go from tens of tons at the earliest to palm tablets now, it is not impossible for a personalized vaccine to cycle from a few months to a few days or even a few hours.

Another way to break the situation is to take a compromise between prevention and treatment, that is, when the cancer is still in the benign/early stage, use cancer vaccines to prevent further deterioration. In fact, this idea has a good performance in precancerous patients with cervical cancer and colon cancer [23, 24], or like the GP2 vaccine strategy mentioned above, it can be used as adjuvant therapy after the patient has received other therapies and stabilized. To prevent recurrence.

Based on the potential value of neoantigen cancer vaccines and cell therapy, data source: [25].

Going back to the original question of the article, whether the cancer vaccine is reliable depends on the definition of reliable. There is nothing wrong with the science of cancer vaccines, but it is still far from being widely used in clinical practice. If you expect to be the savior who can completely cure cancer patients in the short term, you will inevitably be disappointed.

(source:internet, reference only)

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