Learn about the latest advances in immune cell therapy and the past and present of immunotherapy!
September 11, 2018 Source: Shanghai Cell Therapy Center
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At present, CAR-T cell therapy has achieved extraordinary results in hematoma. In 2017, the two approved CAR-T products from Novartis and Kate in the United States are aimed at hematoma, and the effect is much better now than traditional therapy.
However, hematoma only accounts for a part of solid tumors. The vast majority of patients suffer from solid tumors, which are commonly referred to as gastric cancer, liver cancer, lung cancer, etc. For these cancers, CAR-T cell therapy is still not available. Very good therapeutic effect.
The biggest difficulty is two:
First, compared to hematoma, CAR-T cells can reach the solid tumor site and do not kill much.
The cancer cells in the hematoma are in the blood, and the CAR-T cells are directly returned to the human body, so they can be exposed to cancer cells very quickly, but the CAR-T cells are injected intravenously in solid tumors. There are very few cells that reach a solid tumor, which results in a therapeutic effect that CAR-T cell therapy can be much lower than that of a hematoma, and this is indeed the case.
The more important point is that solid tumors will form a set of environments to protect themselves in the tumor, which will greatly reduce the ability of our immune cells to kill, which will lead to a significant reduction in the therapeutic effect of CAR-T cells. The environment in which cancer cells grow is called the tumor microenvironment. There are too few CAR-T cells that can break through the tumor microenvironment and kill cancer cells, which makes our treatment of solid tumors not very effective.
Second, it is difficult to find the difference between solid tumor cells and normal cancer cells.
Immunotherapy is blunt, that is, I don't care how your cancer cells come out. I just need to find the difference between you and normal cells, and then let the CAR-T cells find you and kill them in this unique place.
But unfortunately, many solid tumor cells will disguise themselves as normal cells, so that we can not find the difference between it and normal cells, the natural killing effect is very poor. The effect of hematoma can be achieved so well, because B cells have an ancestral target CD19 relative to other cells, and the treatment of this target will not accidentally injure normal cells.
Even with so many difficulties, we still have to overcome solid tumors, because cancer has become the second leading cause of death from human diseases after cardiovascular disease. Numerous research institutes and institutions, including cell centers, are climbing the peak of cancer treatment.
Today, the top journal "Gut" published by BMJ provides us with a new way of thinking about using CAR-T therapy to overcome solid tumors. It must be said that this is indeed a viable and extremely clever therapeutic entity. The method of tumor.
Since we can't find a target that is completely expressed only by cancer cells and not expressed by normal cells, can we look for targets that are highly expressed in cancer cells but have low expression in normal cells?
Just like in ancient China, it is more difficult to catch a black person like the Africans, but to find a person like Bao Zheng who is so dark, you can still find it. After all, Africa and Asia are not connected at that time. Find a black one. It’s hard to go to heaven.
However, it is no less than the above-mentioned situation to find a target in which cancer cells are expressed and normal cells are not expressed at all. However, it is still possible to find a target with low expression of normal cells but high expression of cancer cells.
However, there is a long-standing problem: the CAR- cells we developed will bind to these targets, and when combined, they will lead to apoptosis. Even if the normal cells are low-inhibited, they will be killed by CAR-T cells. Dead, does this not greatly damage the human body? It may also lead to chaotic attacks on CAR-T cells leading to the appearance of unknown and potentially fatal side effects.
How to do it? Then add a control switch to the CAR-T cells. So what we finally saw was a new CAR-T cell model that was completely different from the CAR-T cells we saw before:
The biggest breakthrough of this model is that it is no longer limited to finding a unique target for cancer cells, but a HER2 target, a target that is highly expressed in cancer cells but low in normal cells.
The biggest problem we face in this way becomes how to control the safety of CAR-T cells instead of finding new targets.
In this study, the results of the study confirmed that switched CAR-T cells are comparable to non-switched CAR-T cells (both targeting HER2 targets) for treating cancer and are harmful to other cells. Less sex!
In other words: in this way, we can indeed be used to improve the therapeutic effect of CAR-T cells, and if we set the switch, the side effects are also controllable!
History of immunotherapy
In 2625 BC, the ancient Egyptian doctor and sister sent the disappointed patients out. In his medical history, the wind blew gently, and the diagnosis of breast cancer fell into the eyes of India and Yan. In the treatment column, the words "no therapy" were so dazzling.
This is the first case of breast cancer recorded by humans.
In the war of more than 4,000 years of human and cancer, countless drugs and therapies such as the squid of the river have been countless, and various remedies have emerged one after another. If you come to 2018, you can see that the 5-year survival rate of breast cancer can exceed 90%. I believe it will be very gratifying. In the treatment column, there will be no treatment.
In 1809, the first surgical case in human history was born. Today, surgical treatment has become the most effective treatment for early cancer and non-metastatic cancer. In 1895, we used X-ray and radium to treat cancer. The prelude to radiotherapy; in the 1940s, the once-shocking biochemical weapon mustard in the Second World War abandoned the darkness of the door, opening the door to human chemotherapy.
Surgery has brought the cure rate of early cancer in humans to a new level. Nowadays, with the improvement of drugs and dosages and the production of complementary drugs, the side effects are decreasing. But these treatments have helped humans win local battles in the anti-cancer war, but we still need new weapons in order to finally win the war.
Thus, a new anti-cancer therapy, immunotherapy, has entered the historical arena.
A hundred years of ups and downs - the past and present of immunotherapy
In 846, the Normans from the Seine River attacked Paris, France. The war-torn and fire-tested soldiers did not fear the blood, but waiting for them was a fierce "slaughter."
When a soldier had acne on his face, he was laughed at by the older soldiers. However, the next day, they couldn’t laugh. A large number of soldiers began to have high fever, acne, and acne began to puff out. Then began to have soldiers die, one after another. The head of the Norman, full of heroic horror, watched the spread of the "plague", and the number of dead people increased from day to day, mourning the wilderness, so the Norman leader ordered the killing of all sick soldiers and nurses and nurses.
This was the only way at the time. This horrible disease plundered the entire planet. In the 18th century, 150 million people died because of this disease. This horrible disease is smallpox.
However, maybe we are a little stranger to smallpox now, and even rarely hear this term, because for smallpox, we have a special medicine.
On May 17, 1796, the British physician Jenner gave himself a special gift and gave him a miracle gift. In Jenner's office, Phipps is eating a lollipop in his mouth. He doesn't know that after a hundred years he will be engraved into history because he became the first person to inoculate a smallpox vaccine. Thinking about whether it is time to go to the grass with Allen.
When the milk-smelting girl Nimes came in, Phipps stared at Nimes's hand curiously, because she had small small pustules on her hands. Jenner carefully stroked a trace on Fip's arm and dripped the pus inside Nim's pustule onto the scratch on the fist's arm. A few weeks later, Jenner once again gave Phipps a complete variola virus. However, Phipps did not infect smallpox!
This is the culmination of centuries in Europe, the worst infectious disease, and the smallpox that took hundreds of millions of lives. At the same time, the fallen ceiling has set a new discipline for humans: modern immunology. We began to realize that the human body is not as fragile as we think, because we have a strong immune system.
Even the powerful smallpox is also overcome by a small vaccine, in which the body's immune system is highly successful. So, in cancer treatment, can our immune system play the same magical role?
In the early 1880s, a case of a recurrent malignant sarcoma patient caught the interest of William Coley. This patient was unfortunately infected with S. pyogenes during the operation. In the absence of antibiotics, patients can only rely on their own immunity to fight against the bacteria. It can also be said that they are resigned. However, fate is on the human side after all: after the patient experienced several high fever, not only the infection of streptococcus was relieved, but even the recurrent malignant sarcoma disappeared miraculously!
William Coley began to realize that the human immune system is far stronger than we thought, so Coley began to treat malignant sarcoma with streptococcal infection. The history of medicine is often uncovered by special cases. This magical self-healing patient not only saved himself, but also made William Coley the "father of tumor immunotherapy", and Coley officially opened the human tumor immunotherapy. Chapter.
At the beginning of the 20th century, the German pharmacologist Paul Ehrlich proposed the theory of side chain formation, which outlines the prototype of antigen-antibody for humans - our current immunotherapeutic treatment concept stems from this. In 1908, he and the Russian scientist Elie Metchnikoff, who founded the theory of cell phagocytosis, boarded the Nobel Prize podium on the top of the science community, and won the Nobel Prize in Physiology and Medicine. Thus, the theoretical framework of human immunology has finally been successfully established.
In 1957, Thomas and Burnett proposed the "immune surveillance" theory, which believed that the immune system has the ability to distinguish and inhibit the growth of tumor cells. However, in 1974, Osias Stutman "proved" that the immune system of the nude mouse was not associated with tumorigenesis. This "proof" made the tumor's immunotherapy fall into a real trough: if the immune system is not related to tumorigenesis, the therapy will be completely shelved. The crisis from theory made it clear that the path of immunotherapy was covered with a thick haze.
However, whenever there is poverty, there will be geniuses coming. In 1984, Rosenberg used IL-2 to cure melanoma patients in clinical trials, suggesting that the immune system does indeed inhibit tumor development, and later, Rosenberg pioneered LAK cell therapy and TILs cell therapy, proving that the immune system is in cancer. Treatment plays an indispensable role.
When theory and practice are completely opposite, people have to face up to the results of practice and re-examine theories. So in 2002, Schreiber published the theory of immuno-editing, which divided the development of cancer into three stages: immune clearance, immune balance and immune escape, which provided a solid theoretical basis for cancer immunotherapy, thus opening up The glorious era of cancer cancer immunotherapy - PD-1, CAR-T and cancer vaccines have really come to the forefront of cancer.
Squandering flowers are fascinating eyes - a variety of cancer immunotherapy
Cancer immunotherapy, as its name implies, is a technique for removing tumor cells by enhancing autoimmune function. Since the 21st century, immunotherapy has gradually matured, resulting in different branches, which can be broadly divided into four main categories: non-specific immunopotentiators, vaccines, adoptive therapies, and immunological checkpoint inhibitors. .
1. Non-specific immune enhancer: kill one thousand, self-destruction eight hundred
Non-specific immunopotentiators treat cancer primarily by modulating the body's immune function as a whole. The most common non-specific immunopotentiators include interleukins and interferon Interferons. Although the enhancer increases the immunity of the body, it does not improve the ability of immune cells in our body to recognize the enemy cells. The cost of greatly enhancing the ability of immune cells to attack cancer cells is that a large number of "injury" the normal cells of the human body, causing serious Side effects such as flu-like symptoms, rash, leukopenia, etc. Because of the effect of non-specific immune enhancers "killing one thousand, self-loss 800", it is usually treated in combination with other immunotherapy or chemotherapy.
2. Cancer vaccine: prevention and treatment
Since the vaccinia vaccine was used to prevent smallpox in 1796, the vaccine has become one of the powerful weapons for humans to fight disease. There are currently four vaccines approved by the US FDA for cancer treatment, namely Gardasil and Cervarix for the prevention of cervical cancer, hepatitis B vaccine for the prevention of liver cancer, and Provenge for the treatment of advanced prostate cancer.
Nine-priced HPV vaccine, hepatitis B vaccine "curve save the country" to prevent cancer
Human papillomavirus HPV is considered to be the cause of more than 90% of cervical cancer, and the highly pathogenic subtypes 16, 18, 31, 33, 45, 52, 58 can be prevented by inoculation with a nine-valent HPV vaccine. . Similarly, more than 90% of primary liver cancer patients in China are HBsAg-positive hepatitis B patients, and the probability of developing liver cancer can be greatly reduced by vaccination with hepatitis B vaccine.
Provenge therapeutic vaccine
Unlike the preventive cancer vaccine that saves the country by preventing cancer-related viral infections, Provenge, a therapeutic cancer vaccine developed by Dendreon, can be called the first true cancer vaccine. Dendreon separates dendritic cells from patients and transforms them into specific cells that recognize prostate cancer cell surface antigens, which are then reintroduced into patients to identify and destroy prostate cancer cells. Help.
Provenge was approved by the FDA in 2010, but due to Dendreon's wrong sales strategy and the successive listing of competitors, the performance in 2013 was bleak and eventually bought ownership by Valeant.
Although Provenge is unfavorable, its emergence suggests the future of cancer vaccines. Many companies have followed suit and invested in the development of cancer vaccines.
At present, there are mainly brain cancer vaccines developed by Northwest Biotherapeutics in the United States, which are in clinical phase III; vaccines for the treatment of pancreatic cancer, non-small cell lung cancer and melanoma developed by Newlink Genetics of Iowa are mostly in clinical phase II or III. Inovio's cervical cancer vaccine, prostate vaccine and breast cancer vaccine; Aduro Biotech uses bacteria instead of virus as a vaccine carrier, mainly for pancreatic cancer, mesothelioma, glioma, lung cancer and prostate cancer.
In addition to conventional vaccines, there is a separate oncolytic virus vaccine that specifically infects tumor cells after genetic modification of the oncolytic virus. Among the oncolytic virus therapies currently on the market, Amgen's Imlygic was also approved for marketing in October 2015, in addition to the H101 of China's Shanghai 3D Biology, which was approved by the CFDA in 2006 and qualified for production.
As of the end of 2013, there were 470 cancer vaccines under research worldwide, targeting molecules from oncogenes, oncoproteins, to epithelial-mesenchymal transitions and angiogenesis during cancer development. The combination of immunotherapy will be the dominant direction for future cancer treatment, and the cancer vaccine that plays the role of "instructor" will undoubtedly have a bright future.
3. Immunological checkpoint inhibitors
In April 2015, an article published in the medical authority magazine "NEJM" caused a huge sensation. A 49-year-old woman with ulcerated melanoma had metastasis and recurrence after two surgical resections of the tumor over the past 4 years, eventually producing a large metastatic tumor under the left breast. But three weeks after receiving the CTLA4 inhibitor Ipilimumab in combination with the PD-1 inhibitor Nivolumab, the repetitive metastatic tumor quickly subsided, and the rate of disappearance was so jawing that even the wound could not be healed. A CT scan six weeks after administration showed that the huge tumor on the chest wall had disappeared completely.
As the youngest member of the cancer immunotherapy family, Immune checkpoint inhibitors (ICIs) have brought us a constant stream of surprises since their inception.
In 1987, French scientists discovered a class of proteins CTLA4 expressed on the surface of T cells. After injection of CTLA4 antibody in mice inoculated with tumor cells, the tumors in the mice completely resolved. The embryonic form of the immunological checkpoint inhibitor was born.
In 1992, Prof. Benjamin of Kyoto University in Japan discovered PD-1. In 1999, Lieping Chen, a professor at Yale University in the United States, discovered PD-L1, which together with CTLA4 formed the immune checkpoint protein family. When activated, these immune checkpoints inhibit T cell proliferation and function, allowing tumor cells to evade detection and attack by the immune system. The appearance of immunological checkpoint inhibitors effectively blocks the pathway and can effectively kill tumor cells.
In 2009, Bristol-Myers Squibb (BMS) acquired the American bio company Medarex, along with its PD-1 inhibitor. The deal is also considered to be the most important acquisition in the history of cancer immunotherapy. In July 2014, BMS's PD-1 inhibitor Nivolumab was approved for marketing in Japan and was used for the treatment of melanoma. In September of the same year, the FDA approved the listing of Merck's PD-1 inhibitor pembrolizumab.
Currently, the FDA has approved the listing of five PD-1/PD-L1 products:
According to Decision Resources, the ICIs market will reach $7 billion by 2020, with PD-1 inhibitors taking the largest share. With the deepening of people's understanding of immune checkpoints, new ICIs targeting IDO1, KIR, LAG3, etc. have gradually entered the clinical stage, and attracted other multinational pharmaceutical companies including Pfizer and Merck KGaA. It can be imagined that in such a segmented market segment, the final competition results will largely change the pattern of the pharmaceutical market, let us wait and see.
4. Adoptive cell therapy
In 1984, Linda Taylor, who had advanced metastatic malignant melanoma, was treated for the first time in desperation by cancer immunologist Steven Rosenberg, who stimulated lymphocytes with high doses of IL-2 to form lymphokine activation and killing. The cells (lymphokine-activated killercell, LAK cell) are re-introduced into the body of Taylor. Unexpectedly, however, Taylor was completely cured by LAK therapy! After more than 30 years, Taylor is still healthy and looks back. Presumably she will definitely play CALL for the original choice.
In the past 30 years, adoptive therapy has also evolved from the first generation of LAK therapy, cytokine-activated killer cell CIK therapy, tumor infiltrating lymphocyte TIL therapy, cytotoxic T lymphocyte CTL therapy to the fifth generation chimeric antigen receptor T. Technical changes in cellular CAR-T and tumor-specific T cell receptor genetically engineered cells TCR-T.
In contrast to the major countries in the ICIs market, the market for adoptive cell therapy is more of a small and medium-sized bio company with a relatively simple product line and relatively rapid technological transformation. Although there is currently no fifth-generation adoptive cell therapy product on the market, the market and investors have placed great expectations on them.
At the end of 2014, Science magazine made predictions for important breakthroughs in technology in 2015, and combined immunotherapy was also among them. As early as the last century, people realized that cancer is far from a change in a gene and a protein in normal cells. Combination therapy is the key to cancer treatment. Today, immunotherapy-centered combination immunotherapy is gradually taking shape and forming a huge market for the Red Sea.
The cornerstone of the development of medicine is life science. With the continuous breakthrough of gene editing methods represented by TALEN and CRISPR and the in-depth study of the phenomenon of tumor development, disease treatment methods will be more diverse. In the near future, drug development for new and high-efficiency tumor targets, safety and economic modification of cell therapy, combination therapy for overcoming drug resistance, and precision medicine for prevention and early detection will be The most compelling direction in the field of cancer treatment.
As people's awareness of cancer continues to deepen, our means of treating cancer continue to innovate, from surgery to chemoradiotherapy to targeted drugs. However, to say that the current anti-cancer field is the most eye-catching, it must be confirmed by immunotherapy.
Whether it is PD-1 or CAR-T treatment, it is the hottest research direction in cancer treatment. But cancer immunotherapy has not only recently emerged. As early as when we studied macrophages, cancer immunotherapy began a long journey...
references:
1.Deepak Raj, Ming-Hsin Yang, David Rodgers, et al. Switchable CAR-T cells mediate remission inmetastatic pancreatic ductal adenocarcinoma, BMJ Gut 2018;0:1–13
2. Kalos M, levine Bl, Porter Dl, et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med 2011; 3: 95ra73.
3. Muselaers cH, Boers-Sonderen MJ, van Oostenbrugge tJ, et al. Phase 2 Study of lutetium 177-labeled anti-carbonic anhydrase iX Monoclonal antibody girentuximab in Patients with advanced renal cell carcinoma. Eur Urol2016;69:767–70
4.Cameron D, Piccart-gebhart MJ, gelber rD, et al. 11 years' follow-up of trastuzumab after adjuvant chemotherapy in Her2-positive early breast cancer: final analysis of the Herceptin adjuvant (Hera) trial. Lancet 2017;389 :1195–205
5. Kim MS, Ma JS, Yun H, et al. redirection of genetically engineered car-t cells using bifunctional small molecules. J Am Chem Soc 2015;137:2832–5
6. Ma JS, Kim JY, Kazane Sa, et al. Versatile strategy for controlling the specificity and activity of engineered t cells. Proc Natl Acad Sci USA 2016;113:e450–8
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