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Mysterious disappearing tumor

In the oncology department for a long time, there is always a chance to meet miracles. About ten years ago, Archie Tse also worked at the Sloan-Kettering Cancer Center. At that time, he took over a patient with advanced pancreatic cancer. The prognosis of most patients with pancreatic cancer was not good. The same happened to her, and the condition was getting worse and worse, probably only a few months left.

 

Her peritoneal cavity has begun to infiltrate a large amount of fluid, and the doctor can only drain it by inserting a catheter. However, due to an infection, the intra-abdominal catheter can only be removed. She was also sent home to recuperate, allowing her to spend the last time in her family.

 

However, after a few months, Tse met the patient again in the hospital. Tse felt very surprised because he did not expect she was still alive. Although the patient did not receive any treatment in the past few months, the fluid in her abdomen had miraculously disappeared. Tse gave the patient a CT scan. The result was clear and her tumor had disappeared.

 

Although many oncologists do not have the chance to see such patients with their own eyes, most doctors have heard similar patients. Physicians call this phenomenon a spontaneous remission, and even a handful of cancer patients are able to relieve themselves even without any treatment.

 

For a long time, researchers have been very curious about this phenomenon. In the end, what causes the patient’s tumor to disappear? Is God’s favor or the power of faith?

 

Perhaps a more reasonable explanation is that these patients’ immune systems are activated, enabling their own immune system to effectively fight tumors and completely eliminate these tumor cells. However, the probability of spontaneous tumor remission is extremely low. Some researchers have speculated that the probability of this phenomenon is about one in 100,000 [1]. Therefore, even if there is a possibility of tumor spontaneous remission, the vast majority of patients cannot benefit from it.

 

So the more important question is, what kind of revelation can we bring about by the spontaneous remission of tumors? Actually, William Coley, a surgeon who also worked at the Sloan-Kettering Cancer Center, studied such cases as early as 100 years ago.

William Coley

William Coley had read Stein’s experience in the medical records left by his mentor. Stein had a large tumor under his left ear, but the tumor gradually disappeared after the infection. This inspired Coley’s inspiration, so Coley began to treat them by injecting inactivated bacteria into the tumor patients in hopes of recurring such a miracle that the patient’s tumor could shrink or even disappear.

In most cases, Coley’s toxins do activate the immune system, enabling those activated immune cells to recognize and attack tumor cells. Although he has cured many patients with cancer, this therapy is not always effective, and there are many restrictive factors, so the treatment ultimately failed to become the mainstream method of cancer treatment.

In the following decades, due to the limitations of people’s understanding of the field of tumor immunity, there has been no significant progress in this area. In the 1960s and 1970s, there were some treatments such as BCG that nonspecifically strengthen the immune system by intratumoral injection or systemic administration. By the 1980s, interferons and IL-2, which were able to activate T cells as well as NK cells, were also tried for cancer treatment (linked from Wei Xixi to Emily Whitehead).

 

However, these methods still have a lot of limitations, and the toxic side effects of many therapies are very strong. However, scientists still did not give up and still hope to reproduce Coley’s miracle. In recent years, more and more scholars and pharmaceutical companies have turned their attention to a new type of therapy. The drug’s target for this therapy is a protein called STING.

The name of STING is derived from the Stimulator of Interferon genes, which can be activated during infection in humans. STING is a component of the human innate immune system. The innate immune system is the first line of defense against the invasion of external pathogens such as bacteria and viruses. When STING is activated, it increases the production of interferon and cytokines, and activates the adaptive immune system and activates T cells through a series of cascade reactions.

In fact, modern medicine has mastered some methods to use T cells to fight tumors, such as Keytruda and Opdivo, the checkpoint inhibitors of Merck and BMS.

In 1999, Tasuku Honjo of Kyoto University in Japan discovered that PD-1 can inhibit the function of the immune system in some cases, and when the gene expressing PD-1 is knocked out, many mice develop autoimmune diseases. The autoimmune response is also an expression of the immune system’s over-expression. In collaboration with Arlene Sharpe and Gordon Freeman of Harvard University, Honjo discovered that some tumor cells have a protein called PD-L1 on the surface that can interact with PD-1 on the surface of T cells to protect them from T cell attack. .

The drugs that act on the above targets are very effective for some patients with cancer, but the overall effectiveness of these drugs is only about 20–30%. Therefore, from the perspective of efficacy, these drugs still have a lot of room for improvement.

 

Therefore, pharmaceutical companies are also trying to find a treatment that can be used in combination with PD-1/L1 inhibitors. The STING agonist may be one of them. PD-1/L1 inhibitors can suppress the activation of T cells, but if there are no T cells inside/near the tumor, this type of drug is also difficult to exert, which is part of the reason for the overall low efficiency of this type of drug.

 

Patients need to have an immune response before using this class of drugs so that checkpoint inhibitors can work. The innate immune system happens to be able to accomplish this task. In other words, activation of STING can provide a basis for the activation and proliferation of T cells, and the use of checkpoint inhibitors later allows T cells to have sufficient capacity to eliminate tumor cells in vivo. This is why in recent years, including BMS, Merck, Novartis and other pharmaceutical companies are trying to find the drugs that can activate STING.

II

STING……STING

When Glen Barber first discovered STING ten years ago, he probably would not have expected that the discovery of STING protein would bring new hope for tumor immunotherapy. When Barber studied the immune system and pathogens at the University of Miami, he discovered that cells lacking the STING protein were very vulnerable to virus invasion [2].

 

Russell Vance of UC Berkeley later discovered that the bacterial molecule c-di-GMP (a cyclic dinucleotide, CDN) binds to mammalian STING receptors and activates the innate immune system [3]. Barber discovered in 2012 that STING could be activated by DNA leaking from dead cells in the same organism, but how STING identified such a large DNA molecule was still unclear.

 

In 2013, Zhijian Chen of the University of Texas Southwestern Medical Center solved the problem: whether the DNA is from a virus, bacteria, or organism itself, it can be associated with an enzyme called cyclic GMP-AMP synthase (cGAS). In combination, cGAS can connect two nucleotides to form a cyclic dinucleotide called cGAMP, which activates STING [4].

 

In this way, the activation process of STING is clearer. DNA in the human body usually does not activate the STING protein because DNA can normally be present in the nucleus (except for mitochondrial DNA). However, if DNA leaks into the cytoplasm, it will activate STING and trigger an immune response. Scientists recently discovered that radiotherapy and chemotherapy can also activate STING, which may also be due to DNA leaking from dead tumor cells that causes STING to be activated.

 

The Tim Mitchison group of Harvard Medical School and the group’s Lingyin Li brought more surprises to STING. Mitchison Laboratories has been working with Novartis to study an antitumor compound DMXAA. Preclinical studies have found that this compound is extremely effective in mouse anti-tumor models, but the subsequent two phase III clinical trials ended in disastrous defeat.

 

After this, Mitchison was disheartened with DMXAA and Li, who was responsible for the project, was unwilling to touch this compound again. But soon Mitchison convinced Li to continue the DMXAA project. However, she had an unexpected discovery this time. Li discovered that DMXAA can activate STING. However, unlike the naturally occurring STING inhibitor CDN, DMXAA binds only to the rat STING protein [5]. This also explains why Novartis’s clinical trials have not been successful and it is this research that has set off an upsurge of STING.

III

upsurge

Aduro Biotech is a small biotechnology company whose researchers found that direct injection of synthetic CDN into mice’s tumors activates STING, activating the innate immune system and triggering a cascade of cascades, and activating T cells to fight tumors. Aduro’s research team also injected more tumor cells into the mice and spread them throughout the lungs. Unexpectedly, a single intratumoral injection of CDN activates T cells of the entire body of the mouse and removes tumors from other parts of the body, including the lungs [6]. If this result can be reproduced in patients, it means that STING agonists will have very bright prospects, because most patients eventually die not from carcinoma in situ, but from the tumors formed by the metastasis of cancer cells.

Novartis also followed closely. They had previously predicted that STING might be a good drug target when working with the Mitchison lab, and Li soon published another article on STING agonists [7]. However, the reported compounds in the Li article have been previously patent protected by Aduro. In March 2015, Novartis reached a partnership with Aduro to jointly develop STING agonists that were still in the preclinical stage. Novartis agreed to pay up to 200 million U.S. dollars in down payment and approximately 500 million U.S. dollar miles.

In the past few years, pharmaceutical companies have become increasingly enthusiastic about STING. In May 2016, STING agonists from Aduro and Novartis entered the first clinical phase. In early 2017, Merck started a clinical study of the combination of Keytruda and STING agonists. In August of last year, BMS acquired pre-clinical STING agonists from IFM Therapeutics by paying $300 million down payment and a $2 billion milestone payment. In September, Novartis announced the effectiveness of its own checkpoint inhibitors in combination with Aduro’s STING agonists (PDR001/ADU-S100). It is believed that many subsequent STING agonists will also be evaluated in similar combinations.

Crystal structure of human STING protein and its agonist ADU-S100. Source:CEN

 

In addition to the exploration in the field of tumor immunotherapy, some pharmaceutical companies are also designing STING antagonists to treat autoimmune diseases by inhibiting overactive STING proteins. In October last year, Celgene and Nimbus Therapeutics reached a cooperation agreement to jointly develop STING antagonists for the treatment of autoimmune diseases. Nimbus also hopes to obtain intravenous or oral STING agonists rather than direct intratumoral injections.

 

In general, naturally occurring CDNs are difficult to develop into drugs because phosphodiesterases in the human body can degrade these compounds quickly. However, chemical modifications can make these compounds more stable. However, it is still very difficult to make CDN into oral medicine.

 

As of now, the development of small-molecule STING agonists based on DMXAA (a murine STING-specific agonist) has been relatively smooth. But some pharmaceutical companies have developed some creative ways to use CDNs for more types of tumors.

 

Spring Bank Pharmaceuticals is developing a CDN-based, intravenously-administrable STING agonist. It is expected that clinical trials for the treatment of liver cancer will be launched at the end of this year. The company is also working with companies developing antibody-conjugated drugs to attach STING agonists to antibodies that allow them to locate tumor cells more accurately. Similarly, iTeos Therapeutics is also working with Cristal Therapeutics to develop a drug delivery system that can target tumors.

 

A century after the emergence of Coley’s Toxin, a new treatment strategy for injecting bacteria into the tumor has emerged, and this time the STING pathway has been activated by injection of genetically engineered bacteria. Synlogic is testing an E. coli strain that produces a high level of bacterial STING agonist c-di-GMP. Similarly, Venn Therapeutics is also developing adenovirus-based gene therapy to deliver intratumoral STING agonists.

 

But whether it is a CDN or a small-molecule drug, even if systemic drug delivery is successful, pharmaceutical companies should pay attention to a dangerous toxic reaction: a cytokine storm. If STING is overactivated, the immune system in the body may lose control. In fact, this condition has occurred in other immunotherapy.

 

Another concern about the therapy came from a preclinical study last year. Researchers at the Tufts University have found that STING agonists can cause T cell death [8], which is exactly contrary to the original intention of this type of drug. Tse of Merck said that the high dose of long-term use of STING inhibitors in this study means that the results of this study may not be clinically relevant. But his team is closely monitoring the patient’s T-cell levels after a dose increase in a phase I clinical trial.

 

The results of Phase 1 clinical trials between Merck and Novartis will likely be announced later this year. Cancer immunotherapy is an exciting, but at the same time full of unknown and challenging areas, whether the drugs that affect the STING pathway can sweep the field of tumor immunity. How many tumor patients can benefit from it? let us wait and see.

references

1 Cancer Immunology, Immunotherapy, 50:391-396. 2001.

2 Nature, 455:674-678. 2008.

3 Nature, 478:515–518. 2011.

4 Science, 339:786-791. 2013.

5 ACS Chemical Biology, 8 (7):1396–1401.2013.

6 Cell Reports, 11(7):1018–1030. 2015.

7 Nature Chemical Biology, 10:1043–1048.2014.

8 Journal of Immunology, 199(2):397-402.2017.

9 CEN, 96(9):24-26. 2018.

10 Nature Reviews Immunology, 15:760-770.2015.

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