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In the middle and late stages of cancer, metastasis of cancer cells is usually the key cause of the worsening and death of patients. In order to completely disintegrate cancer cells at this stage, scientists have developed a variety of cancer therapies. Among them, photothermal therapy and ICB immunotherapy have attracted much attention, but the combination of the two will produce some harmful side effects. Recently, a study published by Soochow University in Science Advances combines the two in a completely new way. However, this treatment sounds a bit scary: to treat cancer, they directly injected a pathogenic bacteria into the patient's blood, Salmonella typhimurium (Salmonella typhimurium ).
Two cutting-edge cancer therapy body
In 2019, Ardeshir R. Rastinehad, a clinician at the Icahn School of Medicine at Mount Sinai, published a study on PNAS as the first author. For the first time, they successfully used a new laser-based cancer treatment technology to treat 15 patients with prostate cancer. In the following year, 13 of the patients showed no signs of recurrence of cancer.
This new technology is called photothermal therapy (PTT). In treatment, Rastinehad et al. used targeted gold-shelled silica nanoparticles, which can encapsulate tumor tissue. When irradiating tumor tissue with near-infrared laser light, these nanoparticles convert light energy into thermal energy, killing these tumors . Research shows the therapeutic potential of this technology, but it also has a clear disadvantage - it can only treat primary malignant tumors and has no choice but to do anything about the metastatic tumor. However, tumor metastasis is often the key cause of the intensification of the patient's condition and death.
In contrast, another cutting-edge cancer treatment, immune checkpoint inhibitor cancer therapy (immune checkpoint blockadetherapy, referred to as ICB immunotherapy), seems to be more prestigious. When cancer cells grow in the human body, they can produce proteins that bind to specific receptors on T cells, inhibit the immune response of T cells and avoid the attack of the immune system. In the 1990s, American immunologist James P Allison discovered the first receptor that can inhibit the response of immune cells - CTLA-4 protein . Japanese immunologist Tasuku Honjo discovered another important T-cell inhibitor receptor (PD-1) in 1992. The two also shared the 2018 Nobel Prize in Physiology or Medicine. Based on their research, other researchers have developed antibodies to block these receptors, effectively treating cancer by re-inducing the body's immune system's attack on cancer cells.
James Allison and Tasuku Honjo
If the two methods can be combined, it may be able to eliminate the primary tumor while inhibiting the metastasis and recurrence of the tumor. However, some previous studies have confirmed that this may produce severe side effects of . For example, the occurrence of a cytokine storm has aggravated the patient's condition. Recently, in a study published in Science Advances, a research team led by Professor Liu Zhuang from the Institute of Functional Nano and Soft Materials of Soochow University innovatively combined these two technologies to create a breakthrough cancer therapy that significantly reduced side effects while exerting the therapeutic effect. Surprisingly, the "protagonist" in this therapy is an pathogenic bacteria - Salmonella typhimurium ( Salmonella typhimurium ).
harmful bacteria out of life
This bacteria can cause acute gastroenteritis in the human body. If not treated in time, it may even cause sepsis and various complications, and it will be more harmful to infants and young children. After entering the human body, because it is more adapted to the microenvironment of hypoxia and inhibited immune response around the tumor, this bacteria will metastasize to the tumor site to survive and reproduce . This phenomenon looks like a mutual benefit and win-win situation between harmful bacteria and cancer cells, causing more serious harm to the human body.
But some researchers realized that attenuated Salmonella typhimurium might be used to target tumors using .In addition to this advantage, this pathogenic bacteria can still cause the body's immune response after attenuation, which is similar to the principle of a vaccine. At this time, because pathogenic bacteria are adsorbed and grown around cancer cells, the human immune system will also attack cancer cell when attacking bacteria, producing some ICB immunotherapy benefits.
Salmonella typhimurium
In 2018, in an article published in ACS Nano, a cancer treatment attempt was made by combining this bacteria and photothermal treatment. At that time, researchers at Sichuan University wrapped Salmonella typhimurium through polydopamine nanoparticles. When Salmonella typhimurium reaches the tumor site, it can convert the received light energy into heat energy and kill tumor cells. However, this system of requires light-absorbing nanomolecules on bacteria, and the system is relatively complex.
In this new study, the Soochow University research team used a simpler new method, and they modified Salmonella typhimurium through gene editing. Edited bacteria have defects in guanosine tetraphosphate (ppGpp) synthesis. When they are enriched in the tumor area for a period of time, the tumor will become significantly black, which will enhance the absorption of near-infrared light .
Treatment Process
Researchers first tested the effects of attenuated Salmonella typhimurium on mice. They found that after one day of intravenous injection of Salmonella typhimurium, most of the mice remained normal in blood indexes, and the number of white blood cells decreased to a certain extent, but they could return to normal levels after one week. In human organs, bacteria are mainly enriched in the liver and spleen 1-3 days after injection, and then is rapidly reduced. After 30 days, due to the organ's own immunity, it is difficult to detect bacteria. Overall, these pathogenic bacteria will cause the mice to have acute inflammatory reactions, and their various blood indicators and weight fluctuate in the short term , but the impact is relatively mild. The mice can fully recover within one week and will not have long-term toxic side effects.
therapeutic effect What is the effect of tumor treatment in this method? After mice received Salmonella injection for 12 hours, near-infrared absorption of tumors in their bodies peaked. When the number of pathogenic bacteria colonies (CFU/each) injected into mice was 5×10⁵, 5×10⁶ and 5×10⁷, under 808 nanometer laser irradiation, the temperature on the tumor surface could rise to 45.5℃, 54.9℃ and 63.1℃, respectively. The increase in tumor temperature was positively correlated with the number of bacteria injected . However, due to the significant reduction in weight in the mice in the highest dose group, the researchers selected the medium dose group (5×10⁶ bacteria) for follow-up studies.
The tumor area becomes significantly darker
When the temperature of the tumor area rises, the blood flow in this area will be abnormal, and bacteria will specifically proliferate in the tumor tissue and cause tumor blood vessels to be destroyed. After the blood components infiltrate the tumor tissue, induces the formation of thrombus in the tumor blood vessels . Since a large amount of red blood cells is enriched in the thrombus, the heme content will increase significantly. enhances the absorption of near-infrared light and further enhances the therapeutic effect of photothermal therapy.
The researchers further used four mouse cancer models (mouse breast cancer, glioblastoma, human pancreatic cancer and human lung cancer) to evaluate the therapeutic effect of this therapy. The results show that samadhi 5 tulinumi can enrich in these tumors, and the tumor can produce black visible to the naked eye after a period of time. Through photothermal therapy, researchers can effectively remove tumors. In addition, memory cells induced by Salmonella can inhibit the recurrence of these tumors during this process. The tumors in the mouse in
experiments are mainly found on the skin, which is different from naturally growing tumors. In this regard, in an interview, Professor Liu Zhuang, the co-author of the article, said: "For naturally growing tumors in the human body, the proliferation of bacteria at the tumor site leads to the destruction of tumor blood vessels and induces the formation of thrombosis in the tumor. This enables the photoacoustic signal of tumor tissues to be enhanced, and can effectively realize photoacoustic imaging of tumor tissues , providing guidance for subsequent photothermal-immunotherapy."
But if you want to completely treat the tumor, you still need to remove the tumors that metastasize to other areas. At this time, what can be relied on is the activation of the mouse's own immune system. They found that after receiving this therapy, the maturity of some antigen presenting cells in the body increased, but it cannot completely remove the tumors in the mouse's body.
8 treatment methods involve surgery, ICB immunotherapy, bacterial therapy and photothermal therapy
When three methods: bacterial injection, photothermal therapy and ICB immunotherapy (line 8), the cancer in the mouse has been obtained more thorough and effective.
In the experiment, they considered 8 methods to treat tumors in mice, but finally found that only when bacterial injection, photothermal therapy and ICB immunotherapy (CTLA-4 antibody) were combined with , can the mice completely eliminate cancer cells in their bodies. At this time, the cytotoxic T lymphocytes, cytokine TNF-α and interferon IFN-γ produced by the mice also reached the highest concentration, which can effectively remove metastatic tumor cells.
When considering the subsequent research plan, Professor Liu Zhuang said: "We will further attenuate Salmonella typhimurium through genetic recombination, or let them express therapeutic proteins and immunomodulatory proteins to better use bacterial therapy for tumor treatment. "At present, attenuated Salmonella typhimurium has entered clinical testing. Although the effect of using alone is not ideal, it can effectively promote the clinical transformation of this new therapy. In addition, when used in combination with ICB immunotherapy (CTLA-4 antibody), it can effectively clear the original site and metastasized tumors, which also shows the huge therapeutic potential of this technology.
written by: Shi Yunlei
Reviewed by: Wu Fei
Reference source:
https://www.nature.com/articles/s41598-018-26978-1
https://pubs.acs.org/doi/pdf/10.1021/acsnano.8b02235
