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Immunotherapy efficacy increased with the discovery of a novel drug that bypassed inhibitory immune cells

The immune system was recruited to tackle tumor cells. The survival rates of millions of cancer patients improved after receiving immunotherapy. But, the treatment method also has a drawback: only one out of five patients had a favorable outcome to treatments of this kind. Researchers at the Washington University of Medicine in St. Louis wanted to understand and address the limitations of immunotherapy. They performed an extensive research study and found that in the fight against cancer, the immune system can act as its worst enemy.

In another study, researchers investigated a subset of immune cells, that is, type 1 regulatory T cells, or Tr1 cells in mice. They found that these cells performed their normal function of preventing an overreaction of the immune system. Meanwhile, they also inadvertently suppressed the cancer-fighting power of immunotherapy. According to senior researchers at the Department of Pathology and Immunology at Washington University School of Medicine, the Tr1 cells have a heretofore character that is considered to be an unrecognized obstacle to the efficacy of immunotherapy.

It suppresses its fight against cancer. Therefore, in the mouse model, the researchers tried to circumvent this limitation. They could revitalize the cancer-fighting cells in the immune system. Thus, this finding is an important development in expanding the benefits of immunotherapy. More and more cancer patients can now avail the novel developments of immunotherapy. A detailed information of this study is available in the journal Nature.

Personalized form of immunotherapy is now available to cancer patients in the form of vaccines. Cancer vaccines are aimed at the mutant proteins, which are specific to a tumor in a patient. These vaccines encourage an attack on tumor cells by boosting the activity of killer T cells. At the same time, they allow the healthy cells to remain unaffected. In another study conducted by Schreiber’s group, it was found that helper T cells are also activated with vaccines that are more effective.

The helper T cells are another type of immune cells. They are used for recruiting and expanding the killer T cells. These cells are known to destroy tumor cells. These researchers tried to supercharge the cancer vaccine by adding an additional amount of helper T cell targets. They found that a different type of T cell was generated. This type of T cell suppressed the rejection of tumor cells.

In another study, a group of researchers laid down the following hypothesis: when the activation of helper T cells was increased, they could induce an enhanced elimination of sarcoma tumors in mice. They injected vaccines in groups of mice with tumors. These vaccines could activate the killer T cells in an equal manner and also trigger different extent of activation of helper T cells.

In their latest study, the researchers were surprised to know the activity of the vaccine. They had developed the vaccine to hyperactivate helper T cells. However, the effect of this vaccine was opposite and it suppressed the rejection of tumor cells. The researchers were of the view that the vaccine should have eliminate the sarcoma tumors in mice as it activated more and more T cells.

The vaccine contained helper T cell targets in higher doses, and this induced inhibitory activity in Tr1 cells. Thus, the elimination of tumor cells was blocked completely. In general, Tr1 cells control an immune system that is overactive. However, ours is the first study to show that they can dampen the fight against cancer. The brakes on the immune system are generally put by Tr1 cells. They prevent the immune system from attacking healthy cells of the human body. However, no previous study has investigated its role in cancer comprehensively.

Previously published data was investigated thoroughly by researchers. They found that more Tr1 cells were present in tumor patients who showed a poor response to immunotherapy treatment. The number of Tr1 cells was lesser in tumor patients who had shown a good response to immunotherapy treatment. When tumors grew bigger in size in mice, the number of Tr1 cells increased proportionately. This made the mice develop an insensitivity to immunotherapy.

Researchers wanted to bypass the inhibiting cells in mice, which were vaccinated. Therefore, they treated these mice with a drug that improved the cancer-fighting power of killer T cells. This drug was developed by Asher Biotherapeutics, which is start up in the field of biotechnology. The drug could carry out modifications in interleukin 2 (IL-2). Please note that IL-2 is a protein that boosts the activity of the immune system. The drug could specifically enhance the activity of killer T cells and reduce the toxicity associated with other treatments that do not modify IL-2.

The inhibition of Tr1 cells was overcome by the additional boost provided by the drug. Thus, the immunotherapy was found to be more effective. The lead researcher said that they are focusing on providing personalized immunotherapy and widening the efficacy of the treatment. The researchers said that in order to attain the most robust anti-tumor response, they had to understand how to trigger the immune system. For this purpose, they referred to related studies in recent decades. These studies investigated the basic immunology of the tumor. In our current study, the main aim of researchers was to improve the immunotherapy and to benefit more patients with cancer.

 

 

 

 

 

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Immunotherapy is now supported by epigenetically active drugs

 

Drugs that are active epigenetically would help a cell in reading the parts of a genome. These parts were either blocked earlier or inaccessible to the cells of the human body. Thus, new mRNA transcripts and proteins can be formed. This important finding has been presented by scientists of the German Cancer Research Center and the University Hospital of Tubingen.

The immune system would be able to identify cancer cells, thanks to the activity of “therapy-induced epitopes.” Immunotherapies are now being provided to treat patients with different types of cancer. But, all the cancer patients do not benefit from immunotherapy. The treatment fails in some cases because the immune system of the patient is not able to identify cancer cells.

Antigens are protein structures, which are transported by cancer cells onto their surface. At this stage, the T cells of the immune system recognize and differentiate them from healthy cells in the human body. In such cases, immunotherapy is effective and successful.

The antigens can be proteins associated with cancer, and they are also known as tumor-associated antigens. Antigens could also be proteins that have been modified by mutations. They are known as completely new gene products. These products are formed in tumor cells when completely new areas of the genes are being read.

Researchers of this study decided to make the immune system quite visible to cancer cells. The cells were equipped with completely new antigens. This was possible due to the help offered by cancer drugs, which were epigenetically active. Many cancer patients are prescribed such types of drugs. The epigenetic markers of the DNA or the proteins associated with the DNA are subjected to these drugs.

Thanks to the epigenetic markers, researchers could determine whether certain parts of the ist genome in mRNA could be translated by cancer cells. Decitabine or the HDAC inhibitors are a class of demethylating drugs, which have epigenetic effect. They help in reading those parts of the genome, which were either blocked or were inaccessible earlier. Thus, new mRNA transcripts can be created in the cells.

In this study, a lung cancer cell line was treated with decitabine and HDAC inhibitor in a culture dish. This induced the formation of several new transcripts, which were detected by RNA analysis. The origin of most of the new transcripts could be traced to endogenous retroviruses. The sequences of these transcripts accounted for upto 8% of the human genome, so they were considered as relics of retroviral infections.

In general, epigenetic mechanisms block their transcription. In cancer cells, the effect of the neoepitopes is much stronger than that in healthy cells. These neoepitopes are induced by Decibtabine and HDAC inhibitors. Cancer cells have high proliferation rate. The researchers now had to determine whether the therapy-induced transcripts could be used for coding segments of immunogenic proteins, that is, peptides.

Mass spectrometry was used for analysis in this study. The researchers were able to identify 45 neoepitopes, which were present on the surface of cancer cells post-treatment. The results obtained were reproducible with a large number of different cancer cell lines. In the culture dish, the cytotoxic T cells could be activated by therapy-induced neoepitopes.

 

 

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Researchers identify the switch that activates programmed death of cancer cells.

The UC Davis Comprehensive Cancer Center has conducted an in-depth research study. The focus was to activate programmed death of cancer cells. A crucial epitope has been identified on the CD95 receptor, and it triggers the death of cells. An epitope is a section of protein that activates the larger protein. As cell death can now be programmed, cancer treatment methods have become effective.

In molecular biology, CD95 receptors are known as Fas and death receptors. These receptors are proteins present in cell membrane. They evoke self-destruction of cells by releasing a signal. This happens when CD95 receptors are activated. By modulating the activity of Fas, researchers extended its benefits to CAR T-cell therapy. This was effective in destroying solid tumours of ovarian cancer.

Managing cancer with better therapies

The conventional method of treating cancer includes chemotherapy, radiotherapy, and surgery. In cases where cancer is diagnosed at an initial stage, these methods are effective. However, cancer cases may relapse, especially when they are therapy-resistant. Recently, CAR T-cell immunotherapy and an immune checkpoint receptor molecule have shown to activate antibodies, and thus they are promising candidates that destroy the cycle of cancerous growth.

These immunotherapeutic agents are effective against only few types of cancer cells, such as ovarian cancer, breast cancer, lung cancer, and pancreatic cancer. In CAR T-cell therapy, researchers engineer the specific type of immune cells, that is, T cells. They graft these cells on a specific antibody that targets specific tumours. The grafted T cells are quite effective in battling leukaemia and other types of blood cancer.

The engineered T cells have not been effective in combating solid tumours; the microenvironment of these tumours drives off T cells and other immune cells. Thus, they cannot provide a therapeutic effect to solid tumours. Although the immune receptor activates antibodies, the T cells cannot infiltrate without additional spaces.

The activity of death receptors

Now, let us understand the activity of death receptors. Through targeted therapy, we can trigger them into programming cell death of tumours. Thus, chemotherapeutic drugs should be such that they induce the activity of death receptors. Many pharmaceutical companies have been slightly successful in targeting the death receptor-5. But the clinical trials of Fas agonists have failed.

Developing the right target

The activity of immune cells is effectively regulated by Fas. However, researchers have proposed that cancer cells can be targeted selectively if they identify the correct epitope. After identifying the targeted epitope, researchers of this study have designed a new type of antibodies. These antibodies show selectivity while binding and activating Fas. With this strategy, specific tumor cells can be destroyed.

 

 

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Researchers develop a remote-controlled cancer immunotherapy system

 

An innovative ultrasound system has been developed to destroy genetically controlled processes in live T cells of the immune system. This team of researchers can destroy cancer cells. By developing non-invasive immunotherapeutic strategies, cancer cells can be manipulated and destroyed.

A novel strategy was used to improve the practical applications of mechanogenetics, which is a scientific discipline that improves the expression of genetics and activity of cells. T cells were mechanically destroyed by ultrasound. To genetically control cells, mechanical signals were used.

This experimental study establishes how mechanogenetics system is remote controlled and T cells are manipulated by chimeric antigen receptor (CAR). Cancer cells can be targeted and killed with this innovative approach. Researchers have modified CAR-T cells with mechano-sensors, genetically transducing modules.

This innovative approach was termed as therapy of CAR-T cells, which provided a paradigm shift for the treatment of cancer. Life-threatening complications develop when CAR-T cells are non-specifically targeted. The precision and the accuracy of CAR-T cell specific immunotherapy was improved in an unprecedented manner.

This innovative immunotherapy was used to target solid tumors. At the same time, off-tumor activities were minimized. Microbubbles were combined with streptavidin and they were attached to cell surface. Mechanical vibration and the stimulation of Piezo1 ion specific channels was performed by microbubbles when they were exposed to waves of ultrasound.

This led to the entry of calcium ions into the cell, triggering the following downstream pathways: the activation of calcineurin, the dephoshorylation of NFAT and the translocation into the nucleus. With recognition and destruction of targeted cancer cells, chimeric antigen receptor (CAR) was used to initiate the expression of genes.

 

 

 

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A promising clinical trial developed a novel immunotherapy for lung cancer

A recent clinical trial of lung cancer has shown promising results, which could be considered as groundbreaking developments. In this clinical trial, a novel immunotherapy combination was very effective in controlling the progression and development of lung cancer. The results of this innovative study were published in the journal The Lancet Oncology. The clinical trial focused on combating non-small cell lung cancer, which is the most common form of lung cancer.

This clinical trial was conducted under the supervision of John Wrangle, M.D. He is a prominent immunologist at the Hollings Cancer Center, which is affiliated to the Medical University of South Carolina. According to Dr. John Wrangle, the clinical trial’s results are promising enough to confirm that the novel therapy can be delivered effectively in an outpatient setting.

In general, metastatic lung cancer is “incurable” in patients till date. But the results of immunotherapy have been promising enough to offer a ray of hope to these patients. . The disease-free survival rate of these patients was drastically improved when they treated with novel immunotherapy.

In the very least of terms, metastatic lung cancer patients cannot be “cured” presently but this novel immunotherapy has certainly increased their chances of survival. .Dr. John Wrangle designed this clinical trial with the help of his colleague Mark Rubinstein, Ph.D. John Wrangle and Mark Rubinstein work together at the Hollings Cancer Center. The clinical trial was started in the year 2016.

Despite receiving chemotherapy at regular intervals, metastatic non-small cell lung cancer always shows signs of progression in most patients. Therefore, these patients are also treated with immunotherapy to combat their deteriorating situation.

Immunotherapy is a recent development in cancer treatment. The principle of immunotherapy is as follows: the immune system of the human body is programmed to fight cancer cells. “Checkpoint inhibitor” is the most common class of immunotherapeutic drugs: white blood cells constitute the most important component of natural defenses in the human body.

White blood cells can effectively target cancer cells when “checkpoint inhibitor drugs” target the checkpoints associated with the regulation of immune system. According to Rubinsetin, the pathophysiology of checkpoint inhibitor drugs is as follows: the drugs cut off the brake cables of white blood cells, which are very effective in killing cancerous cells.

Tumor cells also have their own mechanism for proliferation and progression: Suppressive factors are produced by tumor cells, turning the brakes of white blood cells and preventing them from effecting the apoptosis of tumor cells.

Rubinstein further states the novel immunotherapy is more effective in killing lung cancer cells because it is based on the following principle: apart from cutting the brakes cables of white blood cells, the novel immunotherapy provides fuel so that cancer cells can be killed very effectively.

The novel immunotherapy developed by Wrangle and Rubinstein was based on the following principle: the checkpoint drug nivolumab was combined with ALT-803, which is a novel and powerful drug for stimulating the immune system.

The clinical trial was path-breaking because although the drugs were completely different from each other, they were effectively combined and administered to humans for the first time. Moreover, the results of the clinical trial indicate that these drugs can be administered safely. The evidence is compelling enough to prove that this immunotherapy can also be successful on patients who did not respond well to checkpoint therapy.

Rubinstein and Wrangle reiterate the significance of this novel immunotherapy: checkpoint therapy is not provided to lung cancer patients when they stop responding positively; however, the survival period of these patients can be improved significantly with the addition of ALT-803 drug.

This is because many studies have established that the immune system in the human body is activated by ALT-803 drug. Consequently, the lymphocytes of the immune system may be effectively coaxed to combat tumor cells. In such a scenario, combination treatments may be good enough provided they include the drug ALT-803.

In their clinical trial, they had carefully monitored the condition of 21 patients with metastatic lung cancer. Out of them, 9 patients had become resistant to single-agent immunotherapy after a certain period of time. All the nine patients either had stable disease or they responded partially to the single-agent immunotherapy. Therefore, novel combination therapy is the right step in combating cancer.

Surgery, chemotherapy, and radiation are the conventional modes of treating cancer since several decades. However, the last decade has shown prominent strides in cancer treatment, with promising results shown by targeted therapy and immunotherapy. The balance of power between cancer and human immune system has been tilted with these innovative approaches.

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Researchers develop a remote-controlled cancer immunotherapy system

An innovative ultrasound system has been developed to control genetic processes in live T cells of the immune system. This team of researchers can destroy cancer cells. By developing non-invasive immunotherapeutic strategies, cancer cells can be manipulated and destroyed.

An innovative approach was used to improve practical applications of mechanogenetics: a field of science that improves the expression of genetics and activity of cells. T cells were mechanically destroyed by ultrasound. To genetically control cells, mechanical signals were used.

In this study, it was found that mechanogenetics system could be remote controlled and T cells can be manipulated by chimeric antigen receptor (CAR). Cancer cells can be targeted and killed with this innovative approach.

Researchers have engineered CAR-T cells with mechano-sensors, genetically transducing modules. This innovative approach was termed as CAR-T cell therapy, which provided a paradigm shift for the treatment of cancer.

Life-threatening complications develop when CAR-T cells are non-specifically targeted. Precision and accuracy of CAR-T cell immunotherapy was improved in an unprecedented manner. This innovative immunotherapy was used to target solid tumors. At the same time, off-tumor activities were minimized.

Microbubbles were conjugated to streptavidin and they were attached to cell surface. Mechanical vibration and stimulation of Piezo1 ion channels was performed by microbubbles when they were exposed to ultrasound waves. This led to the entry of calcium ions into the cell, triggering the following downstream pathways: calcineurin activation, NFAT dephoshorylation and translocation into the nucleus.

With recognition and destruction of targeted cancer cells, chimeric antigen receptor (CAR) was used to initiate the expression of genes.

 

 

 

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A new recyclable treatment for destroying cancer cells selectively

Researchers at the University of Warwick have developed a new recyclable treatment for destroying cancer cells. This research study was led by Professor Peter J. Sadler, who works at the Department of Chemistry at the University of Warwick. They have synthesized an organic-osmium compound, which can selectively attack cancer cells. The compound was synthesized using sodium formate in non-toxic dosages. Sodium formate is found in many organisms as a natural product. Ants and nettles also synthesize this natural product.

The novel organic-osmium compound was named JPC11 by researchers. They found that this compound can target metabolic process that governs the survival and proliferation of cancer cells. Cancer cells derive energy for rapid division and proliferation from a key substance, which belongs to the class of pyruvates. This key substance is converted into unnatural lactate by JPC11. The resultant lactate destroys cancer cells.

The significance of this treatment lies in the fact that the chemo-catalyst JPC11 is recyclable; therefore, it can be reused to repeatedly attack a particular cancer cell line. This is a path-breaking innovation in cancer treatment as JPC11 is a novel compound that paves the way for recyclable treatment of cancer. In future, side-effects and toxicity of chemotherapy can be minimized by administering such recyclable drugs in smaller dosages. The functional capacity of JPC11 is unprecedented given the recyclable ability of the compound. Researchers have been now focusing on how this compound can be effectively used to treat ovarian cancer.

It is difficult to treat patients with ovarian cancer because they are usually resistant to conventional chemotherapeutic drugs. In particular, they are highly resistant to the platinum drug cisplatin. This new drug broadens the scope of anticancer treatment given the fact that it is recyclable and reusable. The new drug is promising as it destroys cancer cells through a completely novel mechanism, so ovarian cancer patients may not be resistant to this novel drug.

One of the major attractions of this compound is the fact that it selectively destroys cancer cells. Researchers found that JPC11 compound primarily targeted the expression of cancer cells. The compound did not attack healthy living cells, so they were mostly unaffected by exposure to JPC11 compound. Compared to conventional platinum drugs, the selectivity of JPC11 compound is far more superior and effective. In fact, the conventional platinum drugs would also destroy healthy living cells which were in the vicinity of cancer cells. Thus, the selective activity of JPC11 compound seems to be a major breakthrough in cancer treatment.

According to Dr. James Coverdale, this is a path-breaking discovery in the treatment of cancer. Dr. James Coverdale is a research scholar at the Department of Chemistry, University of Warwick. He worked with his colleagues to develop this innovative compound, which holds promising results in cancer treatment. By synthesizing this compound, they broadened the applications of chemistry in medical science. With this compound, they have come up with a novel strategy for killing cancer cells selectively. The compound JPC11 is a chemo-catalyst with a unique mechanism of action, which seems to be more selective and effective in destroying cancer cells. Given its high selectivity, it paves the way for new treatments that are much safer and effective than conventional treatments.

Peter Sadler is a medicinal chemist who also worked with this research group at the University of Warwick. According to Professor Peter Sadler, cancer chemotherapy mainly involves the use of platinum compounds. However, these drugs have poor selectivity and less safety, so new drugs must be invented to overcome the problem of side-effects and drug-resistance. In this research study, a truly novel drug was discovered for cancer treatment. Professor Peter Sadler believes that chemo-catalysts are promising in cancer treatment since they have immunogenic properties. However, the efficacy of this drug must be further established by conducting clinical trials.

 

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Advanced skin cancer can now be treated with Arthritis drug

According to a latest research study, patients with advanced skin cancer can now be treated more effectively if they are administered a well-known drug, which is normally used to treat rheumatoid arthritis. This drug should be dispensed in combination with conventional drug therapy used to treat skin cancer. This study was conducted on mice by researchers at the University of East Anglia (UEA). Melanoma tumor growth stopped almost completely in mice with advanced skin cancer when they were treated with both conventional medications and arthritis drug. Melanoma tumor occurs only in five percent of patients with skin cancer; however, it is the deadliest form of tumor with high mortality rate. If melanoma growth is diagnosed at an early stage, then it can be completely treated with this combinatorial therapy. However, it is difficult to treat melanoma in metastasis stage.

In recent times, novel treatments have targeted genetic mutations that cause metastatic melanoma in patients. However, metastatic melanoma becomes resistant to drugs very quickly, so researchers are focusing on developing a combination of treatments that can effectively destroy the proliferation of metastatic melanoma. Dr Grant Wheeler was the lead researcher at the School of Biological Sciences, UEA. According to Dr. Wheeler, metastatic melanoma can be attacked from several angles, if researchers provide combinatorial therapies to patients with skin cancer. Melanoma tumors would then find it difficult to develop drug resistance. In their research study, they could further establish the benefits of combinatorial therapies: since they administered arthritis drug along with conventional therapy to mice with skin cancer, the benefits of both therapies were enhanced; therefore, the effects of combinatorial therapies were more than the sum total of all benefits.

In this research study, Dr Wheeler worked with colleagues at the School of Pharmacy in UEA. This study was conducted in collaboration with researchers at the Norwich Medical School. Leflunomide is an immunosuppressive drug that is normally prescribed to patients with rheumatoid arthritis. They investigated how effective was Lelunomide drug in treating skin cancer patients, which were also treated with skin cancer therapy simultaneously.

In a previous study, these researchers had found that Leflunomide was effective when used with drugs that target a certain genetic mutation of melanoma tumor, namely, BRAFV600E. In current research study, they tested the efficacy of leflunomide in combination with seflumetinib, which is a conventional drug used to treat melanoma. They found that this combination of drugs was more effective in treating melanoma. Melanoma depends on a protein called MEK for its survival. The activity of MEK protein is targeted by the drug Selumetinib. Many drugs act as inhibitor of MEK activity. These drugs are used along with BRAF inhibitors to tackle resistance. In current study conducted by Dr Wheeler, it was found that this combination of drugs was more effective when leflunomide was also included in it.

These researchers tested leflunomide on melanoma cells in the laboratory. They found that leflunomide was effective in combating melanoma growth, irrespective of its genetic mutation. This was a path-breaking discovery as leflunomide could now be used to treat all kinds of melanomas, and not just the tumors caused by BRAF mutation. The team of researchers investigated the activity of leflunomide on melanoma cells. They found that leflunomide could arrest of growth of melanoma cells when they were in their early stage of development. Then, leflunomide would initiate controlled cell death, known as apoptosis. It would force melanoma cells to kill themselves.

This group of scientists then tested the efficacy of combining leflunomide with selumetinib. They found that this combination of drugs was more effective in killing melanoma cells. This finding was confirmed by administering leflunomide and selumetinib to mice with melanoma tumors. Over a period of 12 days, this combination of drugs was administered to mice with melanoma tumors. It was found that the combinatorial therapy worked wonders in completing stopping the growth of melanoma tumors. The efficacy of combinatorial therapy was far superior to those of individual drugs. However, further clinical trials need to be carried out to ascertain if melanoma tumors show drug resistance to this combinatorial treatment.

According to Dr. Wheeler, death rate is quite high in patients with melanoma tumors because these tumors usually develop resistance to drugs. Therefore, most patients respond poorly to melanoma treatments. To tackle this problem, doctors are now propagating immunotherapeutic treatments to boost defence mechanisms within the human body. However, researchers are still hopeful that novel combinatorial therapies would work wonders in association with immunotherapy, which is now being provided to most patients with melanoma tumors. According to Dr. Wheeler, the combination of leflunomide and selumetinib can destroy melanoma tumors effectively.