Aug
13
2022

New Immunotherapy Approach against Cancer

By | Cancer, immune system

A recent publication reported about a new immunotherapy approach against cancer. The model it dealt with was a very vicious brain cancer with the name glioblastoma. The results of this research were subsequently transferred to another vicious cancer, osteosarcoma, which is a form of bone cancer with a very poor prognosis. Researchers have to do further clinical experiments to establish this new immunotherapy in osteosarcoma patients. Physicians completed the following experiments and clinical studies.

Oncolytic virus Delta-24-RGD can lead to remission in glioblastoma patients

Researchers at the University of Navarra, Pamplona, Spain together with The University of Texas MD Anderson Cancer Center in the US investigated glioblastoma patients. They found that treatment of glioblastoma patients with oncolytic viruses Delta-24-RGD led to a greater than 3-year remission in 20% of cases. Normally, patients with a glioblastoma survive only 9 months on average. 12% had a greater than 95% reduction in the size of the tumor. This was a phase 1 clinical study with 37 patients who had recurrent malignant glioblastoma. The authors said: “Oncolytic adenoviruses are attractive therapeutic agents because they can kill tumor stem cells and induce cell death by several mechanisms, including direct lysis, expression of toxic proteins, induction of cytokines, and T-cell–mediated immunity.” The particular oncogenic virus that the researchers used was an adenovirus Delta-24-RGD.

Transferring glioblastoma results to a cure for osteosarcoma

The same researchers wanted to see whether the cure rates of treating patients with glioblastoma was transferable to other cancer patients. In particular they were interested in patients with osteosarcoma, which is a similarly vicious cancer. Advanced osteosarcoma has a survival rate of 27% after 5 years. The researchers first did experiments with a human osteosarcoma cell line in tissue culture and at the same time a murine osteosarcoma cell line. Later they tested the action of oncolytic viruses Delta-24-RGD in a mouse model.

Experiments with osteosarcoma cells in tissue culture

The advantage of such experiments is that you can control all the parameters easily in a Petri dish. But critics say that this is far removed from osteosarcoma behavior in humans. Researchers found that the oncolytic virus Delta-24-RGD killed many osteosarcoma cells in vitro. They also were able to insert a new gene into the oncolytic virus, which was equally effective in killing osteosarcoma cells. They called this virus Delta-24-ACT.

Curing osteosarcoma in a mouse model

Next the researchers tested effectiveness of the oncolytic viruses, Delta-24-ACT and Delta-24-RDG in mice. They injected osteosarcoma cells from tissue culture into the tibia of mice. Tumor growth was subsequently measured. The experimental groups were given two oncolytic virus infections, the control group did not. On day 10 and 18 the researchers could see that controls had faster growing tumors compared to the experimental groups. The experimental groups had less tumor side effects. And the experimental mice survived longer than the controls. Further research showed that the oncolytic viruses produced a 4-1BBL protein, which stimulated the animals’ immune system to fight the osteosarcoma.

New immunotherapy approach against cancer: Effector T cells

Researchers could prove that in mice treated with oncolytic viruses it was the special protein (4-1BBL) that stimulated T lymphocytes to become killer T cells. They in turn attacked the osteosarcoma cells.

New immunotherapy approach against cancer: The need for human research

Doing research in humans is more complicated than in a mouse model. But in order to improve survival rates in patients with osteosarcoma human research is absolutely essential. However, research is complex and the effects of oncolytic viruses is only in the 20% range with regard to increasing survival. This requires more research. It may be that instead of oncolytic viruses a stimulatory protein would arm T cells to become killer T cells that fight the cancer.

New Immunotherapy Approach against Cancer

New Immunotherapy Approach against Cancer

Conclusion

Glioblastoma patients had a better survival after treatment with oncolytic viruses Delta-24-RGD. Researchers translated this type of research to another cancer, osteosarcoma. This also has a poor prognosis, Researchers did experiments in tissue culture and in a mouse model. They were able to show that oncolytic viruses produced a 4-1BBL protein, which stimulated the animals’ immune system to fight the osteosarcoma. Specifically, the protein armed T lymphocytes and turned them into killer T lymphocytes. These destroyed osteosarcoma cells in tissue culture or in the mouse model. It is encouraging to see positive results in a laboratory setting of a tissue culture. The step further in an animal experiment is also a positive achievement. More research will improve the cure rates of osteosarcoma. The effective treatment of osteosarcoma in humans is still far away! The next step is human research that shows improvements in patients’ survival rates.

Mar
07
2022

T-Cell Immunotherapy Cures Chronic Lymphocytic Leukemia

By | Cancer, genetic marker, immune system, leukemia

T-cell immunotherapy cures chronic lymphocytic leukemia after 10 years. Researchers were able to use the blood of leukemia patients and modify immune cells to attack their cancer cells. Specifically, they introduced a chimeric antigen receptor into immune cells from patients in the lab. Subsequently they transfused the modified immune cells back into the leukemia patients. After 10 years researchers detected the same active cytotoxic T lymphocytes in both chronic lymphocytic leukemia patients, which contained the chimeric antigen receptor marker. This means that active cytotoxic lymphocytes, that also have the name of killer T cells, continued to eliminate any pathological cells from the lymphocytic leukemia patients.

The immune system explained

The immune system can respond with two major responses. The B lymphocytes originate from the bone marrow and turn into antibody producing plasma cells. With viruses this system works very well as it inactivates viruses that the immune system recognizes don’t belong into the body. The other branch of the immune system are the thymus-processed T cells. These are important to eradicate cancer cells. They are also called CD4 cells or cytotoxic T lymphocytes. Often tumor cells produce specific proteins that suppress the immune cells. But the researchers of these two chronic lymphocytic leukemia patients managed to introduce a chimeric antigen receptor into the CD4 cells that specifically targeted the leukemia cells. The immune system in these patients was working optimally and remained active for 10 years.

Some statistics regarding chronic lymphocytic leukemia

Here are some statistics of chronic lymphocytic leukemia (CLL). There were about 61,090 new cases of leukemia and 23,660 deaths from leukemia in 2021 in the US. Among these were 21,250 new cases of chronic lymphocytic leukemia (CLL). There were about 4,320 deaths from CLL. The average lifetime risk of getting CLL is 1 in 175 people or 0.5% of the population. The risk of getting CLL is slightly higher for men than women. CLL is a leukemia of older people, the average age at the time of diagnosis is 70 years. CLL is rare under the age of 40 and extremely rare in children.

Potential serious side effects of T-cell immunotherapy

Dr. David Porter, one of the authors of the study published in Nature said that this type of immunotherapy can have serious side effects. He added that therapies have become safer over the years. Oncologists are giving immunotherapies like the one which I described to hundreds and thousands of patients.

Here are the more common side effects.

  • The tumor lysis syndrome: when the tumor cells are all attacked at the same time, there is a lot of tumor cell destruction and the contents of the cells end up in the blood. This makes the patient rather sick for a few days. There can be serious electrolyte abnormalities that have to be countered with intravenous fluids. The toxins can also cause kidney damage, which physicians monitor closely.
  • Cytokine release syndrome: With this syndrome people develop a high fever, nausea, vomiting, much like a severe flu. They also develop muscle aches and joint pains. Patients can develop extremely low blood pressure. This occurs because fluid leaks into the lungs, which also causes problems breathing.
  • Neurologic toxicity: There can be a loss of speech and thought disturbances. Seizures can develop and the patients may turn comatose. Nevertheless most patients recover from this spontaneously.

Details of one case of CLL with successful treatment

Doug Olson was one of the patients who was studied in the publication in Nature. His original diagnosis was chronic lymphocytic leukemia when he was 49 years old. For 6 years he did not need much treatment. But then his leukemia flared up and chemotherapy got his CLL into remission for 5 years. Generally, leukemia behaves this way that treatment gets it into remission (meaning the leukemia is controlled). But on another occasion, it gets into a relapse, which means the leukemia flares up again. 11 years after the original diagnosis of the CLL there was a rapid decline due to another relapse. In a bone marrow biopsy 50% of the white blood cells were CLL and 50% were normal.

Infusion of CAR-T cells

He received his first infusion of CAR-T cells in September of 2010. Following this he became very sick and the oncologist hospitalized him for three days. One week later the oncologist could not find any more cancer cells in his body. But the cancer specialists were very reluctant to call it a cure at that time. Fast forward 10 years. And now there are still no cancer cells in Doug’s body. The blood analysis showed that active CAR-T cells are in Doug’s blood monitoring for him that no CLL cells reoccur. Now, 21 years after the initial diagnosis of his CLL the oncologists are convinced that the T-Cell Immunotherapy was what cured Doug.

Discussion

CLL is a special form of blood cancer. Chemotherapy has been successful in increasing survivor rates over the years. But the end of the patient with CLL comes from a final relapse of this leukemia form, which eventually no longer responds to chemotherapy. The researchers in this publication used a novel immunotherapy approach, where they introduced a chimeric antigen receptor into immune cells of patients in the lab. Subsequently they transfused this back into the leukemia patients.

T-cell Immunotherapy used surveillance T cells successfully

These modified immune cells became the “surveillance team” that eradicated new CLL cells and destroyed them on an ongoing basis. This immune therapy is getting rid of the last CLL tumor cell. The two cases described in this paper and investigated thoroughly after 10 years of immunotherapy intervention were completely free of CLL cells in their bone marrow biopsies. Two cases are not enough data, but it is a powerful result for a pilot study. Oncologists have to produce much larger clinical trials with more patients. This establishes that this new immunotherapy is superior to conventional chemotherapy and indeed prolongs survival compared to chemotherapy alone.

T-Cell Immunotherapy Cures Chronic Lymphocytic Leukemia

T-Cell Immunotherapy Cures Chronic Lymphocytic Leukemia

Conclusion

This pilot study showed that the immune system can be stimulated to suppress and eradicate leukemia (CLL) cancer cells. The authors introduced a chimeric antigen receptor into immune cells that were taken from patients. The researchers obtained blood samples. Then they introduced a chimeric antigen receptor into immune cells in the lab. Subsequently they injected these CAR-T cells back into the CLL patients. In these patients the CAR-T cells behaved like surveillance cells, which eradicated leukemia cancer cells on an ongoing basis. After 10 years of follow-up in two patients in this pilot study the clinicians could not find any CLL cancer cells in their bone marrows, but the CAR-T cells were still present. This type of study is encouraging as it is a model for immunotherapy of other cancers. It is a promising start, but obviously researchers need to do more studies to fine-tune cancer immunotherapy.

Dec
07
2019

The Use Of Oncolytic Viruses For Cancer Treatment

By | Cancer, cervical cancer, immune system, prostate cancer, vaccinations

In the first place, preliminary experiments indicate that the use of oncolytic viruses for cancer treatment may become a reality. There are several lines of research that point to the fact that oncolytic viruses can make a difference in treating incurable cancer patients.

Notably, Canadian researchers had reported in 2011 that oncolytic viruses created by genetically modifying smallpox vaccine viruses would enter tumor cells of patients, but not damage normal cells. Specifically, a high percentage of the end stage patients responded with tumor regression.

Shortly after Mayo Clinic physicians were desperate when two patients with end stage multiple myeloma, a vicious bone tumor, did not respond to chemotherapy. Significantly, they tried something unconventional: high doses of the measles vaccine in an attempt to stimulate the immune system. Here is an overview from 2014 that shows that many different cancers respond to various immunological approaches.

Study from Holland regarding end stage melanoma patients

Here is a small human study involving end-stage melanoma patients treated with the oncolytic virus T-VEC combined with pembrolizumab (Keytruda). It is important to realize that Keytruda helps to reactivate a T-cell response to the cancer cells. In this case the cancer cells absorb the oncolytic virus (T-VEC), but it leaves normal cells alone. Inside the cancer cells the oncolytic virus multiplies and destroys the cancer cells. In this 2017 study 21 patients with terminal, nonresectable melanoma received treatment with T-VEC and Keytruda. Specifically, 62% of the patients showed an objective response to the treatment. Moreover, 33% fulfilled the criteria of an immune-related response. In the past terminal patients like these had a 0% response to radiotherapy or chemotherapy.

History of research about oncolytic viruses

To begin with, in 1912 rabies virus treatment against cervical carcinoma was a first attempt to treat cancer. Researchers conducted many experiments between 1950 and 1970 with wild type or naturally attenuated viruses. This included, for example, hepatitis A and B viruses. In 1991 cancer researchers developed the concept of genetically engineered oncolytic viruses. Today cancer researchers know that the protection mechanisms in most cancer cells have deficiencies. This involves the interferon‐beta signal pathway. Having said this, there is an opportunity to let oncolytic viruses destroy cancer cells, while normal cells stay unaffected. An oncolytic virus that cancer experts use in human cancers is the genetically engineered herpes simplex virus type I (HSV‐1). Others that cancer researchers developed have strange names like T‐Vec, G47∆, JX594, CG0070 and Reolysin.

Various cancers that researchers treated with oncolytic viruses

Here are a few examples of cancers where researchers used oncolytic viruses to exert a significant therapeutic effect.

Glioblastoma

Glioblastoma is a deadly form of a brain tumor, which has a high rate of mortality. Researchers have investigated new avenues to treat this cancer. Researchers tested the genetically engineered dendritic vaccine. Initial clinical trials showed significant effectiveness compared to non-treated controls. In a large phase 3 clinical trial 331 patients with newly diagnosed glioblastoma received treatment at the time of neurosurgery with dendritic cell vaccine. 30.2% of the patients were still alive and doing well after 3 1/3 years. Without the added vaccination procedure all of these patients would have died in the past because of the aggressiveness of the glioblastoma.

Multiple myeloma

Researchers could cure multiple myeloma and other cancers by using the measles vaccine. Here is a report by the popular press about two women who had multiple myeloma. One woman got cured by high doses of a measles vaccine. The other women experienced some relief, but did not survive.

This publication explains that oncolytic viral therapy of cancer is a lot more complicated than originally thought.

Prostate cancer

Researchers found that vaccines against prostate cancer were effective with the combination of oncolytic virus therapy with regular anti-cancer treatments. But oncolytic virus therapy alone has a poorer prognosis than a combination of chemotherapy or radiotherapy with oncolytic virus therapy.

Cervical cancer

The high-risk HPV16 strain most often causes cervical cancer. The HPV (human papilloma virus) vaccine targets patients with previous exposure to HPV16. However, researchers have noticed that in some cases a phenomenon called the “HPV immune escape” has allowed in some vaccinated women to still develop cervical cancer. Now a group of researchers are investigating how the vaccine could be improved by finding out how the immune system is being tricked in these cases by the HPV virus to bypass the antibodies of the vaccine.

Pancreatic cancer

This cancer is very difficult to detect in the early stages, and as a result the outlook for chemotherapy or radiotherapy is extremely poor. Researchers have used several approaches as an alternative to conventional therapy. Immunotherapy is an option. Mayo clinic researchers have already announced that the measles vaccine approach will likely be applicable to pancreatic cancer treatment as well in the near future. However, other clinical trials are on the way to use alternative vaccination procedures.

Neuroblastoma, glioma and melanoma

This link shows that the FDA has accepted engineered oncolytic herpes virus (engineered to secrete GM-CSF) as a treatment against melanoma. Other approaches with engineered bacteria can affect neuroblastoma and glioma.

Survival data using oncolytic viruses for cancer treatment

Cancer researchers have completed a number of smaller clinical trials at this point. One of them describes end stage melanoma (stage III and IV) where the only treatment was with the oncolytic virus T‐Vec. The overall response rate compared to the control, which was only 5.7%, the experimental group with T-Vec was 26.4%. This is considered a good response rate given that we are dealing with end stage melanoma patients.

Mechanism of how oncolytic viruses stimulate the immune system to overcome various cancers

As mentioned above oncolytic viruses multiply in the cancer, once they have been incorporated. This leads to cancer cell death. It exposes the dead cancer tissue to the immune system. What helps in the process is that inhibitory proteins from the cancer cells that used to inhibit the immune system are no longer provided by the dead cancer cells. The end result is that the immune system mounts a formidable response against the cancer cells through killer T cells. This immune response also affects remote metastases of the same histological cancer type. This review article summarizes how oncolytic viruses work for cancer cell destruction and how this method can be combined with other treatment modalities.

The Use Of Oncolytic Viruses For Cancer Treatment

The Use Of Oncolytic Viruses For Cancer Treatment

Conclusion

Currently various cancer centers are involved with clinical trials in humans to test the power of oncolytic viruses. What cancer researchers have learnt is that oncolytic viruses are a useful tool to kill cancer cells. But the immune system of cancer patients is in a suppressed state. Pembrolizumab (Keytruda) is a medication that will stimulate the immune system by stimulating killer T cells to destroy cancer cells. The combined effect of killing cancer cells with oncolytic viruses and stimulating the immune system is the big news. This has been the breakthrough that cancer researchers have been waiting for. Now several clinical trials are on the way where survival rates for cancer patients given the new combination therapy are assessed.

Oncolytic virus therapy here to stay

It is a treatment which is no longer a thought model with animal experiments. Well known medical centers are using it in patients, and as the results become more obvious, it will very likely become a new treatment modality for cancer.

Jul
21
2018

Frequent Flying Can Increase Cancer Rates

By | breast cancer, Cancer, cervical cancer, Circadian rhythm, immune system, lung cancer, prostate cancer

A review article from June 25, 2018 discusses that frequent flying can increase cancer rates. A study showed that cancer of the breast, cervix, skin, thyroid and uterus are about twice as common in female stewardesses than in women at large. Also, gastrointestinal system cancers including cancer of the colon, stomach, esophagus, liver and pancreatic cancers are more common. This observation was true in both male and female flying personnel who engage in frequent flying. This publication comes from a scientific paper published on June 26, 2018.

Study of flight attendants

Patients from the National Health and Nutrition Examination Survey (NHANES) served as a control for flight attendants. This control group consisted of 2729 patients; they were of a similar socioeconomic status as the flight attendants. In contrast there were 5366 flight attendants with much higher cancer rates than normally expected. Specifically breast cancer had a 1.51-fold higher frequency than the control group. Melanoma had a frequency of 2.27-fold in comparison to controls, and non-melanoma cancers had a cancer rate of 4.09-fold when compared to controls. Non-melanoma cancer cases include basal cell and squamous cell carcinomas.

Cancer rates in pilots

In a meta-analysis of various studies it became obvious that pilots had 20% more prostate cancer than a non-pilot control group. However their mortality was not higher than controls.

In an interesting study spanning over 60 years Icelandic airline pilots underwent an analysis for cancer development.

83 cancers were registered. The general population (non-pilots) served as controls.  There was an increase of 2.42-fold for all cancers compared to controls. Prostate cancer was higher in these pilots by 2.57-fold. Malignant melanoma had a 9.88-fold increase in pilots in comparison to controls. The basal cell carcinomas in these pilots were 3.61-fold more common than the rates in the controls. With regard to basal cell carcinomas of the trunk there were 6.65-fold more of them in comparison to controls.

The difference between the pilots and the general population was likely due to the higher exposure to cosmic radiation. This is what the authors concluded.

How does cancer develop?

There are several ways cancer can develop. One of the known cancer causations is ionizing radiation. We know a lot about this from the atom bombs of WWII in Japan. There were many more thyroid cancers in children than were normal following the dropping of the atom bombs.

But diagnostic CT scans and X-rays are not without risk of cancer development either. There is a lag period of 10 to 20 years and even longer. But after this time the higher cancer rate becomes measurable. A person who had a CT scan done as a diagnostic test in childhood will still have a 25% higher cancer rate 15 years later. This is how powerful radiation of the DNA of our cells is despite inherent repair mechanisms that fight back to keep things normal.

Single cancers versus multiple cancers

It is interesting that female stewardesses and male pilots came down with a mix of various cancers. There were skin cancers, breast cancers, cancers of the prostate and many gastrointestinal cancers. The numbers were not big enough to show statistical significance for leukemia also being a likely cause of cancer from cosmic radiation.

If cosmic radiation was going through the body randomly hitting various DNA strands in all cell types, which could explain why a random number of cancers develop in those cells that got the highest exposure. The ones who got above average cancer were stewardesses and pilots who were longest on their jobs. A variety of cancers would develop from various tissues. This is exactly what the studies have shown. Radiation exposure following the Fukushima disaster led to thousands of thyroid cancers.

There are frequent flyers like business travelers and vacation seeking retirees who will also be at a higher risk of developing cancer. The more they fly, the higher the risk.

Other causes of cancer

Cosmic radiation is only one cause of cancer. There are many other causes of cancer. If you smoke heavily or abuse alcohol this can cause genetic mutations of cells that can develop into cancer. There is a pathway to cancer, which consists of initiation, promotion and progression. After those initial hurdles the cancer cell will multiply and start metastasizing into other areas of the body.

Carcinogens can damage the DNA of cells. In the case of pollution carcinogens enter the body through the air. But consuming processed meat and red meat has a proven link to cancer development as well, namely colon cancer.

Diverse factors all can cause cancer

Chronic inflammation from chronic infections is also carcinogenic. Chronic gastritis is caused by H. pylori. After years of infection with this pathogen stomach cancer can develop. Hepatitis viruses that are chronically present in liver cells can be the cause of liver cancer. Human papilloma virus (HPV) is the cause for the development of cancer of the cervix. The majority of cancer is caused from the environment or by poor life styles. Only 5 to 10% of cancers are inherited.

Tumor suppressor genes are important in terms of resisting the development of cancer. The TP53 gene produces a protein that interferes with the multiplication of cancer cells. Cancer cells in turn can produce a protein that interferes with TP53 function. The end result is that it will interfere with the body’s immune system to produce killer T cells. This way the cancer has the upper hand. There are some herbs that have shown anti-cancer effects, such as curcumin. https://www.askdrray.com/curcumin-and-cancer/. As I explain in this blog, there are absorption problems with curcumin presently. It is not yet primetime for curcumin, but it could be once the absorption problems are overcome. Nevertheless the research surrounding curcumin is interesting.

Frequent Flying Can Increase Cancer Rates

Frequent Flying Can Increase Cancer Rates

Conclusion

Several interesting studies have shown that stewardesses, pilots and frequent airplane travellers have a higher risk of developing cancer. Research groups have been careful to control these studies for lifestyle factors and other causes of cancer. Exposure to cosmic radiation is the common culprit that is behind this cancer causation. There was a multitude of cancers rather than one single type of cancer in pilots and stewardesses. This makes it more plausible that it is indeed cosmic radiation that caused the cancer increase. But cancer development is complex, and I have summarized this briefly here. It is important to be aware of all the possible causes of cancer. This allows you to minimize your exposure to carcinogens. We all get exposure to carcinogens from pollution. In addition we get exposure to cosmic radiation according to how much time we spend flying to holiday destinations or on business trips. Be safe and be informed!