Intratumoral Chemotherapy and Immunotherapy, to create a power synergy against cancer

So a lot of times, of course we’re talking about injecting immunotherapy into tumors, but one thing that’s been around for a while, but it’s getting a lot more interest is injecting chemotherapy into tumors and so you can inject multiple combinations of chemotherapy directly into the tumor. You’re getting a higher concentration in the tumor, lower concentration in the body. So of course you don’t get the side effects; The big thing, of course now is combining chemo therapy with immunotherapy. So in some of our cases we’ll inject chemo therapy with immunotherapy. The chemotherapy kills cancer which gets us pieces that the immune system needs to see; It also reduces some of the regulatory immune cells, these are cells that are protecting the cancer and chemotherapy has a lot of added benefits and particularly when you combine it with injecting immunotherapy, this is a powerful combination.
More recently they had the checkmate 816 study looking at lung cancer giving patients systemic chemotherapy and systemic immunotherapy and seeing a real benefit.
You know, one of the things of course that the caution is the use of steroids a lot of times when they’re giving systemic chemotherapy, they use steroids,The steroids may suppress the immune response; Of course that’s a nice thing when you inject into the tumor, you don’t have those issues.
You know, you don’t have to use steroids; The doses are so low, you’re not going to have other typical side effects of chemotherapy.
So this is very interesting option and certainly, you know, it’s really gaining a lot of ground with the combination of chemotherapy and immunotherapy. It is certainly worth thinking about.

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BENEFITS OF INTERMITTENT FASTING FOR YOUR HEALTH

Intermittent fasting is an eating model that cycles with periods of fasting and eating. In general, it is not a diet but an eating program. Intermittent fasting isn’t about thinking about what to eat, it’s about focusing on when you should eat.

Intermittent fasting does much more than just restrict calorie intake. It also changes the hormones in the body so that they can make better use of your fat stores.

Fasting is a direct way to take advantage of the inflexibility of cancer. In the absence of glucose, healthy cells burn fat (or ketones), and cancer cells run out of energy, increasing their oxidative stress, and resulting in their death. Including a fasting cycle before undergoing cancer treatment minimizes damage and increases effectiveness. Moreover, intermittent fasting involves completely or partially abstaining from eating for a set amount of time, before eating regularly again.

There are various methods of intermittent fasting. The most popular are:

The 16/8 method: This is known as the “Leangains” method. It consists of eating for 8 hours and then fasting for 16 hours. That is the standard fasting period and includes sleep and a few more hours of fasting. For example, you can avoid eating breakfast, have your first meal at noon, and continue eating until 8.

5:2 Diet: For two days a week, reduce calorie intake to a maximum of 500-600 calories per day. The days do not have to be consecutive. Also, the other five days you eat what you want.

Eat, stop, eat: This intermittent fasting alternates fasting days with eating days. You eat whatever you want for 24 hours and then take a total food break the next day. You must repeat this pattern once or twice a week. Calorie-free beverages (such as coffee, unsweetened tea, etc.) are allowed.

“According to a study, a specific type of intermittent fasting is safe and possible for people diagnosed with cancer and could boost the effectiveness of cancer treatments such as chemotherapy, immunotherapy, and hormone therapy. It is the first time this type of intermittent fasting has been studied in people.”

There are many intermittent fasting programs. For example, with some diets, you fast for a day. It is eaten for the next three days. With other diets, you eat at some specific times of the day, like 8 a.m. to 5 p.m., and nothing at another moment.

References

El ayuno intermitente podría ayudar a que los tratamientos del cáncer funcionen

mejor según un estudio reducido inicial. (s. f.). https://www.breastcancer.org/es/noticias-de-investigacion/ayuno-intermitente-podria-ayudar-a-que-los-tratamientos-del-cancer-funcionen-mejor

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Liquid Biopsy in Cancer

As new Immune Checkpoint Inhibitors (ICI) are being studied in the medical field and used as new therapies to approach and battle cancer, many questions are left about their use: How much is enough? How many ICI therapies will someone need? How do we know it’s doing something?

Liquid biopsies are emerging as a rapid and accurate approach to monitoring tumor burden dynamics during immunotherapy. Liquid biopsies track the circulating cell-free tumor DNA (ctDNA) that serves as a biomarker, helping us understand the molecular wiring of therapeutic responses. It has also been shown to serve as a predictive and prognosis value. For liquid biopsies to work, you give a blood sample, then the blood cells are separated from the plasma, and the new technologies can detect Circulating Tumor Cells (CTC) or ctDNA in the plasma.

Using ctDNA to detect Minimal Residue Disease associated with micrometastatic disease before the development of metastases may guide a way to take advantage of the efficacy of immunotherapy for patients with early-stage disease. It can also help evaluate new immunotherapies’ efficacy faster than conventional methods such as radiographic imaging.

There’s still a long way to improve liquid biopsies; it has some limitations as sensitivity and access to these technologies, which can vary depending on the type of tumor, ctDNA can be modified by the burden and distribution of the disease, and also the economic costs for this study.

So far, it appears to be a great approach to continue monitoring ICI immunotherapies (response and efficacy), and it’s also a novel tool for testing new immunotherapies drug results.

Dr. Barco

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Intratumoral Chemotherapy and Immunotherapy, to create a power synergy against cancer

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Reprogramming Neutrophils to Enhance Cancer Immunotherapy

A new article published in Science Immunology on February 17, 2023, discussed the immune reprogramming of neutrophils in a breast cancer metastasis model.  The article was written by Gong et al., link below.  What makes this finding and paper so important?  As I have mentioned in my book, the immune system has two sides, one that will attack cancer and the other that will protect it.  One critical area that gets less attention than T cells is myeloid cells, part of the innate immune response.  Specifically, in this case, we are discussing neutrophils.  This article discusses that the PGE2-EP2/EP4 pathway is involved in the recruitment and maintenance of cancer-protecting neutrophils in the lung for breast cancer metastasis.  Blocking this pathway at the end of EP2/EP4 can reduce these neutrophils and sensitive cancer to the immune system.  As we have discussed, NSAIDs such as Ibuprofen, Asprin, and Celebrex inhibit PGE2.  However, in this study, Celebrex did not sufficiently block the pathway to affect the neutrophils.

More specific EP2/EP4 inhibition is needed.  They also discuss a partial role in blocking IL-1 and IL-6, both upstream regulators.  This is an area that we have experience with using anakinra and tocilizumab, also mentioned in my book.  As far as an NSAID that blocks, more specifically, EP2/EP4, there are several studies, including one approved for arthritis in dogs about seven years ago.  This is certainly an area that needs more investigation, but the addition of EP2/Ep4 inhibitors to immunotherapy may show some benefit.

Jason R. Williams, MD, DABR

Director of Interventional Oncology/Immunotherapy

Williams Cancer Institute

https://www.science.org/doi/full/10.1126/sciimmunol.add5204?et_rid=162353465&utm_campaign=IMMeToc&af=R&et_cid=4602821&utm_medium=email&utm_content=alert&utm_source=sfmc

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WHAT SHOULD YOU DO TO UNDERSTAND YOUR CANCER DIAGNOSIS?

After finding out that you have cancer disease, the news can be somewhat complicated to understand both for the patient and the people around him, which is why all the information about the condition must be known very well, as the types of treatments that exist.

Each patient has a different case, and it is essential to understand the disease’s phase or state. The doctor can help understand all doubts regarding the illness and thus understand the changes the body is going through and what treatment possibilities the patient has.

Moreover, having a cancer diagnosis creates a lot of worry and stress for patients and their families. It is common to have many doubts and concerns about cancer and how the patient got it.

Cancer is obtained when cells grow uncontrollably and outnumber normal cells, this causes the body to start working differently, and these cancer cells can move to other areas of the body, which is called metastasis.

Another common question that a patient asks himself when diagnosed with cancer is to know the stage in which the cancer is; for this, it is necessary to carry out more tests and thus determine how advanced the cancer is; these tests help the doctor determines the type of treatment the patient needs.

It is difficult to know why cancer appears in the body; some factors make this disease occur more efficiently, such as family history, age, and harmful habits such as the consumption of alcoholic beverages, tobacco, being overweight, and other external factors.

Understanding and accepting this new situation is difficult for the patient and will take time. Later, the patient could make decisions related to the type of treatment, as long as they are appropriate for the patient’s body, according to the results obtained from a biopsy, blood tests, physical examinations, and imaging studies (x-rays and tomographies), in conjunction with whatever problems the cancer is causing.

Most patients will have some form of genetic testing in current cancer treatment.  This is not to see if you inherited cancer; this is to look at the mutations a tumor has that are different from your own body.  This can, in some cases, leads to information on targeted therapies.  In addition, all patients should be tested for their potential response to standard immunotherapy; this includes MMR, TMB, and PD-L1.  In some cases, measuring tumor DNA in the blood, such as Signatera, can help follow your response to therapy.

It is essential always to clarify all doubts with the doctor and be constantly informed of the entire process of coping with the disease and undergoing treatment against the disease.

 

References:

Cómo comprender su diagnóstico. (s. f.).

https://www.cancer.org/es/tratamiento/como-comprender-su-diagnostico.html

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WHAT IS ADENOCARCINOMA CANCER?

Adenocarcinoma cancer develops in one of the glands that line the interior of the organs. This type of cancer generally appears in the prostate, breast, colon, lung, or pancreas.

It is said that adenocarcinoma cancer can develop in different organs of the body, so far there is no list of symptoms that allows us to know if this type of cancer is the one that affects the patient because this type of cancer is asymptomatic. The symptoms that appear can affect the organ where it is and present symptoms in it, for example, breast adenocarcinoma can cause a lump or unusual growth.

Lung adenocarcinoma causes hoarseness, cough, weakness, weight loss, and exhaustion. Adenocarcinoma in the prostate may cause bladder control problems, frequent urination at night, bloody semen, and painful ejaculation. Other symptoms also occur in different parts of the body, so it is advisable to perform different tests that help detect this type of cancer, certain chemicals in the blood may also be associated with specific cancers.

Treatments for adenocarcinoma cancer depend on many factors, one of them is the site of origin of the cancer. Finally, there are many ways to treat this type of cancer, including surgery to remove the tumor, chemotherapy, radiation, targeted therapy, and immunotherapy.

 

References:

¿Qué es el cáncer de adenocarcinoma? (s. f.). Preguntasrespuestas.net.

https://www.preguntasrespuestas.net/articulo/que-es-adenocarcinoma-cancer?utm_content=params:o=1668685&ad=dirN&qo=serpIndex

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An Overview to Achieve Success With Cancer Immunotherapy

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Cytokine Release Syndrome

Cytokine release syndrome (CRS) is one of the most problematic issues in cancer immunotherapy. Originally extremely rare, the incidence of CRS is rapidly increasing, especially with the development of new agents and combination immunotherapy. CRS has given great problems to patients treated with CAR-T, which has been successful in blood born cancers, but carried huge risk. We also began seeing it in more patients, with bulky disease when using combination immunotherapy directly injected into the tumor. Basically, it is a condition caused when the immune cells produce a large amount of immune-stimulating substances called cytokines in response to mounting an immune attack, in this case, against cancer. It seems the larger amount of cancer burden the patient has, the higher the risk there is for CRS. The immune system is used to attacking things that relatively small, such as a viral or bacterial infection that does not have much mass, but cancer tumors can be larger than one of your organs. When the body attacks something so massive it is not without potential consequences.

Symptoms of CRS typically include fatigue, fever, loss of appetite, vomiting, low blood pressure, seizure, headache, and confusion. This is very similar to the symptoms associated with severe infections and sepsis. Fatigue, fever and loss of appetite can be common in immunotherapy, as well, but CRS progresses to these other symptoms, often starting with low blood pressure. For me, this was the major drawback of immunotherapy. I feel it is one reason that it is best to treat patients as early as possible, before their disease becomes too bulky, since increased tumor burden is a risk factor. Other thoughts are to use chemotherapy, radiation, or ablation to reduce tumor volume first, though often this is not possible. However, thankfully, recently some major breakthroughs have been made. They may not eliminate the problem, but hopefully they will make it manageable in most cases.

In a study published in Nature Medicine, May 2018 by Norelli, et al. they showed that cells of the immune system called monocytes produce Interleukin 1(IL-1) and Interleukin 6(IL-6) causing CRS in a specific mouse model. Importantly, the study showed that IL-1 seems to be the source of associated neurotoxicity in CRS. This type of toxicity is normally the most dangerous and fatal aspect.

Besides supportive care, the typical treatments for CRS are steroids, histamine blockers, and potentially the IL-6 blocking agent Tocilizumab. However, this last treatment has not been as successful as hoped, especially in a case where neurological symptoms have developed. Norelli, et al. showed that IL-1 seemed to start this whole cascade and was responsible for the neurological toxicity. This led them to show that the IL-1 blocking drug Anakinra did have success in preventing the neurological related toxicity. This was in the animal model, but it is important enough that we should consider using this therapy in patients right away. Thankfully, Anakinra is already FDA-approved for treatment of rheumatoid arthritis, so it can be used off-label in the U.S.

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Dipyridamole

Dipyridamole is a drug used to treat coronary and peripheral artery disease. It reduces clots and dilates blood vessels. A study published by Rhodes, et al. in Lancet, March 23, 1985 demonstrated that melanoma patients given 300mg of Dipyridamole a day had a 5 year survival of 77%, versus an expected survival of 32% in patients not treated with Dipyridamole. One initial thought was that since this drug reduces platelet aggregation, it might decrease the ability of cancer cells to spread in the blood and adhere to other locations, creating metastasis. In a study published by Spano, et al. in Clinical & Experimental Metastasis, January 2013, titled “Dipyridamole Prevents Triple-negative Breast-cancer Progression,” they demonstrate in the mouse model that Dipyridamole decreased the primary tumor by 67.5% and metastasis formation by 47.5%. In their study, they discovered that Dipyridamole produced a significant decrease in tumor- associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), both which boost the anti-cancer immune response. Dipyridamole also results in a decrease in adenosine, which is a metabolic suppressor of the immune system. As this study shows, basically, there are several mechanisms in which Dipyridamole may help enhance the immune response.

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It does not always matter what type of cancer you have, there can be a potential for immunotherapy to work.

Early efforts to treat cancer had assumed that cancer was cancer. But we now know that there are over two hundreddifferent types of cancer. That means what works for one form of cancer may not work for others. But don’t let that fact discourage you. One of the most exciting features of immunotherapy is that, because it works in conjunction with the body’s natural immune system, it has the potential totreat many types of cancer, and hopefully, as new drugs are developed, maybe all cancers. Different cancers may have their specific immune weaknesses, and those are being rapidly sorted out with current immunotherapy research.

Unfortunately, I often hear from patients who have been told by their doctor that immunotherapy does not work for their cancer type. I think if you look at the research, however, and the swift pace at which immunotherapy is gaining approval, you will agree that it is probably not true. I do admit that the current CTLA-4/PD-1/PD-L1 drugs may still be lacking. While it is true that some cancers are more immunogenic and respond better than others to immunotherapy, there is the potential for all cancers to respond to immunotherapy—particularly when used in combinations, directly injected into the tumor, or together with ablation procedures in a specific manner. I have many patients with lung cancer, bladder cancer and kidney cancer who were told that immunotherapy drugs would not work for their cancer, but now these same drugs have been approved for those cancer types. Because it takes years of research before the FDA will approve a specific drug for a specific form of cancer, the FDA approval process is a slow one.

While drugs cannot be prescribed in the U.S. without having been approved by the FDA, once approved for use for one condition, FDA approval is not necessary for a physician to prescribe that drug for a condition for which it has not beenapproved. This is known as off-label use and is quite common. That means that while Yervoy was first approved for the treatment of melanoma, physicians can still prescribe it to treat other cancers.

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Typically your health insurance will not cover the costs of the drugs without FDA

Typically your health insurance will not cover the costs of the drugs without FDA approval for your specific form of cancer, but combining immunotherapy with cryoablation or directly injecting the drugs into the tumor can drastically reduce the costs of medications.

Unfortunately, insurance carriers will almost never provide coverage for a drug used to treat a condition that the FDA hasn’t approved it to treat. That means that if the drug your physician prescribes has not been approved by the FDA to treat the specific form of cancer you have, it may be almost impossible for him or her to offer you a standardimmunotherapy treatment that is not directly covered by insurance, even if it may work. Yervoy, for example, may be covered by your insurance carrier for treating certain cases of melanoma, but not for treating other cancers. With a price tag at over $30,000 per infusion-
-and a course of treatment requiring a minimum of four infusions—it remains a treatment that many patients cannot afford. Bristol-Myers Squibb, the makers of Yervoy, does offer a patient-assistance program that may reduce cost, but it may still be such a steep price beyond the reach of many. There is also the difficulty of finding doctors who may be willing to offer these medications “off-label.” Also keep in mind that we are mainly discussing advanced, Stage IV patients, for which standard therapies may have failed or been of limited success.

Even though the drugs are available outside the United States, where in most cases they would be much less expensive than they are in the U.S., immunotherapy pricing remains fairly steep throughout the world.

But don’t let the price of these drugs discourage you. The key aspect to injecting the drugs directly into the tumor, rather than into the bloodstream, means that even without ablation, it may be possible to achieve the same or better results with a fraction of the dose—and at a fraction of the costs. In other words, whereas standard immunotherapy treatment involves infusing the drugs into the bloodstream, by combining immunotherapy with cryoablation or directly injecting these medications into the tumor, the effectiveness of the treatment may be enhanced while the price of that treatment is dramatically reduced.

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Akkermansia muciniphila

The human gut microbiome is composed of 1013 micro-organisms; it modulates many host processes, including metabolism, inflammatory response, peristalsis, maturation of immune functions, and maintenance of intestinal epithelial barrier. The relation between cancer and microbes is not well known; microbes present in different types of mucous can be part of the tumor microenvironment and affect cancer’s growth and dissemination.

Akkermansia muciniphila is a typical member of the human gut microbiome; it potentiates anti-tumor efficacy with chemotherapy or immunotherapy. Food supplementation with Akkermansia muciniphila is safe and reduces insulin resistance and dyslipidemia.

Recently Akkermansia muciniphila has been shown to influence the effectiveness of Immune Checkpoints Inhibitors and has been associated with clinical benefits in people with certain cancers who were treated with immune checkpoints inhibitors immunotherapy; an immunomodulatory perspective affected patients colonized with Akkermansia muciniphila had a more robust CD4+ T helper cell activation which is helpful to maintain an immune response against cancer.

Studies published by Nature Medicine show that in patients with non-small-cell lung cancer, the abundance of Akkermansia muciniphila could help predict the survival of these patients and be a potential biomarker to identify who is more likely to respond to immunotherapy.

The exact mechanism of Akkermansia muciniphila modulating anti-tumor response is still being investigated. Still, studies have sustained that the presence of Akkermansia muciniphila is a modifier in the treatment with Immune checkpoint inhibitors immunotherapy and is yet to be validated as a new prognosis factor.

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