Friday, April 21, 2023

Selenium in Cancer Treatment

Selenium in Cancer Treatment





Selenium was first discovered in 1817 by Jöns Jacob Berzelius, it’s named after “Selene” the Greek Goddess of the moon. Selenium is found in a few rare minerals. It is an essential trace element for some species, including humans. Our bodies contain about 14 milligrams, and every cell in a human body contains more than a million selenium atoms. Selenium has been shown to have an immune-boosting and immune suppressing effect. It’s boosting effects are due to it’s involvement in enhancing activation and proliferation of B cells and/or it’s ability to promote immune cell differentiation; in a study conducted by Hoffman et al. demonstrated that supplementing this element in mice promoted T cell receptor signaling that pushed T cell differentiation toward Th1 by increasing interlukin -2 and interferon gamma production; another study in human subjects showed that selenium supplementation resulted in substantially higher levels of both Th1 and Th2 and, also increased plasma selenium levels. In cancer, selenium down-regulates Hypoxia-Inducible Factor (produced by cancer cells as response to hypoxia that promotes angiogenesis to deliver nutrients and oxygen to the growing tumor) leading to the downregulation in expression of several genes involved in angiogenesis such as VEGF. Selenium also helps with DNA repair in response to DNA-damaging agents improving the effectiveness of chemotherapeutic agents and protecting normal cells from their toxicity. Also, it was shown to reduce drug detoxification and increase cytotoxic effects of anti-cancer drugs in cancer cells and increasing detoxification and reducing cytotoxic effects in normal tissues by maintaining redox homeostasis.



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Thursday, April 20, 2023

Intratumoral immunotherapy with Pulsed Electrical Field (PEF)

Intratumoral immunotherapy with Pulsed Electrical Field (PEF)





Intratumoral immunotherapy with Pulsed Electrical Field (PEF) is an emerging approach to cancer treatment that combines the benefits of immunotherapy and PEF technology. This technique involves the local administration of immunotherapeutic agents, such as checkpoint inhibitors or cytokines, into a tumor followed by the application of PEF to enhance their effectiveness PEF technology can increase the uptake and activation of immunotherapeutic agents by tumor cells, leading to a stronger immune response against cancer. PEF also has a direct cytotoxic effect on cancer cells, which can further enhance the effectiveness of immunotherapy.

Intratumoral immunotherapy with PEF has shown promising results in preclinical studies and early clinical trials, particularly in the treatment of solid tumors. This approach has the potential to overcome the limitations of systemic immunotherapy, such as poor tumor penetration and off-target effects, by delivering the treatment directly to the tumor site.

Overall, intratumoral immunotherapy with PEF represents a novel and promising approach
to cancer treatment that warrants further investigation in clinical trials.


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Wednesday, April 19, 2023

Reprogramming Neutrophils to Enhance Cancer Immunotherapy

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


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source https://williamscancerinstitute.com/reprogramming-neutrophils-to-enhance-cancer-immunotherapy-2/?utm_source=rss&utm_medium=rss&utm_campaign=reprogramming-neutrophils-to-enhance-cancer-immunotherapy-2
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Reprogramming Neutrophils to Enhance Cancer Immunotherapy

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


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Tuesday, April 18, 2023

Tertiary Lymphoid Structures, An Indicator of Anti-Cancer Immune Response

Tertiary Lymphoid Structures, An Indicator of Anti-Cancer Immune Response





Tertiary lymphoid structures (TLSs) are organized collections of immune cells that resemble lymph nodes and form outside lymphoid organs, often in areas of inflammation, infection, or cancer. TLSs are thought to play an essential role in the anti-tumor immune response. They can promote immune cells’ activation and expansion, including T and B cells, in the tumor microenvironment. I would compare these with a military base, where the immune cells can hang out and get prepared to attack cancer, staying close to the tumor itself. This again supports that much of the action of the immune response is at or around the tumor, so treating directly with intratumoral immunotherapy gets you right into the heart of the action.

TLSs have been associated with improved outcomes in various cancers, including melanoma, breast and lung cancer. In addition, some studies have suggested that TLSs in the tumor microenvironment may predict response to immunotherapy.

Cancer immunotherapies that target immune checkpoints, such as PD-1/PD-L1 inhibitors, have been shown to promote the formation of TLSs in some cancer patients. In addition, some studies have suggested that other cancer treatments, especially PEF (Pulsed Electrical Field), may also promote the formation of TLSs in the tumor microenvironment.

Research is ongoing to understand better the role of TLSs in the anti-tumor immune response and to develop new strategies to target and enhance their formation in cancer patients. NanoString, which I have discussed before, can be used to identify and characterize these TLS. If successful, these strategies may provide a new approach to cancer immunotherapy that targets the formation of TLSs to promote anti-tumor immunity.
References:


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Monday, April 17, 2023

NanoString, Powerful Cancer Immune Profiling That Can Determine Immune Targets Guiding Precision Medicine

NanoString, Powerful Cancer Immune Profiling That Can Determine Immune Targets Guiding Precision Medicine





What if it was possible to analyze all the potential immune checkpoints, costimulatory molecules, and cellular aspects to guide the treatment of immunotherapy? NanoString, a DNA barcode-based immune profiler, has this capability. The data it provides is far ahead of what standard immunotherapies are typically available. However, this technology, as a research tool, can direct treatment options. This is for resaerch, so it is not used in standard patients. It is unlikely that patients would have this done unless they are in a research protocol. It has helped guide treatment, especially when you run into resistant cancers. We have seen several patterns in cancers that we treated. One is LAG3, an immune checkpoint that can inhibit an anti-cancer immune response. With the NanoString analysis that we performed, in many cases when tumors were pressured with PD-1 and CTLA-4 inhibitors, we would see a subsequent upregulation of LAG-3, which may play a role in suppressing the anti-cancer immune response. Of course, a LAG-3 inhibitor, Opdualag, is now available, with approval just over a year ago.
Another example is that in many cases, we also identified upregulation of B7H3, another critical checkpoint shutting down the immune response. These are just a few of the actionable changes in the immune profile of the cancer that we have identified with NanoString. Like the CIA, NanoString gives you all the intelligence you need to fight your enemy, in this case, cancer. Though it is currently limited for research, it should be an available analysis for all patients in the future, guiding the “precision” immunotherapy treatment of cancer.
NanoString’s immune profiling assays enable researchers to analyze the immune microenvironment of cancer samples comprehensively. The assays use the nCounter Analysis System to simultaneously measure the expression of hundreds of genes associated with immune cell types, checkpoints, and other immune-related pathways.

The PanCancer Immune Profiling Panel includes probes for 770 genes across 20 immune pathways and enables the analysis of the tumor-immune microenvironment in a wide range of cancer types. The panel provides a comprehensive view of the immune cell types and immune-related pathways involved in the tumor microenvironment, including the presence and activity of immune cells, expression of immune checkpoint genes, and other critical immune-related genes.

In addition, NanoString offers a range of other immune profiling assays, including the Tumor Inflammation Signature (TIS) Panel, which measures the expression of 18 genes that are associated with immune cytolytic activity, and the myeloid panel, which measures the expression of genes related to myeloid-derived suppressor cells and tumor-associated macrophages.

Overall, NanoString’s immune profiling assays offer a powerful tool for researchers studying the immune microenvironment of cancer and have the potential to improve our understanding of the immune response to cancer and to guide the development of more effective immunotherapies.
The Williams Cancer Foundation has purchased a new NanoString with NCounter and GeoMx, bringing patients the most advanced treatment options.
Jason R. Williams, MD, DABR
Chief of Interventional Immuno Oncology
Williams Cancer Institute
Author of: “The Immunotherapy Revolution”
References:


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Friday, April 14, 2023

IMMUNOTHERAPY STUDIES THAT COULD CHANGE CONVENTIONAL CANCER TREATMENTS

IMMUNOTHERAPY STUDIES THAT COULD CHANGE CONVENTIONAL CANCER TREATMENTS





Some studies have shown that immunotherapy can cure locally advanced cancers in a period of between 1 and 6 months in the best cases. These cancers are characterized by having tumors that generally remain limited to the original site but can also spread to nearby lymph nodes. The patients who participated in the study had specific genetic changes that made them good candidates for immunotherapy. These genetic changes are called high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR).

In the study, half of the population received the immunotherapy drugs pembrolizumab and Keytruda for a period of 6 months. After immunotherapy treatment, these patients underwent surgery to remove any remaining tumor tissue. In half of these patients, no trace of the tumor that previously existed was found, which is known as a complete pathological response. The other patients received treatment with pembrolizumab alone for a period of 1 year, and only 1 out of 18 patients had an improvement in tumor size. Overall, immunotherapy shows an improvement compared to conventional treatments. For some people with these cancers in earlier stages, the complete treatment could be just a short course of immunotherapy.

The one key is that these patients have damaged or mutated DNA repair genes. This is relatively rare, but it gives a key insight that can be applied to all patients. Medications can be used to block the DNA repair, making even typical patients responsive to immunotherapy.

Currently, immunotherapy is a standard treatment used by oncologists to treat an increasing number of cancer types. The role of immunotherapy in treatment has evolved to improve the quality of life of cancer patients and eradicate cancer from their lives.



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