CXCR1/2 Inhibitors and MDSC, A Promising Future Immunotherapy Target

CXCR1/2 inhibitors have been shown to target myeloid-derived suppressor cells (MDSCs), which are immune cells that suppress the anti-tumor immune response and promote tumor growth. CXCR1/2 is involved in the recruitment of MDSCs to the tumor microenvironment, and inhibiting CXCR1/2 can prevent the recruitment of MDSCs, potentially enhancing the anti-tumor immune response.

Preclinical studies have shown that CXCR1/2 inhibitors can reduce the number of MDSCs in the tumor microenvironment and enhance the effectiveness of cancer immunotherapy in animal models. For example, combining a CXCR1/2 inhibitor with an immune checkpoint inhibitor has been shown to reduce the number of MDSCs in the tumor microenvironment and enhance anti-tumor immunity in preclinical models of melanoma.

Several clinical trials are currently underway to evaluate the safety and efficacy of CXCR1/2 inhibitors, including SX-682, in cancer patients. The goal of these trials is to determine whether targeting CXCR1/2 can reduce the number of MDSCs in the tumor microenvironment and enhance the anti-tumor immune response. If successful, CXCR1/2 inhibitors could provide a new treatment option for cancer patients who do not respond to existing immunotherapies.

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Pulsed Electrical Field (PEF)

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El
campo eléctrico pulsado (PEF, por sus siglas en inglés) es una técnica prometedora para el tratamiento del cáncer que utiliza pulsos cortos de electricidad de alto voltaje para atacar selectivamente las células cancerosas mientras deja

células sanas ilesas. Se ha demostrado que el PEF es eficaz en una serie de estudios preclínicos y actualmente se está estudiando en ensayos clínicos para el tratamiento de varios tipos de cáncer.

Durante el tratamiento con PEF, se colocan electrodos en la superficie de la piel o se insertan en el tumor. Luego se envían pulsos cortos de electricidad de alto voltaje al tumor, lo que crea un campo eléctrico que hace que se formen poros en las membranas celulares de las células cancerosas.

Estos poros rompen la membrana celular, lo que lleva a la muerte celular.

Una ventaja del PEF sobre los tratamientos tradicionales contra el cáncer, como la quimioterapia y la radioterapia, es que no es invasivo y no causa el mismo nivel de efectos secundarios. Se ha demostrado que el PEF es bien tolerado en ensayos clínicos, con pocos efectos adversos informados.

El PEF también es muy selectivo y se dirige a las células cancerosas sin dañar las células sanas.

Esto significa que el PEF tiene el potencial de usarse en combinación con otros tratamientos contra el cáncer, como la quimioterapia y la radioterapia, para mejorar su eficacia y reducir los efectos secundarios.

Si bien el PEF muestra una gran promesa como tratamiento contra el cáncer, se necesita más investigación para comprender completamente sus posibles aplicaciones y optimizar su uso. Los ensayos clínicos están actualmente

en marcha para evaluar la seguridad y eficacia del PEF en el tratamiento de varios tipos de cáncer.

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ARID1A Mutation and Potential Response to Immunotherapy for Cancer

Often when doctors determine if a patient may respond to standard immune checkpoint therapy, mainly meaning PD-1 inhibitors, Opdivo or Keytruda, they look at the PD-L1 status of the tumor. This is to see if the tumor has the receptor PD-L1, which correlates with blocking the corresponding receptor PD-1, removing one of the potential “brakes” of the immune system. We know, however that this is an imperfect marker; patients can respond with our without PD-L1 expression on the tumor, though generally, ones that do express PD-L1 would have a higher chance to respond. One study had even indicated that PD-L1 expression on the macrophage was more predictive than the tumor, but this is not what is used. In addition, looking at DNA repair genes, known as MMR, is another, though very rarely do patients have this. The other is tumor mutational burden. However,, we also know other gene mutations are associated with improved responses, but they are not used as selection criteria to give patients immunotherapy. This means that some patients who may respond are missing out. One of these described in a study published by Sarfatay, et al discusses a mutation in the gene ARID1A in cases of bladder cancer. We know it is probably any cancer, not just bladder. Patients with an ARID1A mutation may have a better chance to respond, and certainly should be considered for immunotherapy. Unfortunaltey, this still does not fit in the selection criteria for insurance coverage.

ARID1A is a gene that encodes a protein involved in regulating chromatin structure and gene expression. Chromatin is the complex of DNA and proteins that makes up the chromosomes inside the nucleus of cells, and its structure can impact how genes are expressed or repressed. ARID1A is often mutated or deleted in various types of cancer, including ovarian, endometrial, gastric, pancreatic, bladder, and liver cancer.

The loss of ARID1A function can lead to changes in gene expression, which can contribute to the development and progression of cancer. In particular, ARID1A mutations have been associated with alterations in DNA repair mechanisms, immune system regulation, and cellular metabolism, all of which can promote tumor growth and survival.

ARID1A mutations have also been studied as a potential biomarker for predicting response to specific cancer treatments, such as immune checkpoint inhibitors. Some studies have suggested that patients with ARID1A mutations may be more likely to respond to immunotherapy. However, more research is needed to confirm these findings and determine how they can be applied in clinical practice.

Overall, ARID1A is an important gene in cancer biology and is being studied as a potential therapeutic target and biomarker for various types of cancer.

Jason R. Williams, MD, DABR

Reference

Sarfaty M, Golkaram M, Funt SA, et al. Novel genetic subtypes of urothelial carcinoma with differential outcomes on immune checkpoint blockade. [published online ahead of print, 2023 Mar 16]. J Clin Oncol. Published online March 16, 2023. doi:10.1200/JCO.22.02144

https://www.cancernetwork.com/view/select-molecular-subgroups-may-predict-icb-responses-in-bladder-cancer

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B7H3 Is An Up-and-coming ImmunotherapyTarget

B7H3 Is An Up-and-coming ImmunotherapyTarget

B7H3 is a protein that is overexpressed in many types of cancer, including prostate cancer and is believed to play a role in regulating the immune system and developing tumors. Therefore, targeting B7H3 with immunotherapy drugs may be a promising approach for the treatment of prostate cancer.

This is an area of great interest for me. In many of the NanoString analyses we performed on patients during immunotherapy treatment, the upregulation of B7H3 was a significant resistance mechanism. We certainly have seen success in working with this checkpoint inhibitor in many cancer types. It may be proven as or more important than current FDA-approved immunotherapy. The combination of all these, injected into the cancer, is where the real success is found.

Several studies have investigated the use of B7H3-targeted immunotherapy drugs in prostate cancer. For example, a phase 1 clinical trial tested an anti-B7H3 antibody called 8H9 in patients with advanced prostate cancer and found that the drug was well-tolerated and showed some evidence of clinical activity.

Another clinical trial tested an anti-B7H3 antibody called enoblituzumab in patients with localized prostate cancer who were not eligible for surgery or radiation therapy. The trial found that enoblituzumab was well-tolerated by patients and showed promising efficacy in shrinking tumors and delaying disease progression.

In addition to antibodies, other types of immunotherapy drugs targeting B7H3 are also being investigated for the treatment of prostate cancer. For example, a phase 1 clinical trial tested a B7H3-targeted CAR T cell therapy in patients with advanced prostate cancer. The treatment was safe and showed some evidence of clinical activity.

While the results of these studies are promising, more research is needed to fully understand the potential of B7H3 as a target for prostate cancer immunotherapy and to determine the optimal use of B7H3-targeted drugs in combination with other therapies.

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INCLUDING PAPAYA IN YOUR DIET CAN HELP YOU HEAL MANY DISEASES, INCLUDING CANCER.

Papaya is native to Mexico but also grows naturally in the Caribbean and Florida. It is one of the most recommended fruits for preventing diseases such as cancer due to its high antioxidant and vitamin C content. Additionally, it has other nutrients that help prevent its occurrences, such as beta-cryptoxanthin, carotenoids, alfa-carotene, and beta-carotene, making it an anticancer fruit.

Papayas grow in tropical climates and are characterized by their sweet taste, vibrant color, and a wide variety of health benefits. It is recommended to consume this fruit at least 2-3 times a week, not only to prevent the occurrence of cancer but also to improve digestion. You can add it to salads, smoothies, and other dishes.

Consumption of papaya is associated with a lower risk of heart disease, diabetes, and cancer, as well as an improvement in digestion, blood glucose control in people with diabetes, reduction in blood pressure, and improvement in wound healing.

It is important to avoid bad habits such as smoking, alcoholism, drug addiction, obesity, lack of sleep, and stress, as these habits only harm and make the body sick. Don’t forget to exercise or engage in regular physical activity.

 

Reference:

Ware, M. R. (2021, 11^th January). ¿Cuáles son los beneficios de la papaya

para la salud? https://www.medicalnewstoday.com/articles/es/fruta-de-papaya

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Does Black Pepper enhance the Curcumin effect?

We had previously discussed Curcumin properties that included anti-inflammatory, antioxidant, and anti-carcinogenic by acting on cell proliferation, cell survival, death receptors, and tumor suppression pathways. However, ingesting curcumin alone does not lead to the associated health benefits due to its poor bioavailability, which appears to be due to poor absorption, rapid metabolism, and rapid elimination; curcumin doesn’t absorb into the bloodstream easily and therefore relies on methods to increase bioavailability. This is where consuming it with black pepper is important.

Black pepper’s active ingredient, piperine, is responsible for black pepper’s rich flavor and helps inhibit drug metabolism; piperine helps increase the rate at which curcumin is absorbed by the body and its bioavailability in the body; for example, the liver is in charge of getting rid of substances by making them water-soluble so they can be excreted, and piperine acts on this effect so curcumin is not excreted as fast, and its effects can be enhanced; it has been shown that piperine can increase curcumin bioavailability by 2000%, so all of the health effects of curcumin as antioxidant, anti-inflammatory, anti-carcinogenic, the effect on metabolic syndrome and arthritis are enhanced and, therefore, your overall health.

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Toll Like Receptors (TLR) Cancer Immunotherapy

Toll-like receptors (TLRs) are a type of protein that play a crucial role in the immune system’s response to infection and inflammation. TLR agonists are compounds that activate TLRs, leading to an immune response.

There is growing interest in the potential of TLR agonists as a cancer immunotherapy approach. By activating TLRs, TLR agonists can stimulate the immune system to attack cancer cells, leading to tumor cell death and tumor regression.

Several TLR agonists are currently being studied as potential cancer immunotherapy agents, including imiquimod, a TLR7 agonist, and CpG oligodeoxynucleotides, which are TLR9 agonists. These compounds have been shown to enhance the immune response against cancer cells in preclinical studies.

Clinical trials are ongoing to evaluate the safety and effectiveness of TLR agonists in human cancer patients. Some early studies have shown promising results, with some patients showing tumor shrinkage and prolonged survival.

Overall, TLR agonists represent a promising approach to cancer immunotherapy, and may offer a new way to enhance the immune response against cancer cells. However, more research is needed to fully understand the safety and effectiveness of this approach, and to determine which types of cancer and patient populations may benefit most from this therapy.

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