Blocking DNA Repair to Enhance Immunotherapy

Blocking DNA repair to enhance immunotherapy is an emerging approach to cancer treatment that aims to increase the effectiveness of immunotherapy by inhibiting the ability of cancer cells to repair DNA damage caused by immune-mediated cell death.

The immune system recognizes cancer by the differences it has from normal cells, due to mutations, However, cancer cells also have the ability to repair DNA damage that reduces mutations, which can reduce the effectiveness of immunotherapy.

By inhibiting DNA repair pathways, it is possible to increase the accumulation of DNA damage in cancer cells, which can enhance the effectiveness of immunotherapy. For example, preclinical studies have shown that combining immunotherapy with inhibitors of DNA repair pathways, such as PARP inhibitors or ATR inhibitors, can result in enhanced tumor regression and prolonged survival in mouse models of cancer. Patients who have mutations in the DNA repair, known as Mismatch Repair Deficiency (dMMR) have a better response to immunotherapy. Unfortunately, these are the minority of patients. There are other DNA repair genes, such as ATM, ATR, RAD-3 and CHEK2. Mutations in DNA repair genes leads to increased mutations and can be associated with and improved response to immunotherapy. Patients who don’t have mutations in these genes can achieve improved responses to immunotherapy by blocking some of these DNA repair mechanisms. This allows a better response, closer to what was seen in people who naturally have mutations, like those in the MSK dostarlimab study for rectal cancer, reported to be 100% cured in 14/14 patients.

Several clinical trials are currently underway to evaluate the efficacy and safety of combining immunotherapy with DNA repair inhibitors in various types of cancer. While the results of these trials are still preliminary, they suggest that this approach has the potential to improve the response rate and duration of response to immunotherapy, particularly in patients with tumors that are resistant to conventional therapies.

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VITAMIN D3

There are many questions regarding whether supplementing Vitamin D can cause a decrease in cancer incidence and whether you should take this vitamin. One normally produces Vitamin D when exposed to sunlight, but we can also find it in foods such as fish, mushrooms, milk, and some cereals.

Vitamin D can downregulate growth hormones and suppress proliferation in many cancers. Vitamin D receptors are widely expressed throughout the body, and experimental evidence suggests that vitamin D has antineoplastic activity. Vitamin D binding to its receptor results in transcriptional activation and repression of target genes producing apoptosis, antiproliferative effects, autophagic cell death and angiogenesis, and immunomodulatory effects that contribute to reduced metastatic disease and fatal cancer.

It has been shown that vitamin D is able not only to potentiate the effects of traditional cancer therapy as gemcitabine, cisplatin, doxorubicin, and proton therapy but can even contribute to overcoming the molecular mechanisms of drug resistance; it can act at various levels through the regulation of growth of cancer stem cells and the epithelial-mesenchymal transition and the modulation of miRNA gene expression.

This antitumor action is probably because it influences intracellular calcium oscillations capable of influencing cell mechanisms of growth and apoptosis. In recent years, vitamin D has modulated the inflammatory state of the tumor microenvironment by affecting immunological infiltrations.

Harvard researchers set out in 2011 a large study with 25,871 people with randomized vitamin D supplementation. The results showed that the rate of fatal or metastatic cancer was 17% lower in those taking vitamin D supplements and 38% in people with a healthy weight.

Although it has been proven that Vitamin D3 can reduce the risk of advanced cancer, metastasis, and fatal cancer, it is not associated with cancer prevention.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7353389/#:~:text=Conversely%2C%20several%20molecular%20studies%20are,activation%20of%20different%20molecular%20pathways.

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2773074#:~:text=Vitamin%20D%20may%20decrease%20tumor,leading%20to%20reduced%20cancer%20mortality.&text=Higher%20serum%2025%2Dhydroxyvitamin%20D,longer%20survival%20in%20cancer%20patients.

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Intratumoral anti-CD47 Immunotherapy

CD47 is a protein that is overexpressed on the surface of many cancer cells, and it interacts with the immune system to inhibit phagocytosis, or the process by which immune cells engulf and destroy cancer cells. This interaction between CD47 and immune cells, including macrophages, can contribute to tumor growth and resistance to immunotherapy.

Intratumoral CD47 blockade is an emerging approach to cancer therapy that involves delivering CD47-blocking agents directly into the tumor site. The goal of this approach is to enhance the phagocytosis of cancer cells by macrophages, thereby reducing tumor growth and enhancing the effectiveness of immunotherapy.

Preclinical studies have shown that intratumoral CD47 blockade can result in tumor regression and improved survival in mouse models of cancer. For example, a study published in the journal Nature in 2016 showed that intratumoral injection of a CD47-blocking antibody enhanced the phagocytosis of cancer cells by macrophages and resulted in the regression of multiple types of tumors, including breast cancer, ovarian cancer, and lymphoma.

Clinical trials evaluating intratumoral CD47 blockade are currently underway in various types of cancer, including solid tumors and hematological malignancies. While the results of these trials are still preliminary, they suggest that intratumoral CD47 blockade has the potential to be an effective cancer therapy, particularly in combination with other immunotherapeutic agents.

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Exposure to Antibiotics Before Immune Checkpoint Inhibitor Therapy and Overall Survival in Elderly Patients with Cancer

Exposure to antibiotics during the first year after starting immune checkpoint inhibitor therapy has been found to be associated with worse survival among patients with cancer aged 65 years or older.

After conducting multiple studies, it was found that 59% of patients that received antibiotics during the first year and 19% during the 60 days after starting immune checkpoint inhibitors, researchers have observed that exposure to antibiotics, specifically fluoroquinolones, before immune checkpoint inhibitor therapy was associated with worse overall survival among older adults with cancer. Interventions targeted at altering the gut microbiome to increase immunogenicity may help improve outcomes for patients receiving immune checkpoint inhibitors with prior antibiotic exposure.

Lawson Eng, MD, SM, from the Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, is the corresponding author of the article in the Journal of Clinical Oncology.

Disclosure: The study was supported by ICES, which is funded by an annual grant from the Ministry of Health and Long-Term Care of Ontario, the ASCO/Conquer Cancer Foundation Young Investigator Award, and others. For full disclosure information on the study authors, visit ascopubs.org.

 

 

 

Reference:

Antibiotic Exposure Before Immune Checkpoint Inhibitor Treatment and

Overall Survival in Older Patients With Cancer – The ASCO Post. (s. f.). https://ascopost.com/news/march-2023/antibiotic-exposure-before-immune-checkpoint-inhibitor-treatment-and-overall-survival-in-older-patients-with-cancer/?utm_source=TAP-EN-030823-Trending_LUNG

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Do you know about the injectable gel that cures metastasis in a “cold” cancer model?

The hydrogel drug (Imigel) is an immunoadjuvant drug for treating cancer.
Image-guided therapy in mice turned a “cold” tumor, one that is resistant to immunotherapy, into a “hot” immunotherapy-sensitive tumor, allowing immune cells to target and attack the tumor both locally and systemically. The image-guided therapy converted a “cold” tumor, one
that is resistant to immunotherapy, into a “hot” immunotherapy-sensitive tumor, allowing immune cells to target and attack the tumor both locally and systemically.

This finding was named “Image-guided intratumoral cancer vaccine for treating metastatic immunotherapy-resistant cancer with and without cryoablation.” The researchers wanted to discover a mechanism for injecting imiquimod, a topical cancer drug approved by the US Food and Drug Administration, and getting it to rem,main in the tumor for about 5 days, which is the time it can take to activate the immune system. It was also expected to be used to optimize image guidance.

The problem with imiquimod is that it is a small molecule, so it disappears very quickly. One of the elements that has been a challenge for many of our intratumoral injections is the lack of retention of the medicines. Working in collaboration with the interventional radiologist laboratory of MGH Eric Wehrenberg-Klee, MD, and engineering collaborators at the Massachusetts Institute of Technology (MIT), they developed a radiopaque gel that becomes liquid at room temperature but solidifies in the tumor in the body.

Using two metastatic mouse tumor models resistant to checkpoint inhibitors (CPIs), the researchers evaluated 90-day survival after injection with and without cryoablation. Cryoablation has long been shown to have an immune-stimulating effect, meaning they were able to demonstrate that complete regression of a relatively large tumor that they had implanted distally in the site they treated could be obtained, which could be considered as a personalized cancer vaccine. Thus, by taking a clinically approved drug, using materials that are recognized as safe, combining them, and then injecting the material with and without cryoablation, they were able to demonstrate that yes, indeed, we can heat up a cold tumor in many ways simply by improving the retention of drugs that we already have.

“Unfortunately, many people still do not know that interventional radiology exists.” Certainly injecting tumors directly with immunotherapy is the future of cancer treatment. Hydrogels and other agents such as ionic liquids make very promising delivery options to help keep the medication in the tumor site. These techniques are advancing Intratumoral immunotherapy to the next level.

Reference:
Powers, M. P. (2023a, marzo 5). Injectable gel platform cures cancer
metastasis in a «cold» model. IR Quarterly.
http://irq.sirweb.org/sirtoday/injectable-gel-platform-cures-cancermetastasis-in-a-cold/

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Mepazine/Biperiden

Mepazine is a phenothiazine antipsychotic medication. Biperiden is a medication used to treat Parkinson’s disease and is a synthetic acetylcholine antagonist. Both of these drugs inhibit MALT1, which is associated with the CBM signalosome complex. Pilato, et al. published an article in Nature Research; Oct 2018 titled “Targeting the CBM Complex Causes Treg Cells to Prime Tumours for Immune Checkpoint Therapy.” They demonstrated that using Mepazine to inhibit MALT1 could help convert immunologically cold tumors to hot ones. In the animal model, they showed the combination of Mepazine with PD-1 inhibitors causes the development of an anti-cancer immune response with relapse-free tumor control in a model that does not respond to PD-1 therapy alone. This is important, as the majority of cancers do not respond to PD-1 therapy due to a lack of infiltration of attacking immune cells and a predominance of tumor-protecting regulatory immune cells. They also showed that MALT1 inhibition could actually convert regulatory cells into ones that are more tumor-attacking. The big advantage here is that most strategies are to decrease regulatory cells, generally by killing them. This drug may be able to make good use of those regulatory cells in the tumor environment to convert them into attacking the tumor.

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BIFIDOBACTERIUM

Most bacteria species used as probiotics are under the genera Bifidobacterium and Lactobacillus; the genus Bifidobacterium contains approximately 57 subspecies, and it’s the dominant bacterial population in the gastrointestinal tract; the changes in the number of their population are one of the most frequent situations that are present on gastrointestinal diseases like inflammatory bowel disease, colorectal cancer, or/and irritable bowel syndrome. Recently Bifidobacterium spp has caught attention in the cancer field because of its pro-apoptotic effects. Many studies have been made regarding colorectal cancer to demonstrate this effect. Evidence from many studies suggests mechanism probiotics benefit colorectal cancer, including improvement in the host’s immune response, induction of apoptosis, and inhibition of tyrosine kinase signaling pathways, the epidermal growth factor receptor pathway on of them. Some species of Bifidobacterium can decrease carcinogen-induced DNA damage, pre-neoplastic lesions, and tumor in colons of rats, according to previous studies.

Sepideh Bahmani and colleagues conducted a study in 2019 resulting in Bifidobacterium bifidum being effective in combating cancer cells and associated with improved gastrointestinal cancer and concluded that the produced cell-free supernatants could inhibit the growth of cancer cells.

Bifidobacterium and Lactobacillus exert anticancer effects through the production of antioxidative enzymes, binding to reactive oxygen species, chelating heavy metals, neutralizing carcinogens, and they can regulate the cell cycle in cancer cells, inhibiting their proliferation, making them susceptible to apoptosis. The mechanism of action shown in different studies in which Bifidobacterium can act on cancer cell apoptosis resistance is via upregulation and downregulation of effective genes with pro-apoptotic and anti-apoptotic activities.

In a recent study by Zeinab Faghfoori et al., they found that the secretion metabolites of Bifidobacteria spp can induce intrinsic and extrinsic apoptosis pathways in human colorectal cancer cells.

With all the discussion and conclusions of different studies regarding the anti-cancer effect of Bifidobacterium species, we can conclude that, as for now, it is safe to use as a supplement in patients with cancer, especially colorectal cancer. More studies need to be made regarding which species of Bifidobacterium has the most benefits for battling against cancer and if there is a proper dose to achieve this effect.

https://pubmed.ncbi.nlm.nih.gov/31530527/

Faghfoori, Z., Faghfoori, M.H., Saber, A. et al. Anticancer effects of bifidobacteria on colon cancer cell lines. Cancer Cell Int 21, 258 (2021). https://doi.org/10.1186/s12935-021-01971-3

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7219778/

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