A new line of attack for doctors treating mesothelioma.

Recent advancements in immunotherapy and epigenetic therapies for mesothelioma treatment offer a glimmer of hope for improving outcomes in PM patients.

Pleural mesothelioma (PM) remains a rare and fatal disease originating from the pleural membranes lining the lungs. Despite the global ban on asbestos usage in most countries, the slow increase in PM cases continues due to past occupational exposure.

The current standard treatment involves a combination of cisplatin o carboplatin y pemetrexed, but the overall survival remains unsatisfactory. This article explores the recent advancements in pleural mesothelioma treatment involving immunotherapy and epigenetic therapies, offering unusual good news in the battle.

Glossary for Understanding Mesothelioma Science
Term	Definition
Pleural Mesothelioma (PM)	A rare and serious cancer that starts in the protective lining of the lungs, often caused by exposure to asbestos. It poses a significant health risk due to its aggressive nature and limited treatment options.
Inmunoterapia	A cutting-edge cancer treatment that harnesses the body’s immune system to fight cancer cells. By enhancing the body’s natural defenses, immunotherapy provides a promising alternative to traditional treatments like chemotherapy.
Epigenetic Therapy	An innovative approach to cancer treatment that focuses on modifying how genes are expressed without changing their fundamental structure. This method offers new possibilities for targeting and treating various cancers.
DNA Methylation	The addition of tiny chemical tags to the DNA molecule, influencing how genes work. Changes in DNA methylation can impact cancer development, providing valuable insights into understanding and treating the disease.
Histological Classification	The categorization of tumors based on their appearance under a microscope, helping doctors identify specific subtypes and predict how they might behave. This classification aids in tailoring effective treatment strategies.
Angiogenesis	The natural process of forming new blood vessels. In cancer, angiogenesis enables tumors to establish a dedicated blood supply, sustaining their growth and survival. Understanding and targeting this process are crucial for cancer treatment.
Tumor Microenvironment (TME)	The environment surrounding a tumor, consisting of blood vessels, immune cells, and other supporting structures. The tumor microenvironment plays a vital role in cancer progression and influences how tumors respond to treatment.
Immune Checkpoint Inhibitors (ICI)	Medications that block specific proteins on immune cells or cancer cells, helping the immune system recognize and attack cancer more effectively. These inhibitors represent a significant advancement in cancer immunotherapy.
Free Radicals	Unstable molecules with an unpaired electron that can cause damage to cells. In cancer, free radicals contribute to DNA damage, fostering an environment conducive to tumor growth. Understanding and managing free radicals are essential in cancer prevention.
Blood Vessel Growth Inhibitors	Medications that target the process of angiogenesis, aiming to disrupt the formation of new blood vessels and limit the nutrient supply to tumors. These inhibitors show promise in slowing down tumor growth and improving cancer treatment outcomes.
Exposición al Asbesto	Breathing or swallowing tiny asbestos fibers, which can lead to an increased risk of developing mesothelioma and other asbestos-related diseases. Understanding the dangers of asbestos exposure is crucial for preventing associated health risks.
Inflamación	The body’s natural response to injury or infection, characterized by redness, swelling, and pain. Chronic inflammation can contribute to cancer development, emphasizing the importance of managing inflammation for overall health.
Gene Expression	The process by which information from a gene is used to create functional products like proteins. Modifying gene expression through therapies like epigenetic treatments offers innovative possibilities for cancer treatment.
Cytotoxic T Cells	Specialized immune cells that directly kill cancer cells. Enhancing the activity of cytotoxic T cells is a key goal in cancer immunotherapy, as these cells play a crucial role in the body’s defense against cancer.
Chimeric Antigen Receptor (CAR) T Cell Therapy	A type of immunotherapy where a patient’s T cells are genetically engineered to recognize and target cancer cells. This personalized approach has shown promising results in improving the body’s ability to fight cancer.
Tumor Mutational Burden (TMB)	The number of mutations present in a tumor’s DNA. High TMB is associated with better responses to certain cancer treatments, providing insights into predicting and improving treatment outcomes.
Epigenomic Signatures	Patterns of epigenetic modifications across the genome. Studying these signatures provides valuable information about how genes are regulated in cancer, opening avenues for developing targeted and effective treatments.

Current Treatment Landscape:

Historically, mesothelioma is aggressive and often treatment-resistant.

The standard therapeutic scheme for unresectable PM has seen limited progress in the past 15 years, with the combination of cisplatin or carboplatin and pemetrexed being the reference treatment. However, the efficacy of this regimen remains suboptimal, with a median overall survival (mOS) ranging between 12 and 14 months, and less than 5% achieving a 5-year survival.

Better results in newer studies of mesothelioma treatment

Despite the discouraging statistics, the MAPS phase 3 clinical trial in 2016 revealed promising results by combining bevacizumab with the cisplatin-pemetrexed regimen, extending mOS to 18.8 months. Unfortunately, this approach is currently limited to selected PM patients in France, leaving a significant treatment gap for many.

What is immunotherapy?

Immunotherapy is a groundbreaking approach in cancer treatment that harnesses the body’s own immune system to fight against cancer cells.

Unlike traditional treatments such as chemotherapy, which directly target cancer cells, immunotherapy empowers the immune system to recognize and attack these cells. This innovative concept started gaining attention in the late 19th century, but significant breakthroughs came in the 21st century, particularly with the development of immune checkpoint inhibitors.

These inhibitors, like nivolumab y ipilimumab, allow the immune system to better identify and attack cancer cells, marking a paradigm shift in cancer treatment.

The breakthrough nature of immunotherapy lies in its ability to unleash the body’s natural defense mechanisms against cancer. Cancer cells often find ways to evade the immune system, but immunotherapy helps overcome these evasive tactics. This approach has shown remarkable success, especially in previously challenging-to-treat cancers like pleural mesothelioma. By enhancing the immune system’s ability to recognize and destroy cancer cells, immunotherapy offers a more targeted and less toxic alternative to traditional treatments.

What is epigenetic therapy?

Traditionally, we believed that our genes were fixed and unchanging, like an unalterable blueprint for our bodies.

But epigenetic therapy has revealed a more dynamic aspect of our genetic makeup.

Epigenetic Therapy: Unveiling the Dynamic Nature of Genes

Epigenetics refers to changes in gene expression without altering the underlying DNA sequence. This field has transformed our understanding, showing that genes can evolve and change in response to external factors.

Epigenetic therapy explores the influence of environmental factors on gene activity. In the context of pleural mesothelioma, where asbestos exposure is a significant risk factor, understanding these changes becomes crucial. Asbestos can influence the epigenetic makeup of cells, affecting the way genes are expressed and regulated.

Asbestos, DNA, and Free Radicals: Unraveling the Connection

Asbestos exposure not only poses a direct risk to the lungs but also affects the growth DNA of cells. This means that asbestos can lead to changes in the way cells behave and multiply, increasing the risk of cancerous growth. To comprehend this risk, it’s essential to understand the role of free radicals.

Free radicals are highly reactive molecules that can damage cells, including their DNA. Asbestos exposure can lead to the generation of free radicals in the body, creating an environment conducive to the formation of cancerous tumors. The damage caused by free radicals can disrupt the normal functioning of cells, potentially leading to uncontrolled cell division and the development of cancer.

In simpler terms, think of free radicals as tiny troublemakers within our cells. When asbestos exposure introduces these troublemakers, they can wreak havoc on the DNA, creating a chaotic environment where cancerous tumors may form. Epigenetic therapy becomes crucial in this context, offering a way to intervene in the gene activity influenced by asbestos exposure and potentially prevent or slow down the progression of mesothelioma.

In summary, immunotherapy empowers our immune system to fight cancer, representing a game-changing approach in cancer treatment. On the other hand, epigenetic therapy reveals the dynamic nature of our genes and their response to environmental factors, offering insights into how asbestos exposure can influence the development of mesothelioma. Understanding the connection between asbestos, DNA changes, and the role of free radicals provides a clearer picture of the complex mechanisms at play in the formation of cancerous tumors.

What is angiogenesis?

Angiogenesis is a critical process in our bodies that involves the formation of new blood vessels.

While this is usually a necessary and healthy occurrence for wound healing and growth, it can take a dark turn in the context of cancer.

Understanding angiogenesis is crucial, especially in diseases like pleural mesothelioma, where abnormal blood vessel growth can contribute to tumor progression.

Angiogenesis: Unveiling the Blood Vessels that Feed Tumors

The spotlight on angiogenesis in cancer research intensified in the 20th century. Dr. Judah Folkman, often regarded as the pioneer in this field, proposed that tumors couldn’t grow beyond a certain size without a blood supply. In the 1970s, his groundbreaking work laid the foundation for targeting angiogenesis as a potential strategy to starve tumors of the nutrients they need to thrive.

Angiogenesis Breakthrough: Disrupting Tumor Blood Supply

The breakthrough in understanding angiogenesis’s role in cancer lies in the realization that tumors manipulate this process to sustain their growth. In cancers like pleural mesothelioma, asbestos exposure triggers inflammation, setting the stage for angiogenesis. As tumors grow, they release signals that prompt nearby blood vessels to sprout new branches, providing the tumor with a dedicated blood supply.

The significance of this breakthrough is profound. By disrupting angiogenesis, researchers aimed to cut off the blood supply to tumors, essentially starving them of the nutrients they require to flourish. Drugs like bevacizumab, which targets a protein crucial for angiogenesis, have shown promise in slowing tumor growth and improving outcomes for certain cancers.

Asbestos, Inflammation, and Angiogenesis: A Risky Connection

In the case of pleural mesothelioma, asbestos exposure triggers chronic inflammation in the lungs, creating an environment conducive to angiogenesis. The inflammation prompts the release of signals that stimulate the formation of new blood vessels, creating a network that nourishes the growing tumor. This connection between asbestos, inflammation, and angiogenesis highlights how external factors can hijack normal bodily processes, contributing to cancer development.

Free Radicals: The Culprits in Angiogenesis and Cancer

Much like in the context of epigenetic changes, free radicals play a significant role in angiogenesis. Asbestos exposure can lead to the generation of free radicals, creating a cascade of events that contribute to both inflammation and angiogenesis. Free radicals damage cells and trigger signaling pathways that promote the growth of blood vessels, fostering an environment favorable for tumor progression.

In simpler terms, think of angiogenesis as the construction of a tumor’s private highway, fueled by new blood vessels. Asbestos exposure initiates this process, and free radicals act as the construction crew, building the pathways that support tumor growth.

Understanding the intricate relationship between asbestos, inflammation, angiogenesis, and free radicals provides insights into how pleural mesothelioma progresses. Targeting angiogenesis represents a therapeutic avenue to disrupt this intricate dance and potentially hinder the tumor’s ability to thrive. The breakthrough lies not just in recognizing the process but in developing strategies to intervene and alter the course of cancer progression.

Targeting Angiogenesis and Immunotherapy:

One avenue explored to improve treatment of pleural mesothelioma involves targeting angiogenesis, with mixed success. The MAPS trial’s positive outcome has not been replicated in subsequent trials using antibodies and multitargeted small molecule inhibitors. A groundbreaking approach involves combining immune checkpoint inhibitors (ICI) with epigenetic therapy, acknowledging the immune system’s role in PM progression and resistance to treatment.

Epigenetic Therapy and Immunotherapy:

Recent studies highlight the potential of epigenetic therapy in enhancing the efficacy of ICI-based immunotherapy for PM. DNA methylation profiles in PM cells have been explored, revealing distinct patterns associated with asbestos exposure and clinical outcomes. Epigenetic changes contribute to immunotherapy resistance by downregulating antigen presentation genes and upregulating immune checkpoint proteins. Drugs like DNA hypomethylating agents (DHA) and histone deacetylase inhibitors (HDACi) have shown promise in reversing these changes.

Decitabine y guadecitabine, among other DHA, enhance immune-related molecule expression in PM cells, making them more recognizable by immune cells. HDACi like valproic acid (VPA) and vorinostat synergize with DHA to induce tumor antigen expression and sensitize PM cells to immune responses.

Immunomodulatory Activities of Epigenetic Drugs:

Epigenetic inhibitors, including DHA, HDACi, and enhancer of zeste homolog 2 inhibitors (EZH2i), have demonstrated their potential in modulating the immune response. Preclinical studies indicate that these drugs can enhance the immunogenicity of PM cells, increase immune cell recognition, and promote an immune response against tumor cells. Clinical trials combining anti-PD-1 monoclonal antibodies and EZH2i are being considered, offering a novel epigenetic-based immunotherapy approach for PM.

Non-ICI Based Immunotherapy – Dendritic Cell Vaccination:

Dendritic cell vaccination presents a promising avenue for PM treatment. DCs, the most potent antigen-presenting cells, can be manipulated ex vivo to stimulate an immune response against tumor cells. Early clinical trials have shown promising results, with DC vaccination demonstrating a median overall survival of about 19 months in PM patients.

Ongoing studies, such as the DENIM trial, are investigating the efficacy of DC vaccination with Allogeneic Tumor Cell Lysate, providing hope for a potential breakthrough in PM immunotherapy.

Understanding the Tumor Microenvironment:

PM’s immunologically cold tumor nature, characterized by low tumor mutational burden and an immune-suppressive tumor microenvironment, poses challenges for effective immunotherapy. Tumor-associated macrophages (TAMs) play a crucial role in shaping the TME, promoting tumor growth and resistance to treatment. Strategies targeting TAMs, such as chimeric antigen receptor (CAR) T cell therapy, show promise in preclinical studies and early-phase clinical trials.

Conclusion and Future Directions:

While PM treatment has seen limited progress for decades, recent advancements in immunotherapy and epigenetic therapies offer new hope. The combination of ICI with epigenetic drugs and innovative approaches like dendritic cell vaccination shows promise in preclinical and early clinical studies. Understanding the complex interplay between the tumor and its microenvironment is crucial for developing effective immunotherapeutic strategies.

Ongoing clinical trials and a deeper comprehension of these interactions hold the key to transforming the landscape of PM treatment. As research progresses, a multidimensional approach involving immunotherapy, epigenetic therapies, and innovative strategies like CAR T cell therapy may pave the way for improved outcomes in this challenging disease.