Parp-Inhibitors show promise in mesothelioma treatment

At this year’s American Association for Cancer Research, investigators from the United Kingdom announced the positive results of a mesothelioma clinical trial testing a relatively new class of targeted drugs: the PARP inhibitors.

The study Niraparib Efficacy in Patients With Unresectable Mesothelioma (NERO) enrolled 88 patients randomized into two groups showed that those treated with niraparib extended the median progression-free survival by 1.5 months compared to the arm of patients who only received symptom management care.

Eligible patients had already undergone standard chemotherapy treatment for mesothelioma with success, but they relapsed with the cancer coming back or growing.

Currently, there are no proven therapies for mesothelioma beyond initial treatment and after recurrence. Data on the efficacy of chemotherapy are limited, and immunotherapy retreatment has been only a recent addition to the doctors’ treatment arsenal.

What are PARP inhibitors?

Simply put, PARP inhibitors are drugs that prevent the enzyme known as poly ADP ribose polymerase (PARP) from doing its job of repairing damaged DNA in cells. If not repaired, damaged cells, including cancer cells, die. Conversely, if repaired, even if the repair is erroneous, the cells go on to survive and replicate which can be problematic with cancerous cells. Typically, patients who responded to chemotherapy previously are more likely to see a benefit from this class of drugs. While this study did not require patients enrolled to have a somatic BAP1 deletion, other studies looking into this agent often do. Somatic mutations are those not passed down to offspring and are instead acquired in the cells over time. BAP1 is a tumor suppressor gene, therefore its deletion is understood as consequential in mesothelioma.

Clinical trials employing PARP inhibitors currently available in the United States

While this study took place in the United Kingdom, in the U.S. clinical studies utilizing PARP inhibitors have been available to mesothelioma patients who fit certain eligibility criteria. Currently, one of those studies is still open and enrolling.

Olaparib in Patients with HRD Malignant Mesothelioma is available at the University of Chicago Medicine to patients with the loss of BAP1 and/or a germline (passed down from parents) or somatic (acquired over lifetime) mutation that disrupts protein function in at least one of the patient’s genes.

Could there be another mesothelioma cell type beyond epithelioid, sarcomatoid, and biphasic?

In recent years, mesothelioma histology has become more important than ever, as researchers find that certain treatments are more effective against different cell types. The epitheliod subtype of mesothelioma is by far the most common and is considered the least aggressive of the three types. The sarcomatoid subtype is less common but most aggressive. When a tumor contains both types of cells, it is known as biphasic.

As far as treatment goes, epitheliod mesothelioma tends to respond to chemotherapy better than the sarcomatoid subtype, while benefits of immunotherapy are more pronounced in patients with the more aggressive sarcomatoid subtype.

But now, researchers believe to have identified mesothelioma cells that are neither sarcomatoid nor epitheliod. In the preprint article “Comprehensive multi-site profiling of the malignant pleural mesothelioma micro-environment identifies candidate molecular determinants of histopathologic type,” by Raphael Bueno, MD, et al., the authors suggest that a third category of cells exist in the tumor microenvironment of mesothelioma and are most prevalent in tumors of patients with biphasic disease. Those cells have been named “uncommitted” because the idea is that at some point they might take on an epitheliod or sarcomatoid appearance.

As the researchers examined tumor samples, they noticed that in predominantly epitheliod, and in predominantly sarcomatoid mesotheliomas, such uncommitted cells were few, but in biphasic mesothelioma they were substantial.

Significance of histology (tumor cell type) for mesothelioma patients

The cellular type of the mesothelioma tumor helps doctors determine the prognosis and best treatment for a patient. For example, it is currently known that survival varies depending on the cell type. Patients with epitheliod mesothelioma have the best prognosis, and those with sarcomatoid the worst. The biphasic patients tend to fall in between depending on the proportion of epitheliod vs sarcomatoid cells in their tumors. Moreover, tumor histology helps doctors identify the best treatment for a patient. Sarcomatoid and biphasic tumors have shown the greatest benefit when treated with immunotherapy, and the least benefit when treated with chemotherapy. As mesothelioma research continues to advance, the tumor microenvironment is seen as far more important than individual cells in the proliferation of this cancer.

Because mesothelioma prognosis currently relies so heavily on histology, this discovery adds another layer of nuance to an already complex disease. In addition to understanding the significance and purpose of these uncommitted cells, another question for researchers to untangle in the future will be to understand whether these uncommitted cells ultimately become committed, and whether they commit to the epitheliod or sarcomatoid type and why.

effectiveness of immunotherapy for mesothelioma

Predicting effectiveness of mesothelioma immunotherapy

In recent years, immunotherapy has revolutionized cancer treatment for most cancers, and even the notably difficult-to-treat mesothelioma has reaped benefits. However, despite two new FDA treatment approvals featuring immunotherapy, this treatment only works for a minority of mesothelioma patients and the benefit is most obvious in the most aggressive, sarcomatoid group. This fact, paired with concerns of immune toxicity, can make some patients and physicians wish they had more tools to gauge if immunotherapy will be more useful than harmful. But are we able to predict its effectiveness before starting treatment?

Drs. Farhad Kosari and Maria Disselhorst of the Mayo Clinic, among others, have been studying exactly this problem. In their paper “Tumor Junction Burden and Antigen Presentation as Predictors of Survival in Mesothelioma Treated with Immune Checkpoint Inhibitors” published in the Journal of Thoracic Oncology, the authors conclude that an analysis of tumor genetics for mutations may facilitate patient selection for immunotherapy treatments based on checkpoint inhibitors.

Why is mesothelioma so difficult to treat?

There are many reasons for mesothelioma’s resistance to treatment. When it comes to the immune system’s role in this cancer’s proliferation, patients may hear researchers discuss its “low mutation burden.” What this means is that the cancer cells don’t look that different from the body’s non-cancerous cells on a genetic level. In other words, the number of gene mutations in a mesothelioma tumor are so few that the tumor looks like a normal cell to the immune system, which is in part how it evades it.

Based on scientific studies, the tumor mutation burden generally predicts the effectiveness of the immune checkpoint inhibitor therapy used for other cancers. The more mutations there are on the tumor that differentiate it from normal tissue, the easier it is for the primed immune system to see it and attack it, and the easier it is to target the tumor with therapies.

The flipside of this, of course, is that with mesothelioma that’s not the case, which begs the question: why do some mesothelioma patients respond to immunotherapy, while others don’t? What is so different about the ones who respond?

Tumor junction burden and antigen presentation as predictors of survival in mesothelioma

Researchers looked at 68 patients who had been treated with nivolumab and ipilimumab and nivolumab alone. Of these patients, 44 had sufficient DNA and RNA content derived from biopsy to be part of this analysis. What they concluded is that patients with a high tumor junction burden and antigen presentation survived longer than those without suggesting that it may be possible to use this information to select which patients might benefit from immunotherapy.

As mesothelioma treatment continues to head in the direction of targeted therapies, the expectation is that molecular and genetic knowledge acquired over the last decade will be incorporated into new generation treatment paradigms so doctors and patients can make fully informed decisions about treatment based on each individual patient’s circumstances.

A new worldwide clinical trial for mesothelioma is now open for enrollment

The “handshake” between the tumor and T cell prevents a T cell immune attack against mesothelioma. Disrupting the “handshake” holds the key to an immune response against this cancer. This Phase 3 immunotherapy clinical trial for mesothelioma tests a drug made to do exactly that and is now available to patients in the United States and across the world.

A new phase 3 clinical trial testing the efficacy of dual checkpoint inhibitor immunotherapy in combination with chemotherapy is now available to patients in the United States as well as around the world. The official name for the study is MEDI5752 in Combination With Carboplatin Plus Pemetrexed in Unresectable Pleural Mesothelioma and the shortened name is eVOLVE-Meso.

This AstraZeneca study tests a single immunotherapy agent called volrustomig in combination with standard chemotherapy against either standard of care chemotherapy alone or immunotherapy alone. The study builds on the recent FDA-approval of immunotherapy for mesothelioma which saw two agents, nivolumab (Opdivo) and ipilimumab (Yervoy), activate the immune system against cancer cells by binding to two receptors located on the T cell: the PD-1 and the CTLA-4. Single agent volrustomig targets the same two proteins, but the study also adds standard chemotherapy to its protocol.

How to inquire about enrollment?

The clinical trial is widely available at centers across the United States. A patient should contact their treating physician to discuss enrollment. Locations where the Evolve-Meso clinical trial is available are listed here: https://clinicaltrials.gov/study/NCT06097728#contacts-and-locations.

How does immunotherapy work to kill mesothelioma cells?

To understand how immunotherapy treatment works, we must first understand why the immune system tends to stay inactive against mesothelioma cells. Both the T cell and other cells, including tumors, express proteins. When certain proteins on the T cell bind to their counterparts on a healthy cell, this communicates to the T cell to not attack the healthy cell. This is an important preservation mechanism that prevents autoimmune reactions. So when the tumor’s proteins bind to the ones on the T cell, they tell the immune system not to attack which allows the cancer to proliferate. Immunotherapy medications act as a decoy binding protein that binds to either the T cell or the tumor cell, disrupting their ability to bind with one another.

immunotherapy working against mesothelioma

In the top part of this image, the T cell and the tumor cell connect causing no immune response against the tumor. In the bottom part of the image, the immunotherapy drugs connect to the expressed proteins on either the T cell or tumor thus inhibiting the connection between the two which in turn creates an immune reaction against the tumor. This is the basis of checkpoint inhibitor immunotherapy.

Immunotherapy + Chemotherapy: what is the rationale?

A common and valid question about combining chemotherapy with immunotherapy is: are we just throwing the kitchen sink at mesothelioma to see what sticks?

The answer is no.

There are, in fact, scientific reasons that would suggest that combining these two methods would lead to better results than administering them one at a time. Reason number one can be found in the answer to the question “why does the immune system not recognize mesothelioma as a foreign entity worth attacking from the beginning?” The answer is that mesothelioma cells’ receptors mimic those on the surface of healthy cells and they use the brakes built into the immune system to their advantage. But when chemotherapy is used to kill the cancer, the by-product of those dead cancer cells is seen as a foreign body by the immune system. So, adding chemotherapy to an immunotherapy regimen is one way to maximize the anti-tumor activity of both agents.

Timeline of FDA-approvals for mesothelioma

2004: Chemotherapy (Alimta/cisplatin)

2022: Immunotherapy (nivolumab / ipilimumab)

2024: Immunotherapy + chemotherapy for advanced mesothelioma (pembrolizumab also known by the brand name Keytruda, which is an anti-PD-1 agent, plus standard chemotherapy)

What is the difference between volrustomig and other immunotherapy agents used against mesothelioma

The volrustomig study is different from the 2024 immunotherapy (Keytruda) plus chemotherapy combination approval because volrustomig singularly binds to both the PD-1 and CTLA-4 receptors. Immunotherapy drugs targeting only the PD-1 or PDL1 receptors have shown to not be as effective as those also targeting the CTLA-4 receptor.

These two proteins, also known as checkpoint inhibitors, are located on the T cell. There, they play a crucial role in signaling to the immune system whether to attack the cancer cells or not. Without immunotherapy treatment, the tumor receptors (PD-L1 and CD80) bind to the reciprocal T cell receptors, signaling to the immune system not to attack the tumor. With immunotherapy that binds to them instead, the “handshake” between the tumor and the T cell is disrupted letting the immune system to attack the tumor.

Why should a patient consider participation in this study?

Mesothelioma patients have limited options for treatment available to them while the cancer is aggressive and moves fast. This study is an opportunity to try the combination of chemotherapy plus immunotherapy to potentially reap the most benefits.

What are the risks?

As with any study and/or treatment, one risk is that the treatment won’t work. With mesothelioma, this is a significant risk because the disease is quick and aggressive. However, over time, survival for mesothelioma patients has increased at least in part due to advancements in treatment options, and this study is one such option. Being a Phase 3 clinical trial, the drugs it uses have already been extensively studied for safety, but it is important to note that undergoing any type of immunotherapy can cause unintended immune reactions some of which can be life threatening. Speaking with the treating physician about potential risks and benefits is an important part of enrolling into a clinical trial.

What other treatments are in the works for mesothelioma?

Two other significant studies have been released in the last two years, both holding promise with regards to further treatment approvals. Both studies showed an improvement in survival in the most aggressive type of mesothelioma called the sarcomatoid subtype.

One of these studies combined Alimta/cisplatin (chemotherapy) with atezolizumab (immunotherapy) and also with bevacizumab (a VEGF inhibitor agent that limits vascular development leading to the tumor).

The other study, called ATOMIC, was successful in improving survival in the sarcomatoid and biphasic mesothelioma subtypes (most aggressive) by depriving the cancer cells of arginine, which is generally widely present in the most aggressive mesotheliomas.

New episode of Meet the Mesothelioma Experts About Financial Compensation for Mesothelioma

Last week, the Mesothelioma Applied Research Foundation released a new episode of its Meet the Mesothelioma Experts: Legal Edition series discussing financial compensation issues for mesothelioma patients. Featured guest of the program was Joseph Belluck, partner with the Belluck & Fox firm, who was interviewed by the organization’s board of directors’ member, Cheryl Bruner. Mr. Belluck answered a number of questions of interest to those who have just had a mesothelioma diagnosis and their families.

Acting with Urgency

One of the take-home messages is that while a mesothelioma diagnosis requires medical urgency and treatment, so does the legal process. This is due to a number of issues, the statute of limitations being one, but not the only one. As Mr. Belluck states in this program, it is important to file a lawsuit as soon as realistically possible in order to get a place in line, even if later adjustments are necessary. An experienced law firm will know enough information about a case very quickly and will be able to proceed with expedience.

“Usually, right after contact, we file the case, we start working on the bankruptcy trust claims and also starting to work on the lawsuit, which we do in tandem. Typically, the first settlements will come in about 45 – 60 days and the whole case will be completed within 12 months,” said Mr. Belluck in the program.

Mr. Belluck adds that whether a patient chooses to hire his firm or another firm, he still encourages them to make sure to do so quickly for the reasons outlined above.

Watch the video:

00:00 Introduction
1:11 Why Belluck & Fox chooses to sponsor the Meso Foundation and how their mission resonates
6:15 How Belluck & Fox works within the meso community
7:47 Next steps in the legal process after diagnosis
11:05 Litigation timeline after choosing a law firm
14:01 How much time and effort is anticipated to dedicate to litigation
16:14 Options for taking legal action
21:58 Timeline of settlement funds
28:05 How much of a settlement does a patient/family receive
35:37 Advice for future clients in deciding legal action

Compensation Programs for Mesothelioma Patients and their Families

There are several main compensation programs that are typically available to mesothelioma patients. They include simple programs like health insurance, private disability insurance, social security disability benefits, and workers compensation if the person is still employed. Additionally, veterans’ benefits are available for people who served in the military and have a service connection to asbestos exposure. Mesothelioma bankruptcy trusts are another avenue to pursue for compensation. There are about 40-50 individual funds that have been set up by companies that made asbestos products and went into bankruptcy. As part of their bankruptcy reorganization, they set up a fund for their product. And the last option available is to file a lawsuit individually, not a class action, against the companies that made asbestos products that the patient was exposed to.

Mr. Belluck and his law firm offer free consultations by submitting a quick form on the firm’s website at www.belluckfox.com.

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