CA-170 May Help Fight Mesothelioma

Mesothelioma is a rare and extremely aggressive form of cancer that affects the lining around the lungs, heart and abdominal cavity. It is caused by exposure to asbestos, but symptoms often remain dormant for years or decades. It is difficult to treat and has a five-year survival rate of only 9%, according to the Mesothelioma and Asbestos Awareness Center. Recently, a new clinical trial has begun enrolling and treating mesothelioma patients with an experimental immunotherapy drug called CA-170 in hopes of improving the prognosis.

The current study is a Phase I, open-label dose-escalation and dose-expansion trial that is focusing on studying the safety and initial clinical efficacy of CA-170 in patients. Two dosages are being tested on study participants.

CA-170 is a dual inhibitor of the VISTA protein and the PDL1 protein receptor and is currently the only anti-VISTA therapy being studied. The VISTA protein is present in 90% of mesothelioma tumors and helps cancer cells avoid attack from the immune system. High levels of VISTA expression have also been noted in other cancers, including ovarian, endometrial and non-small cell lung cancer. This suggests that the results from this study could have broader impact if CA-170 proves effective against the VISTA protein.

The PDL1 receptor also stops the immune system from attacking a cancer cell. By stopping both the VISTA and PDL1 communications to the immune system that the cell shouldn’t be attacked, the immune system is able to recognize the cancerous cells and begins attacking the diseased cells.

There are several PDL1 inhibitors currently on the market, including Tecentriq and Imfinzi, which have shown promise in treating mesothelioma. Researchers hope that by combining these effects with a drug that is able to also inhibit the VISTA protein, they will be able to better treat mesothelioma tumors.

The mesothelioma cohort is actually a sub-section of a larger study that has been active since 2016. Other groups in the study are being observed for how CA-170 affects advanced solid tumors and lymphomas, but they focus on a different protein. So far, the drug has shown promising results, as it has been well tolerated with no significant toxicity, as well as preliminary signs of tumor shrinkage.

The Food and Drug Administration has not approved a new treatment for mesothelioma since 2004, when a combination of the chemotherapies, Alimta and cisplatin, became the standard treatment of choice.

What Are Tyrosine Kinase Inhibitors?

Cancer treatments have dozens of names and acronyms associated with them. Each type of cancer generally responds to a different medication, and even within a cancer type, there are subtypes depending on the mutations present in a specific tumor. Tyrosine kinase inhibitors (TKIs) are a form of targeted therapy that are used to treat many types of leukemia, as well as solid tumors such as non-small cell lung cancer (NSCLC). Targeted therapies have become extremely common in cancer treatment, because they are able to identify and attack cancer cells while causing much less damage to healthy cells.

TKIs block the action of enzymes called tyrosine kinases. Tyrosine kinases are involved in multiple cell functions, including cell signaling, growth and division. When these enzymes are overactive or mutated, they can cause cells to grow uncontrollable (resulting in cancer). TKIs work by blocking these enzymes, which, in turn, stops cancer cells from growing and helps slow  the disease down dramatically in many cases.

TKIs are used both as an initial treatment method, as well as in cases of resistance when treating cancer. Initial treatments are the first-line therapy used on a patient to treat a disease. If the initial therapy fails to work on the patient, meaning the cancer doesn’t respond or the person isn’t able to tolerate the side effects, another treatment option is often prescribed. Certain TKIs, such as imatinib mesylate and dasatinib, are used as first and second-line therapies, while other medications, such as bosutinib and ponatinib, are used generally when patients have failed one of the front-line treatments. Second- and other later line therapies are often created to specifically overcome resistances created by one or more earlier lines of treatment.

Patients with NSCLC and certain forms of leukemia are the most common recipients of TKIs. Patients with chronic myeloid leukemia (CML) are often treated with TKIs, because they are able to target the abnormal ALK or BCR-ABL protein, respectively that causes uncontrollable cell growth. TKIs block the protein’s function causing cells to stop growing and die.

TKIs are also used to treat Philadelphia chromosome-positive acute lymphoblastic eukemia (Ph+ ALL). Before the discovery of TKIs in the early 2000s, patients diagnosed with Ph+ ALL had less than a 20% chance of long-term survival. When TKIs were introduced into treatment protocols alongside standard chemotherapy, the 5-year survival rate more than doubled. Recent studies have shown that second-generation TKIs are even more effective than their predecessors at combating this disease.

Patients with NSCLC are also treated with TKIs, particularly those who have a overactive or mutated forms of epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK). Studies have shown that patients treated with EGFR TKIs have improved overall response rates and progression-free survival rates, as well as a better quality of life. Recently, second-generation TKIs targeting the T790M mutation of EGFR have become available for patients with this advanced form of NSCLC.  

Molecular Vulnerabilities Discovered in Cancer

Synovial sarcomas and rhabdoid tumors are two of the most difficult types of cancer to treat. Synovial sarcomas are found in the soft tissues and are most often diagnosed in young adults. Rhabdoid tumors typically develop in the brain, kidney and other organs of children under two. Both of these cancers are deadly and have survival rates around 30 percent, but a recent discovery of a molecular vulnerability by scientists at the Dana-Farber Cancer Institute could offer new treatment options.

Researchers discovered a “molecular machine” called ncBAF that regulates gene activity. This molecular machine, called a chromatin-remodeling complex, is essential to the development and maintenance of cancer. These complexes are made of proteins that determine how DNA is packaged in a cell and regulate which genes are expressed. Researchers found that disabling components of the molecule hindered the cancer’s ability to reproduce. Dr. Cigall Kadoch was senior author of the report published in Nature Cell Biology.

Kadoch’s team focused on a group of complexes called the SWI/SNF family. They found that the molecules travel to different locations in the DNA within a cell and impact the genes that are turned on, as well as the creation of proteins. It is estimated that 20 percent of human cancers are associated with mutations in the chromatin-remodeling complex, disrupting gene expression and causing tumors to develop.

Researchers found the ncBAF complex is essential for synovial sarcoma and rhabdoid tumors to maintain cell division and growth. Researchers believe that disrupting ncBAF could be the key to treating these tumors, deeming it a “synthetic lethal target.”

Kadoch and her colleagues further focused on the BRD9 subunit of the ncBAF complex, noting that there are current treatments under investigation focused on blocking BRD9. Researchers are also working on protein degraders that are designed to eliminate BRD9 in cells. Kadoch hopes her team’s findings will assist other researchers as they work on blocking the BRD9 protein and fighting cancer.

Combatting the EZH2 Enzyme

Chemotherapy has been the standard cancer treatment method for lung cancer, but it is known to cause problems, including harming healthy cells and not killing all cancer cells. These cells are often changed as a result of the chemotherapy, making them more difficult to treat with standard methods. As a result, these cells evade further treatment, causing the cancer to return. More recently, immunotherapy with checkpoint inhibitors have become the mainstay of first line and follow on therapy in various types of lung cancers.  

A recent study by Dr. Gaetano Gargiulo at the Helmholtz Association in Germany has discovered a potential way to treat cells that have been altered by chemotherapy treatment. His research was recently published in the Journal of Experimental Medicine and focused on non-small cell lung cancer (NSCLC), the most common type of lung cancer, which includes several subtypes.

While chemotherapy is often successful in stopping cells from dividing in NSCLC patients, aggressive cancer cells can survive the treatment and end up altered as a result. These remaining cells are dangerous because they have changed in a way that can leave doctors unsure as to what type of cancer they are dealing with and how to best treat it.

Dr. Gargiulo’s team investigated an enzyme, called Enhancer of Zeste 2 (EZH2), that promotes lung cancer. They treated test mice with drugs that inhibited EZH2, and soon found that it caused the cancer cells to become more aggressive due to inflammation in the cells. Instead of seeing this as a problem, researchers saw an opportunity to outsmart the cancer. The researchers encouraged the cells to become inflamed and then ambushed them by giving the mice an anti-inflammatory drug, leaving the aggressive cells exposed and vulnerable to treatment.

Early tests suggest this could be a potential strategy to explore in treating lung cancer patients. Gargiulo made a point of noting that making cancer more aggressive can be very dangerous, and researchers must be cautious when pursuing this experimental path.  

FDA Approves New Medications for Acute Myeloid Leukemia

Two medications, Daurismo and Venclexta, have passed the final rounds of review by the US Food and Drug Administration (FDA) and been approved for patients with acute myeloid leukemia (AML). These drugs are intended for use in patients who are not candidates for intensive chemotherapy. Intensive chemotherapy is not recommended for patients over the age of 75 or those with certain health conditions due to the severe side effects that it causes.

Daurismo, marketed by Pfizer, was tested in clinical trials in combination with a low-dose of the chemotherapy drug, cytarabine. Known as a hedgehog inhibitor, Daurismo is a targeted medicine that interferes with the hedgehog-signaling pathway. The hedgehog-signaling pathway is involved in cell differentiation and growth, and problems in this pathway can cause out-of-control cell growth and lead to certain types of cancers, such as AML. Daurismo was tested in a randomized clinical trial of approximately 100 people. Patients who received Daurismo in addition to cytarabine lived an average of four months longer than those who only received the chemotherapy.

The drug Venclexta is already available to patients with chronic lymphocytic leukemia, but the FDA expanded its approved indications to include AML after two non-randomized clinical trials. These trials measured the number of AML patients who went into complete remission, meaning there were no traces of cancer in the body, and how long they stayed in remission.

In the first trial, 37 percent of patients achieved complete remission after receiving Venclexta along with the chemotherapy drug azacitidine and stayed in remission for an average of 5.5 months. In the same study, 54 percent of patients who received Venclexta and decitabine, another chemotherapy drug, went into complete remission that lasted for an average of 4.7 months. In the other trial, 21 percent of patients achieved complete remission for an average of six months when Venclexta was used with cytarabine. Venclexta was developed by AbbVie and is marketed by AbbVie and Genentech USA Inc (Roche).

Both medications were reviewed under special FDA procedures that are used to speed up the approval process for medicines to treat serious illnesses without adequate alternatives. They were also granted orphan drug designation, which provides modest financial incentives to companies to encourage the development of drugs for rare diseases.

A Potential Vaccine for Glioblastoma Patients

A study by investigators at the Dana-Farber Cancer Institute suggests that neoantigens could play a role in treating glioblastomas. Patients in this study received a personalized vaccine that led to longer survival compared to most patients with glioblastomas, suggesting that selectively stimulating these tumors could be the key to curing them.

Glioblastomas are malignant brain tumors that are usually slow growing but can become aggressive. By the time these tumors are discovered, they are typically Grade IV, meaning they grow rapidly, have bizarre cellular appearances and easily infiltrate nearby brain tissue. They are also capable of forming new blood vessels (angiogenesis), which allows them to absorb more nutrients and continue growing. In addition to their location and rapid growth, glioblastomas are “cold” tumors, meaning they contain very few immune cells. Immune cells are recognized by the body as cells requiring action; since these tumors contain very few of those cells, the immune system does not respond properly.

To combat the lack of immune cells, David Reardon, clinical director of the Center for Neuro-Oncology at Dana-Farber, performed a study with a neoantigen vaccine for glioblastomas, published in Nature. The vaccine used in the study was a personalized ‘neoantigen’ serum that caused an immune response against glioblastomas. Like other cancers, glioblastomas contain DNA mutations that cause cells to reproduce rapidly and create tumors. Some of these mutations, including those in glioblastomas, cause cancer cells to display peptide molecules — or neoantigens — on the cell’s surface. Neoantigens are not present on healthy cells, making them relatively easy targets for the immune system.

To attack the tumor cells, researchers created personalized vaccines by removing and analyzing tissue from tumor and healthy cells in the patient. Once they identified which neoantigens were present in the tumor, proteins from the neoantigens were synthesized in a laboratory to form the base of the vaccine. After being administered, the vaccine encourages the body to create T-cells that migrate to the brain tumor, causing inflammation around the cancer cells. Then, the neoantigens in the serum “teach” the patient’s immune system how to detect and attack tumor cells.

The eight patients in the study received vaccines containing between seven and twenty neoantigen peptides. All of the patients ultimately died from their tumors, but they survived longer than average for glioblastoma patients. Reardon is encouraged by the results of this preliminary study.

“The next step is to add an immunotherapy drug called a checkpoint inhibitor, aimed at freeing the immune response from molecular ‘brakes’ so that the T-cells can react more strongly against the tumor,” Reardon said.

The combination of a neoantigen vaccine with a checkpoint inhibitor should lead to a stronger immune response and potentially extended survival without tumor spread and thus, the possibility of a cure.

Nobel Prize in Medicine Honors Immunotherapy Researchers

For many years cancer treatment involved chemotherapy, surgery and radiation to stop the growth of cancer cells. But in the past few decades, researchers began studying how the human body’s immune system could be bolstered to fight the disease itself.

After losing friends and family to cancer, James Allison and Tasuku Honjo each became interested in studying cancer and understanding the way it changes the body, particularly immune cells. Their groundbreaking research opened the door for immunotherapy.

Allison’s research focused on the CTLA-4 protein, which regulates T-cells, the workhorses of the immune system. Oftentimes the protein blocks the immune system from attacking cancerous cells. However, Allison developed an antibody to inhibit the CTLA-4 protein and in 2011, the FDA approved ipilmumab, or Yervoy, to treat advanced melanoma.

Yervoy led to the creation of a new drug class called checkpoint inhibitors. Checkpoint inhibitors stop proteins from blocking an immune response and free T-cells to attack malignant tumors. Studies have shown that these inhibitors work in patients with melanoma, as well many other solid tumors.

In 1992, Tasuku Honjo, a professor of immunology at Kyoto University, discovered a protein called Programmed Cell Death Protein 1 (PD1), which is on the surface of immune cells and determines if cells grow normally or turn cancerous. His research showed that the protein inhibits the function of the body’s natural immune defenses.

Working from this discovery, a 2012 study showed that blocking the protein could help the body fight cancer. This led to the development of pembrolizumab, or Keytruda, and nivolumab, or Opdivo, both approved in 2014 to treat melanoma. Subsequent clinical trials have demonstrated the safety and efficacy of these and other checkpoint inhibitors in many different forms of solid tumors, including lung cancer, head and neck cancer, and others.

The groundbreaking research by both Allison and Honjo has opened new doors for cancer research and led to the creation many checkpoint inhibitors, leading to the extensive study of these new medicines. Their discoveries have given many cancer patients a chance at living more normal lives and living longer.  

The Mystery of TP53 Unraveled

Mutations within a person’s DNA is one of the most common causes of cancer. p53 is one of the most commonly mutated genes among cancer patients and is a tumor-suppressor that works to regulate cell division and prevent cells from reproducing too quickly. However, when the DNA is mutated, the gene can lose this function and allow cells to grow out of control. Mutations in p53 are found in almost every kind of cancer, including lung, ovarian and laryngeal, among others.

For years, this mutation has intrigued scientists, as the DNA changes can occur at over 1,100 sites within the gene, though there are places, called “hot spots,” where mutations most frequently occur.

A recent study published in Nature Genetics by researchers from the Dana-Farber Cancer Institute, the Broad Institute of MIT and Harvard, and others, found that hotspot mutations are not more likely to produce cancer than mutations at other points within the genetic code.

The study used the newest technology available to create a library of all possible variants of the p53 gene — 8,258 in total. After sequencing the genes, researchers compared hot spot mutations to others and found that they were no more likely to promote cancer than mutations in other locations. They concluded that the tendency of mutations to occur in those locations is due to the way mutations occur and which parts of the body are exposed to carcinogens.

“This indicates we’re correct that mutations in p53 are focused on certain hot spots because those spots are targeted by the specific carcinogens to which cells are exposed,” said William Hahn of Dana-Farber in an interview. Hahn was the senior author of the study and serves as the deputy scientific officer at Dana-Farber.

Understanding the role gene mutation plays in causing cancer is imperative as gene sequencing becomes more common in cancer treatment.

Yale Study Affirms Treatment Guidelines for Polycythemia Vera

Polycythemia Vera (PV) is a deadly form of blood cancer that occurs when a mutated gene causes bone marrow to create extra red blood cells. The additional cells cause the blood to thicken, slowing its movement through veins and increasing the risk of blood clots. Patients over the age of 60 are at the highest risk for death related to PV. Standard treatments for this condition are phlebotomies and cytoreductive therapy with the drug hydroxyurea. Hydroxyurea (HU) is the more commonly used therapy, but both solutions are often underutilized in PV patients, according to the Yale School of Medicine.

Investigators at Yale recently performed a study of high-risk PV patients and their treatment methods to determine the best course of action for improving life expectancy. The high-risk PV patients involved were 66 years or older, with the median age being 77. Investigators searched patients records for evidence of thrombotic events, as well as treatments used in the past.

Of the 820 patients in the study, those who received phlebotomies had a 35% reduction in death and a 48% reduction in the risk of developing blood clots. When patients also received HU, researchers found that patients who used the medication longer had a lower risk of death.

Phlebotomies are used as a therapeutic “bloodletting” process for PV patients to reduce the amount of blood in their body while HU is used to suppress the bone marrow’s ability to produce excess red blood cells. The study found that a combination of the phlebotomies and HU saved lives, but it also showed that most patients were not receiving these recommended treatments. Analysis showed that almost 40 percent of PV patients were under-treated, receiving neither the recommended treatment nor just phlebotomies. Researchers in the study hope that their results will raise awareness of the two treatment options available for PV patients and the improved outcomes when both are used.

Immunotherapy Offers Melanoma Patients New Hope

Metastatic melanoma is one of the most difficult forms of cancer to treat, with survival rates as low as 15% for those with a stage IV diagnosis. These low survival rates began to improve with the 2011 approval of ipilimumab, the first checkpoint inhibitor. Checkpoint inhibitors work on T-cells and reactivate the immune system so it continues fighting cancer cells. Nivolumab is another checkpoint inhibitor that is also used to treat melanoma patients, alone or in combination with other medicines. A recent study at Dana Farber tested combining ipilimumab and nivolumab in patients with advanced melanoma who had not previously been treated. Results of the study showed that 53 percent of patients who received this combination of drugs were alive four years later, a remarkable result in melanoma clinical research.

The study followed 945 patients who had untreated and inoperable stage III or stage IV melanoma. They were separated into three groups, with one receiving the combination of nivolumab and ipilimumab, another receiving just nivolumab and the final group receiving just ipilimumab. Fifty-eight percent of patients treated with the two drugs had their cancer shrink, compared to only 45 percent of patients who received nivolumab alone and 19 percent for those who received ipilimumab alone. Additionally, several patients treated with the combination had their tumors disappear completely.

The median length of survival for patients varied greatly, ranging from 19.9 months in the ipilimumab group to a currently unknown number in the group treated with both drugs, because patients continue to do well and a median outcome cannot yet be established.

Treatment was given to patients in this study until they received the maximum clinical benefit, were experiencing unacceptable side effects or the patient asked to have treatment discontinued. For patients who survived four years, 71 percent of those treated with the drug combination were no longer receiving treatment along with 50 percent of the nivolumab group and 39 percent of the ipilimumab group being off treatment as well.

Patients who received the combination of drugs experienced a higher rate of adverse side effects — 59 percent — compared to 22 and 28 percent in the nivolumab and ipilimumab groups respectively. Despite these side effects, authors of the study believe this is an important discovery for melanoma patients and will improve long-term survival rates in the coming years.