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.