New PD-L1 Inhibitor Could Make Mesothelioma Immunotherapy Safer

A new PD-L1 inhibitor may be on the horizon for people with malignant mesothelioma. A Phase I trial suggests it may be safer than some previous immunotherapy drugs. 

PD-L1 is a protein that helps mesothelioma cancer cells hide from the immune system. Several of the most promising immunotherapy drugs for mesothelioma block PD-L1.

But the new PD-L1 inhibitor is different. CX-072 (pacmilimab) has the ability to specifically target the tumor. This could reduce the risk for dangerous side effects since normal cells are less likely to be affected. 

San Francisco-based CytomX Therapeutics developed CX-072 and a team of international researchers has been studying it. This week, they released the findings of their Phase I trial. The trial included patients with a variety of solid tumors, including mesothelioma.

How a PD-L1 Inhibitor Fights Cancer

A healthy immune system is constantly on the alert. Immune system cells “patrol” for other cells that might turn into malignant mesothelioma or another cancer. When it finds these cells, it destroys them. 

When everything is functioning normally, PD-L1 helps keep the immune system from harming normal cells. But mesothelioma tumors can stimulate the release of extra PD-L1. This helps protect them from attack by T-cells. 

A PD-L1 inhibitor prevents the protein from fulfilling its protective function. This leaves mesothelioma cells vulnerable to attack. Unfortunately, it can also leave healthy cells more vulnerable, too. 

Its developers call CX-072 a “Probody” PD-L1 inhibitor. Probody therapeutics are drugs designed to be activated by substances only found right around a tumor (the “tumor microenvironment”). 

“This conditional activation restricts antibody binding to the tumor microenvironment, thereby minimizing ‘off-tumor’ toxicity,” explains researcher Rachel Sanford in the Journal for Immunotherapy of Cancer. 

Less “off-tumor” toxicity could mean fewer complications for mesothelioma patients. 

First Human Test of CX-072

The new report marks the first time researchers have studied the PD-L1 inhibitor CX-072 in human patients. The trial combined CX-072 with another immunotherapy drug called ipilimumab. 

The study took place from January 2017 to September 2019. It included 27 patients with advanced cancer. Mesothelioma was one of several cancers represented. Malignant mesothelioma is an extremely rare asbestos-linked cancer with no known cure. Pleural mesothelioma is the most common type. 

Researchers divided the patients into smaller groups to test different doses of CX-072 and ipilimumab. The goal of a Phase I trial is to make sure a drug is safe and to determine the “maximum tolerable dose” (MTD). 

The research team determined that 10 mg/kg of CX-072 with 3 mg/kg of ipilimumab was ideal. Patients received the combination every three weeks for four doses. Then they received CX-072 by itself every two weeks.

Overall, about one in five patients responded to the PD-L1 inhibitor, including the mesothelioma patient. Four of those responses lasted for more than a year. Some patients had responses that lasted as long as 32 months. 

The next step for this PD-L1 Inhibitor will be a Phase II trial of its effectiveness. Surviving Mesothelioma will continue to follow this drug’s progress and will bring you updates as they are available. 

Source:

Sanborn, R, et al, “CX-072 (pacmilimab), a Probody PD-L1 inhibitor, in combination with ipilimumab in patients with advanced solid tumors (PROCLAIM-CX-072): a first-in-human, dose-finding study”, July 2021, Journal for Immunotherapy in Cancer, Volume 9, Issue 7, https://jitc.bmj.com/content/9/7/e002446