Immune checkpoint strides

Research indicates cancer immunotherapies have potential for a long-lasting response to treatment

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SOUTH SAN FRANCISCO, Calif.—Promising clinical responses in patients with various cancer types have recently been achieved with checkpoint blockade immunotherapies, which work by reawakening the immune system’s response to tumors. Five new studies published recently in Nature—three of them illustrating clearly how Genentech is making strides in this area—expand the number of cancers now known to respond to this type of therapy and provide some insight into the tumor characteristics that correlate with effective responses.
Immune checkpoints are inhibitory pathways that dampen or block ongoing immune responses. Immune checkpoint blockade therapies are designed to block or inhibit these inhibitory pathways. Targeting one such inhibitory pathway, the PD-1 pathway (by blocking the PD-1 receptor itself or the protein it recognizes, the PD-L1 ligand) leads to disinhibition of a type of immune cell called the T cell, allowing it to attack and kill cancer cells.
“We’re screening for highly expressed proteins,” says Dr. Dan Chen, who heads up the MPDL3280A program at Genentech. This therapy reportedly has promising tumor responses from 13 of 30 PD-L1-positive patients with advanced urothelial bladder cancer, a 43-percent response rate and evidence of a durable effect that can hold cancer at bay.
Two papers, by Thomas Powles of Queen Mary University of London and Roy Herbst of Yale School of Medicine, describe data from Phase 1 clinical trials with an antibody that blocks the PD-L1 ligand. Powles shows that this treatment is effective in patients with metastatic urothelial bladder cancer. Herbst and colleagues demonstrate that checkpoint blockade produces durable responses in patients with forms of lung, skin and kidney cancer and identify biomarkers linked to treatment responses.
A study by Antoni Ribas of the University of California, Los Angeles, also identifies biomarkers to predict treatment response by analyzing samples of tumor tissue taken during treatment with an antibody blocking the PD-1 receptor. Tumors that express PD-L1, and tumors that have attracted CD8 T cells and other immune cells expressing PD-1 and PD-L1, have enhanced sensitivity to checkpoint blockade with these antibodies.
Papers by Lélia Delamarre of Genentech and Robert Schreiber of the University of Washington show that in mouse models, the infiltrating T cells responding to the cancer often recognize proteins in the tumor that have been altered by mutations. Both studies devise strategies to identify mutant determinants that are recognized by the immune system.  
Chen explains that Genentech is looking at ways for the immune system to recognize and target multiple threats or mutations and have long-term resistance to them. “Mutations make cancer resistant to drugs but make them look more foreign to the immune system,” he says. “Cancer may be hard to treat with traditional therapies, but when the immune system recognizes something foreign, it may be easier to treat with immunotherapies or a combination of immunotherapies and traditional therapies.”
While it may be too soon to predict the response to therapy, there are markers of pre-existing immune response to cancer, according to Chen. “Predictive efforts identify which patients have a strong immune response by showing how PDL-1 is expressed in cells.”
Currently, mutations can be predicted with high-throughput sequencing. Evaluating PD-1 and PDL-1 could be one way, says Chen. Genomics and bioinformatics approaches can identify tumor-specific mutant proteins as a major class of T cell rejection antigens as researchers look at the sequence and determine whether antigens will initiate an immune response.
“A lot has been done in preclinical models, but we have to show that vaccines can be efficacious in patients with advanced cancer,” Chen notes. “We may need to combine vaccines and blockers of PDL-1. Meanwhile, we’re encouraged by early data where we’re seeing durable responses to metastatic bladder cancer. It’s important to develop this therapy as soon as possible.”
He concludes, “I could not be more excited about the developments in this field. The responses feel different and could drastically change the outcomes of cancer treatment. This is an exciting time for patients and a new playground for human biology.”

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