In the realm of immunotherapy for cancer, checkpoint inhibitors tend to garner most of the glory. They are, after all, the main class of active drugs in this field.
These groundbreaking drugs strengthen the body’s response against cancer by blocking natural “checkpoints,” or regulators, that keep the immune system from revving into overdrive. Drugs approved over the past half a decade, such as Keytruda (pembrolizumab), Opdivo (nivolumab) and Yervoy (ipilimumab), accomplish this by targeting and inhibiting a few of these checkpoints: the proteins PD-1/ PD-L1 and CTLA-4.
Despite being widely celebrated, checkpoint inhibitors work for only about one-third of patients who are eligible to take them, with success rates varying according to tumor type. But that doesn’t mean that immunotherapy will remain out of reach for those still in need. Researchers are developing new approaches, including checkpoint inhibitors that target different proteins, as well as alternative therapies to build on the activity of checkpoint inhibitors and enhance their antitumor effects.
To jump-start the immune system, some of these promising treatments release the hold on its brakes, while others effectively step on its gas pedal, according to Michael A. Postow, M.D., a medical oncologist in the Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Cancer Center in New York City. During the 2018 Clinical Immuno-Oncology Symposium, held in January in San Francisco by the American Society of Clinical Oncology and the Society for Immunotherapy of Cancer, Postow discussed the road ahead regarding immunotherapy.
He touched on treatments, including approved and experimental checkpoint inhibitors, that put a damper on certain cellular activities to take the brakes off the immune system. He also discussed an opposite approach that directly stimulates the immune system via molecules that activate T cells, the body’s army against dangerous invaders.
TAKING THE BRAKES OFF
Checkpoint receptors that sit on the surface of T cells help keep the immune system quiet. When a checkpoint such as CTLA-4 binds with the protein B7 on the surface of a cancer cell, it prevents the T cell from recognizing or fighting the disease. A checkpoint inhibitor like Yervoy disables CTLA-4 so that it can’t bind with B7. This makes it more likely that a different protein on a T cell will bind with B7, signaling the immune cell to kill the cancer.
Researchers are particularly interested in lymphocyteactivation gene 3 (LAG-3). This immune checkpoint molecule is expressed by activated T cells nearing the end of their normal function, or experiencing “T-cell exhaustion,” Postow said. Blocking LAG-3 on T cells may enhance their activity.
The most mature data for LAG-3 as a checkpoint come from a study in which the LAG-3 inhibitor relatlimab was combined with Opdivo in 61 patients with melanoma whose disease had progressed on prior PD-1/PD-L1 immunotherapy. The overall response rate was 11.5 percent. In patients who had LAG-3 expression of 1 percent or more in the tumor microenvironment, the overall response rate was 18 percent, and 45 percent of this subset experienced tumor reduction.
“(These are) very early data,” said Postow. “It’s really hard to say that LAG-3 expression is a clear biomarker in this kind of setting. A very interesting finding is that now we have a patient population (whose disease) progressed on a PD-1 or PD-L1 (inhibitor), and when we combine PD-1 with another checkpoint inhibitor, like LAG-3, we can see (a response) in a subset of these patients.”
Another brake-releasing tactic revolves around T regulatory (Treg) cells, which can live within the tumor microenvironment and dampen immune response there. In early phase clinical trials, investigators are exploring ways to eliminate Treg cells from that microenvironment, Postow said.
“We have antibodies that globally free up the immune system by blocking important checkpoints like PD-1, PD-L1 and CTLA-4. But what if there was a way that this kind of activation would only happen where we want it to (within the tumor microenvironment)?” he asked. Agents known as prodrugs — protease-activated antibody drugs — can be administered in an inert form and then activated within target tissues such as tumors, and are being explored for this purpose.
The PD-L1 inhibitor CX-072, classified as a prodrug, is under investigation. When CX-072 enters the tumor, it is kept intact by a “masked peptide” — a group of amino acids. Once inside, the peptide can be broken only by specific enzymes in the tumor microenvironment. This interaction allows the antibody (immune-enhancing) portion of CX-072 to link to PD-L1 in the tumor. Ultimately, Postow said, that prevents PD-L1 from binding to PD-1 on T cells, leaving the immune cells free to activate and fight.
“The idea of all of this is to relieve (the) toxicity of some of these checkpoint antibody approaches,” Postow said. “Our hope is that by modifying these antibodies in these different kinds of ways, we can get better efficacy and hopefully less toxicity.”
A phase 1/2 first-in-human study of CX-072 as either a single agent or combined with Yervoy or the targeted drug Zelboraf (vemurafenib) is ongoing in adult patients with solid tumors or lymphomas (NCT03013491). The two immunotherapies together might simultaneously inhibit two checkpoints. Furthermore, it’s thought that combining the potential effectiveness of Zelboraf with the typically more durable effects of immunotherapy might benefit patients with BRAF-mutated disease.
REVVING UP THE IMMUNE SYSTEM
A number of targets that stimulate the immune system are also being explored in early phase clinical studies. One involves enhancing the work of killer T cells by activating certain co-stimulatory proteins that sit on their surfaces, such as CD28, CD27 or CD122. “By hitting co-stimulatory molecules harder, the idea is that the T cells will be better at killing tumors,” Postow said.
Varlilumab, for instance, is a first-in-class, experimental antibody that stimulates the CD27 pathway to activate T cells. A phase 1 study of 25 patients with advanced solid tumors showed biological and clinical activity.
The co-stimulatory molecule OX40 increases the proliferation and function of T cells. Results from an early clinical study demonstrated evidence of antitumor activity, with two partial responses in an ongoing phase 1 investigation in patients with solid tumors (NCT01644968), Postow said. Co-stimulatory antibodies may cause a cytokine releasetype syndrome in which the immune system attacks healthy organs, resulting in mild fever and chills, he said. In addition, the dosage and timing of administration may be critical — preclinical evidence suggests that large doses or administration along with a PD-1/PD-L1 inhibitor may produce inferior antitumor immunity due to hyperactivation and potential death of T cells.
Another immune-stimulating strategy involves an experimental class of drugs called STING agonists, which target a protein called stimulator of interferon genes, part of the normal human immune system. By activating STING, these agonists spur the production of interferons and cytokines, proteins that can pump up the immune system with extra T cells so it can better fight cancer. A phase 1b trial, now enrolling, will test the STING agonist MIW815, combined with PD-1 inhibitor PDR001, in patients with solid tumors and lymphomas (NCT03172936).
LOOKING DOWN THE ROAD
Although moving forward with newer immunotherapy targets usually involves partnership with PD-1/PD-L1 drug inhibitors, the necessity of that approach may be questionable, especially with preclinical data suggesting how a co-stimulator may interact with PD-1/PD-L1. “It’s important to be mindful that sequencing and/or timing would be critical in those studies,” Postow said.
In the future, it will become increasingly important for scientists to find, and doctors to rely upon, biomarkers for matching patients with immunotherapies, particularly combination regimens. Biomarkers could include specific tumor characteristics or factors observed in the peripheral blood of patients, Postow said. The hope is that conditions that typically resist immunotherapy, such as pancreatic and prostate cancers, will become more responsive once their immune mechanisms are better understood, he said.