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ASCO 2016 presenters share how combination therapies and biomarkers can better identify which tumors are likely to succumb to particular immunotherapies
With cancer immunotherapy’s successes have come growing pains and some unexpected challenges, experts said during a session entitled “What’s Next for Immunotherapy?” at the American Society of Clinical Oncology (ASCO) 2016 Annual Meeting.
Research is under way to overcome these challenges. Combination therapies and biomarkers that can better identify which tumors are likely to succumb to particular immunotherapies, top the list.
“We’ve known for decades that cancer immunity matters,” noted session chair Vamsidhar Velcheti, MD, a professor of medicine at the Cleveland Clinic Lerner College of Medicine, during the June 6 presentation.
But it’s only been more recently that the molecular details of how tumors evade immune system attacks have yielded effective clinical treatment options, he said-most famously, immune checkpoint inhibitors such as agents that target programmed cell-death protein 1 (PD-1) and anti-PD-Ligand 1 (PD-L1).
Immune checkpoints are often likened to a car’s brakes: a safety mechanism that slows immune T-cell activation in order to prevent autoimmune attacks on the body’s own cells. Tumors can evolve to hit these brakes, suppressing T-cell attacks on cancer cells. Immune checkpoint blockade, like PD-1 inhibition, releases the immune system’s brakes.
“We’ve seen remarkable advances in immunotherapy, especially in the last year-an explosion of clinical trials for PD-1 immune checkpoint inhibitors,” Velcheti said.
New opportunities to address “moving targets”
PD-1 and PD-L1 inhibitors are now known to offer some patients durable responses against multiple cancer types, from melanoma and lung cancer to kidney, bladder, oropharyngeal and breast cancers.
But the “elephant in the room,” Velcheti acknowledged, is that not all patients benefit.
There are many potential reasons for that, including the fact that tumors represent a moving target. Even when targeting immune checkpoint blockade works initially, it will often eventually fail.
“Tumors evolve all the time,” Velcheti explained. “Immunogenic cancer clones are eradicated [by T cells] and there is selection for immune-evading cancer cells.”
Epigenetic silencing of cancer cell surface antigens
One mechanism for secondary or evolved immune escape is epigenetic silencing of cancer cell surface antigens (proteins recognized by T cells), that make tumors invisible to the immune system.
Researchers are developing epigenetic therapies to pull away that molecular cloak.
“You can use epigenetic therapies to reverse this process and make tumor cells immunogenic again,” explained Velcheti. “Epigenetic therapy can improve antigen presentation and make tumors more susceptible to immunotherapy.”
Combining epigenetic and immune checkpoint-inhibitor therapy should take off the immune-checkpoint brakes while hitting the antigen-presentation gas pedal, experts said. More than a dozen clinical trials are currently under way for such combination therapies, employing immunotherapy agents like pembrolizumab and nivolumab with epigenetic drugs like HDAC and DNMT1 inhibitors, Velcheti noted.
“Epigenetic immunotherapy has a good scientific rationale but is limited so far by pharmacology,” Velcheti said. DNMT1 inhibitors like decitabine and 5-azacytidine often exhibit “negligible biodistribution” into solid tissues like tumors, he said.
Researchers are working on how best to overcome this DNMT1 biodistribution challenge, using novel formulations that are resistant to the cytidine-deaminase enzyme deactivation believed to be responsible. Clinical trials are under way.
Because tumors use non-redundant immune evasion pathways, there is also the opportunity to better match a particular tumor to a particular immunotherapy-in other words, to “personalize” cancer immunotherapy.
That’s where biomarkers come in.
“Interrogation of the immune-evasive pathways can guide treatment,” Velcheti explained. “That’s really key.”
New biomarkers needed
A widespread assumption that tumors’ cell-surface expression levels of PD-L1 proteins alone would suffice as a biomarker of vulnerability to checkpoint inhibitor therapy, now faces scrutiny.
TopalianNew biomarkers are needed to identify patients and the tumor types most likely to respond to anti-PD-1, agreed Suzanne Louise Topalian, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore.
Recognizing the importance of biomarkers in helping to realize the full potential of cancer immunotherapy, the FDA has provided new regulatory terminology, differentiating “companion” from “complementary” diagnostic immunotherapy biomarkers, Topalian noted.
Companion biomarkers provide information “essential” for safe and effective use of a drug or biological product, such as the PD-L1 IHC 22C3 biomarker for pembrolizumab in non-small cell lung cancer. In contrast, complementary diagnostic biomarkers are not required but help assess a drug’s risks and benefits for individual patients, such as the PD-L1 IHC 28-8 biomarker for nivolumab in NSCLC and melanoma, or PD-L1 IHC SP142 for atezolizumab for bladder cancer, Topalian explained.
Most FDA biomarker approvals to date have involved complementary markers, she noted.
But more sophisticated and predictive biomarkers are needed, Topalian and Velcheti agreed.
“Areas of opportunity for mechanism-based biomarker development for anti-PD-1 therapies include immunologic, genetic, and viral approaches,” Topalian said. “A multifactorial approach to developing biomarkers for anti-PD-1 therapies may be more highly-predictive of response.”
Such multifactorial biomarkers-including PD-L1 expression on tumor cells, tumors’ mutation levels (“mutational burden”), and even their expression of viral antigens, for example-could help guide combination therapies, Topalian said.
“The design of synergistic treatment combinations to enhance the therapeutic impact of anti-PD-1 drugs may be guided by immunologic markers,” she added.