“It was the Rodney Dangerfield space – couldn’t get no respect”
One would never guess those words were used to describe immuno-oncology, a field that has recently bloomed into full-fledged frenzy – with private companies raising unprecedented Series As, impressive data being announced and Science designating the field “Breakthrough of the Year” all in 2013. Yet Dr. Jeffrey Weber, an early member in the “i-onc” research community likened the past several decades of immuno-oncology to Dangerfield during ’I’ on Oncology– an ASCO Preview panel at the 16th Annual BIO CEO & Investor Conference.
For such a seemingly simple yet powerful idea of using one’s own army of immune cells against tumorous ones, the field has endured countless setbacks. A panel of distinguished speakers reminisced about the past, present and future of i-onc, bringing it from a promising hypothesis to a new modality of cancer treatment of today. Weber participated along with Annalisa Jenkins, MBBS, MRCP, of Merck KGaA, Peter Traber, MD, of Galectin Therapeutics, and Samuel Waksal, PhD, of Kadmon Corporation. Mike King, Senior Analyst, Biotechnology, of JMP, led the discussion.
Waksal recalled his days at the National Cancer Institute (NCI) in the 1970s when i-onc was all the rage, but resulted in failure after failure in the clinic. Still researchers pressed on. Dr. Steven Rosenberg’s team at the NCI, successfully treated their first patient with high doses of IL-2 in 1984, demonstrating a glimmer of hope for the field. Shortly thereafter, Weber joined Rosenberg’s lab as a trained immunologist was fascinated with this approach – he believed that immune regulation could have a profound effect on tumor growth. It drew him into i-onc and kept him there for the next 30 years through countless clinical trials.
The spotlight was again turned to the field with the approval of ipilimumab, a monoclonal antibody directed against CTLA-4, in 2011 for the treatment of metastatic melanoma. Clinical development of ipilimumab, referred to as “ipi” by those in the know, or its commercial name, Yervoy®, began in the early 2000s, and Jenkins described the excitement around its development when she was at BMS (which acquired the asset when it bought Medarex for $2.4 billion in 2009), “We had patients from the Phase 1/2 cohort that were still alive years later, and we couldn’t explain it. We didn’t believe what we were seeing.”
In essence, ipi works by interfering with the body’s natural brake for the immune system, keeping T cells active while destroying melanoma cells. Weber explained that the immune system has many accelerators and brakes built in to be able to quickly respond to a pathogen and just as quickly turn the system off once the infection has subsided – presenting many possible targets for cancer drug developers.
However, there appear to be several reasons that cancerous cells are tricky for the immune system and drug developers alike. Waskal pointed out that tumor cells look a lot like normal cells; some are more normal-looking than others, but sometimes the immune system has difficulty discerning between the two and therefore will not attack these diseased cells. Also, tumor cells are very heterogeneous, so a target that is present on one cell might not be on the next, making it nearly impossible to seek out one target. Finally, Traber described how tumors hide from the immune system, in part by secreting a protein (galectin-3) that inhibits immune cell activation. The more researchers understand these mechanisms, the easier drug development will become.
In the panelists’ minds, the field really came alive when i-onc’s promise was extended to solid tumors, led by the so-called checkpoint inhibitors. These include Merck’s anti-PD-1 candidate, lambrolizumab with positive results in non-small cell lung cancer (NSCLC), and Roche’s anti-PDL-1 candidate, MPDL3280A, also demonstrating positive data in NSCLC. BMS, which many view as the leader in the immuno-oncology field, is pursuing another anti-PD-1 candidate, nivolumab.
But Waksal believes in ten years, there will be better drugs for different targets, and Weber says there are at least half a dozen other targets worth looking at in the field now. The key, as all panelists pointed out, is going to be combination therapy. “I-onc is not checkpoint inhibition; it’s a much broader space including the tumor microenvironment. To seek a cure, we will have to go into the microenvironment, there will be combination therapy, and it will be biomarker driven,” said Jenkins.
To Jenkins point on biomarkers, Weber agreed that it isn’t easy to find them, but they are necessary, and as Waksal pointed out, they can allow a company to do smaller clinical studies with less patients, leading to faster approval in niche markets. If i-onc is to continue to progress, Jenkins believes that three areas need to evolve: the precompetitive space (focusing on the biology), the regulatory market access space (FDA and reimbursement) and the clinical trial environment (endpoints, patients and biomarkers). Traber added that the consortiums and partnerships forming between the big pharmas are important, but the smaller companies have to carve their way into this network as quickly as possible.
I-onc is a hot field right now with plenty of respect and will continue to flourish with the acceleration of the basic understanding of the biology in combination with the new drug technologies now available to drug developers. But, as Jenkins reminds the audience, this field is not for the faint of heart.
Michelle Avery, Ph.D., is an associate account executive with MacDougall Biomedical Communications. Learn more.