Jonathan Skipper, PhD
Ever since ipilimumab (Yervoy) gained FDA approval in 2011 for the treatment of metastatic melanoma, the immune checkpoint blockade strategy that the agent employs has been an intense focus of interest in research and pharmaceutical circles. Now, the concept of manipulating the immune system’s regulatory processes to attack cancer is branching out in new directions.
Ludwig Cancer Research recently announced plans to explore three monoclonal antibodies aimed at two different checkpoint modulators. The term encompasses antibodies devised to block receptors that inhibit the immune response against cancer as well as those that bind and activate receptors known to have the opposite effect.
Launched in 1971, Ludwig Cancer Research is a global network of more than 600 researchers located on four continents working collaboratively to advance the diagnosis, treatment, and prevention of cancer. The network has also established several partnerships with other research institutions and private companies to translate laboratory discoveries into clinical applications.
In March, Ludwig Cancer Research and Agenus Inc, a Massachusetts- based company, said they would advance a novel CTLA-4 antagonist (inhibitor) and two GITR agonists (activators) into preclinical development. In addition, the partners are working on other checkpoint modulators, including OX40 agonists and antagonists of LAG-3, TIM-3, and PD-1 (Table). Ludwig has established similar partnerships with several other companies, including MedImmune, CureVac, and Recepta Biopharma, to advance immunotherapies and other interventions. It has a longstanding partnership with the Cancer Research Institute (CRI) to establish clinical trials with immunotherapies. And, it has also spun off many biopharmaceutical firms in its efforts to help ensure that Ludwig discoveries are translated into products that ultimately benefit cancer patients. The Agenus antibodies, which are derived from human immunoglobulin genes, were selected using platform technology that 4-Antibody AG, a European biopharmaceutical company, created. Agenus acquired 4-Antibody in January.
Two of the targets covered by the partnership, CTLA-4 and PD-1, have become quite familiar in oncology drug development. CTLA-4 is the target of ipilimumab, a monoclonal antibody that blocks CTLA- 4 from binding with its ligands to dampen T-cell activation. PD-1, which interacts with its ligand PD-L1 to shield tumors from an immune response, has become a top target for anticancer agents, particularly in non-small cell lung cancer.
The focus on checkpoint modulators is in keeping with Ludwig’s rich history in the field of immunotherapy. The late Lloyd J. Old, MD, who helped establish the Ludwig Institute and held several leadership posts over the years, is widely recognized as one of the most important figures in modern tumor immunology. His pioneering work in the field includes exploring bacille Calmette-Guérin as an anticancer therapy, discovering tumor necrosis factor, and a series of discoveries that significantly advanced the immune surveillance hypothesis, the theoretical framework on which modern immunotherapy rests.
Among the scientists working with the network today is Jedd D. Wolchok, MD, PhD, director of the Ludwig Collaborative Laboratory and associate director of the Ludwig Center at Memorial Sloan Kettering Cancer Center in New York City (Ludwig MSK). Wolchok played a major role in the clinical studies that led to the FDA’s approval of ipilimumab. His current projects include exploring GITR and OX40, which are activating receptors in the immune system.
In an interview with OncologyLive, Jonathan Skipper, PhD, executive director of Technology Development for the Ludwig Institute for Cancer Research, discussed efforts to target checkpoints.OncologyLive: Why is there so much excitement about immunotherapy in the research community?Skipper:
I believe it is in part because of what we’ve seen from the first set of results using immune modulators to treat cancers, and in part because of the promise such therapies hold. What generates particular excitement is the prospect of harnessing the body’s own defense systems to control cancers, since those mechanisms are highly adaptive and have the potential—with some help—to address the extraordinary adaptability of most malignancies. This means that the responses generated by the right immunotherapy, or the right combination of such therapies, could induce durable control and perhaps, in some cases, even a cure of some cancers. Indeed, long-term studies of patients who responded to ipilimumab seem to suggest that this mode of checkpoint blockade can sometimes induce complete control of cancer for periods lasting several years.