Initially, interference with the PD-1 pathway was not considered a viable therapeutic option, because early knockout mice studies suggested that PD-1 deficiency increased the incidence of autoimmune diseases. This reality has been borne out in the rheumatology clinic, where some cancer patients who have responded remarkably to PD-1 inhibitor drugs began to manifest features of systemic rheumatic diseases.
Anti-PD therapy has grabbed the headlines, for example, following the use of pembrolizumab to successfully induce remission of President Jimmy Carter’s metastatic melanoma.8 Distinct from prior immune therapeutic agents, which primarily boost systemic immune responses or generate de novo immunity against cancer, anti-PD-1 therapy modulates immune responses at the tumor site, targets tumor-induced immune defects and repairs ongoing immune responses.9
Far afield from cancer, there may be other therapeutic benefits to checkpoint inhibition. Preliminary studies in rodent models of Alzheimer’s disease (AD) observed that PD-1 pathway inhibition evoked an interferon (IFN) γ-dependent systemic immune response, which was followed by the recruitment of monocyte-derived macrophages to the brain. This immunological response improved cognitive performance and resulted in the clearance of cerebral amyloid-β (Aβ) plaques, a critical finding in patients with AD.10
With regard to CTLA-4, another immune checkpoint, our clinical experience using abatacept to treat patients with RA has taught us that turning a switch off instead of on can make all the difference between killing a cancer cell and taming an autoimmune disorder.
A New Way to Wage War
Waging a battle against cancer or autoimmune diseases remains an uphill struggle. Yes, there have been victories, but the beasts have not been vanquished. To paraphrase Sir Winston Churchill, the pathogenesis of most of these conditions remains a riddle wrapped in a mystery inside an enigma. Beating these diseases requires a prolonged conflict, perhaps another Hundred Years’ War.
But this reality does not sit well with some young, wealthy entrepreneurs who have grown impatient with the slow speed of scientific discovery. They are more accustomed to the frenetic pace of technological progress, where advances are achieved in a matter of months, not decades.
These billionaires have decided to apply the lessons they learned while amassing their fortunes to a full-throttle effort to defeat their targeted disease. This is not a new phenomenon; nearly a century ago, the Rockefellers endowed an illustrious medical research university bearing their name; the recluse Howard Hughes left behind an estate recently valued at over $16 billion for the creation of a medical institute; and the serial entrepreneur Eli Broad funded a world class genomics research center bearing his name.
