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It’s been said that there is no greater bully pulpit than the American presidency. Linking the force of moral persuasion to this most powerful office—one that is capable of issuing executive orders and bypassing the wishes of Congress or rousing public opinion in favor of or against bills that are in the process of being crafted—many of its recent incumbents have seized upon this authority to declare a war on something.
These are not the usual proclamations that serve to mobilize and unite the nation in times of battle. No, these are the rallying calls, the pep talks used by the commander in chief to cajole the members of Congress and inspire the public to work diligently toward achieving some worthy goals.
For John F. Kennedy, this war was his call for an all-out technological effort to beat the Soviets in the race to the moon. For Lyndon Johnson, it was the war on poverty, a series of federal programs that sought to alter the bleak economic landscape that affected one-fifth of the population, which was mired in poverty during his presidency. For some presidents, including Richard Nixon, Ronald Reagan, George W. Bush, George H.W. Bush and Bill Clinton, it has been the enduring war on drugs, focused on ending illicit drug use, a battle with mixed results that rages on.
And then there was one other skirmish started by a most unlikely White House incumbent, President Nixon. Entangled in a deeply unpopular war in Southeast Asia, President Nixon sought some dramatic initiative that could signify to voters that he was more than a warmonger, an appellation commonly affixed to his name.1 Six months before the infamous Watergate burglary, during his 1971 State of the Union address, he telegraphed his intentions to vanquish cancer when he pledged $100 million toward this battle. President Nixon declared, “I hope in the years ahead we will look back on this action today as the most significant action taken during my administration.”2
I will let others judge whether this laudable effort compensates for President Nixon’s policy blunders in Vietnam or his impeachable behavior during the Watergate scandal. Immediately after declaring this war, President Nixon—always the shrewd politician—ordered the conversion of the Army’s Fort Detrick, Md., biological warfare facility to a cancer research center, a biblical gesture. A depot of germ warfare was transformed into the Frederick Cancer Research and Development Center, an internationally recognized facility for cancer and AIDS research.1
Some historians have argued that the war on cancer was, in part, a stealth effort by President Nixon to rein in the independence of medical scientists by creating a federal structure through which the executive branch would exert some control over their funding. Others hold a less cynical view, believing that the war ushered in a restructuring of clinical cancer research, replacing what had been, until then, an unfettered approach to cancer medicine in which investigators would be free to test some fairly outlandish theories at the bedside without encountering interference from regulatory bodies.3
Four decades forward, it was President Barack Obama’s turn to launch his war on something.
Discarding the bellicose terminology of his predecessors, President Obama chose a more soothing moniker, the Precision Medicine Initiative, to describe his vision for “a new model of patient-powered research that promises to accelerate biomedical discoveries and provide clinicians with new tools, knowledge and therapies to select which treatments will work best for which patients.”4 All rainbows and sunshine. It seems that this mellow approach failed to trigger the widespread excitement that the White House had anticipated.
At his final State of the Union address this past February, President Obama relaunched the effort by rebranding it a National Cancer Moonshot, to be led by Vice President Joe Biden, whose goal is to achieve “a decade’s worth of advances in five years.”5 Lesson learned. Precision, initiative, these are words that belong in PowerPoint presentations. Moonshot—now that’s a term to rally the troops!
The War Against Autoimmunity
If one decides to wage war against a disease in the hopes of stirring the public sentiment, choosing cancer as the target will invariably garner the most attention. Politicians are not the only ones who are keenly aware of this reality.
Every weekend this past winter, I met hundreds of charity-sponsored runners running along my beaten trail, the Heartbreak Hills of Newton, Mass. Nearly all were training for the Boston Marathon and most had qualified, not by having completed a prior marathon at a grueling pace, but by pledging to raise thousands of dollars on behalf of a particular illness. Hands down, these pledges nearly always were in support of cancer research: breast, brain, colon, pancreatic, prostate, liver, lymphoma, retinoblastoma—the list was endless. Cancer seizes our attention unlike any other disease. And it terrifies us, unlike any other disease.
Fortunately, rheumatologists and their patients have benefited from some of the seminal discoveries made during the course of the war on cancer. Among the most consequential breakthroughs was the elucidation of the role of tumor necrosis factor (TNF) in the mediation of autoimmunity and inflammation (see “A Short History of RA Therapeutics,” The Rheumatologist, January 2012). The name tumor necrotizing factor was first coined in 1962 to describe sarcoma regression activity induced in the serum of mice treated with Serratia marcescens polysaccharide. This endotoxin-induced serum factor that caused necrosis of tumors was elegantly characterized by researchers at the M.D. Anderson Cancer Center in Houston.6 Due to its highly potent pro-inflammatory effects, efforts to harness TNF as a systemic therapy met with failure. However, evidence was mounting that TNF served key roles in non-cancer pathways, in particular, sepsis and shock.
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 & repairs ongoing immune responses.
The focus then shifted to developing a treatment for overwhelming infection by creating antibodies targeting TNF, but after a series of experiments failed to demonstrate the benefit of these antibodies in protecting mice against the ravages of septic shock, TNF blockade appeared to be headed to the pile of discarded ideas.
Then came the serendipitous discovery that anti-TNF antibodies markedly improved the synovitis and systemic features in patients with rheumatoid arthritis (RA), ushering in our current era of using biological therapeutics in clinical medicine.
Another successful offshoot of the cancer wars was the recognition that the anti-B cell therapy, rituximab—originally developed as a treatment for lymphoma—was highly useful in combating a variety of autoimmune diseases, including RA, vasculitis and a host of rarer conditions—some B cell mediated and others not.
Not all of rheumatology’s novel therapies were derived from the cancer research lab. For example, the realization that interleukin-6 (IL-6) was a critical mediator of systemic inflammation was understood in the 1980s, although it took another decade of research, primarily in Japan, to develop the first monoclonal antibody targeting the IL-6 receptor.
Beating these diseases requires a prolonged conflict, perhaps another Hundred Years’ War.
Sometimes, the flow of discovery shifts into reverse and the rheumatology lab becomes the source of a novel cancer therapy. One recent example was the elegant elucidation of how extracellular cues are sensed by living cells and translated into the control of gene expression. This work, carefully ushered from the bench to the bedside, was based on the pivotal research of John O’Shea, MD, senior investigator in the Molecular Immunology and Inflammation Branch of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) in Bethesda, Md., and colleagues. Their work helped identify the critical role of tyrosine kinases in cell signaling via the Janus kinase-signal transducer and activator of transcription pathway, better known by its acronym, Jak-STAT.7 The pharmacologic inhibition of this pathway has led to the creation of several drugs that have shown efficacy in treating RA and an array of cancers, as well.
The Intersection of Cancer & Autoimmunity
Historically, the drugs in the rheumatologist’s armamentarium have evolved from a number of broad-based therapies that have a wide array of effects (think prednisone), some good and some not. The story is no different for oncologists. Perhaps the greatest thrust of the Cancer Moonshot and similar efforts has been to supplant some of the highly toxic alkylating cancer drugs with an ever-widening selection of more targeted therapies.
Lately, the buzz has been all about drugs that can deactivate the switches that, when tampered with, unleash the power of the immune system. Move over Bacillus Calmette-Guerin! These switches, better known as the checkpoints, include the solemnly named programmed death-1 (PD-1), a term that conjures up images of a heavy metal band, and the equally dour, cytotoxic T-lymphocyte-associated protein-4 (CTLA-4). Checkpoints normally prevent the immune system from attacking its unsuspecting host, a deleterious activity that can trigger the development of autoimmune diseases.
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.
The techies from Silicon Valley have now entered the fray. A prime example is Sean Parker, of Napster and Facebook fame, who has recruited a distinguished mass of scientists in the field of immunotherapy in the hope that, together, they can move research along faster than by working alone.
According to Mr. Parker, the refreshing difference is that “everyone in our network can play in it. They are able to borrow things from each other’s labs and use discoveries without compromising or encumbering their intellectual properties.”11 So far, his consortium includes the M.D. Anderson Cancer Center, Memorial Sloan Kettering in New York City, Stanford University in Palo Alto, Calif., the University of Pennsylvania in Philadelphia and the University of California at Los Angeles and at San Francisco. That’s quite an army assembled for this battle, where the foe is far deadlier than those whom Mr. Parker has previously faced, such as the record company executives fighting his revolutionary free music file sharing technology or the other whiz kids who thought they could outrace “the Facebook” in the early years of its development. Perhaps Sean Parker would rather be known as a key player in the battle to cure cancer than as the person who convinced Mark Zuckerberg to drop “the” from Facebook’s name.
A Last Wish
One day, when cancer is conquered and the most stubborn autoimmune diseases get tamed, let’s hope that our ability to provide our patients with the care they deserve is not scuttled by the sound of some fax machine spewing out reams of red tape in the form of paperwork sent on behalf of insurers and pharmacy benefit managers. Sometimes, small details can ruin a victory parade.
Simon M. Helfgott, MD, is associate professor of medicine in the Division of Rheumatology, Immunology and Allergy at Harvard Medical School in Boston.
References
- Crewdson J. Richard Nixon’s 30-year war—and still counting. Chicago Tribune. 2000 Feb 27.
- National Cancer Institute. Milestone 1971: National Cancer Act of 1971.
- Mukherjee S. (2010) The emperor of all maladies: A biography of cancer. New York: Simon & Schuster.
- Fact sheet: President Obama’s precision medicine initiative. 2015 Jan 30.
- Fact sheet: Investing in the national cancer moonshot. 2016 Feb 1.
- Aggarwal BB, Gupta SC, Kim JH. Historical perspectives on tumor necrosis factor and its superfamily: 25 years later, a golden journey. Blood. 2012 Jan 19;119(3):651–665.
- O’Shea JJ, Gadina M, Kanno Y. Cytokine signaling: Birth of a pathway. J Immunol. 2011 Dec 1;187(11):5475–5478.
- Swetlitz I. ‘I want what Jimmy Carter had’: Patients clamor for the president’s cancer drug. STAT. 2015 Dec 18.
- Chen L, Han X. Anti–PD-1/PD-L1 therapy of human cancer: Past, present, and future. J Clin Invest. 2015 Sep;125(9):3384–3391.
- Kuti Baruch K, Deczkowska A, Rosenzweig N. PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer’s disease. Nat Med. 2016 Feb;22(2):135–137.
- Cha AE. Sean Parker, Silicon Valley’s bad boy genius, wants to kick the *!$% out of cancer. Washington Post. 2016 Apr 15. http://wpo.st/U3eW1.
