There is No Such Thing as a Free Lunch

Issue: February 2017

For generations, it has been a dream of oncologists to harness the immune system to defeat cancer. William B. Coley, MD, an innovative cancer surgeon of the late 19th century, recognized the likelihood for regression of head and neck cancers when the immune system was stimulated by certain infections.

These early clinical observations led to the development of “Coley’s toxins,” a mixture of killed bacteria that was used clinically for more than 50 years before being designated a research therapy by the FDA. The concept was simple: use the host’s integrated immune response and its exquisite property of specificity to arrest tumor growth, while leaving host tissues unharmed. It should be noted by the rheumatology community that these observations were the forerunner of the discovery of tumor necrosis factor – now recognized as a pivotal point in the evolution of our profession.

Cell-mediated Immunity

Harnessing cell-mediated immunity (vis-a-vis stimulating effector cells) came later, leading to the notorious TGN1412 trial in 2006. In this phase 1 study of a CD28 agonist, six healthy volunteers developed life-threatening adverse events (AEs) in the form of systemic immune reactions. The events of this trial fundamentally changed the way clinical trials are performed. For a time after, TGN1412 immunotherapy research languished.

It took a while but fortunately, immuno-oncology researchers drew on progress in basic laboratory research from the late 1980s, which led to major breakthroughs in patient care in the 2010s. The research conducted almost 30 years ago elucidated a system of immunologic checkpoints which down-regulate immune activation and effector mechanism functioning to control and mute ongoing immune responses. By exploiting negative regulatory circuits, these checkpoint inhibitors effectively took the brake off functionally exhausted effector cellular pathways leading to, at times, dramatic clinical effects. In particular, two molecular pathways have been therapeutically targeted (CTLA4–CD80/86 and PD1–PDL1/PDL2). There are now four approved agents in general use with more candidate molecules in varying phases of clinical trials.

The impact of these new agents cannot be overstated. Collectively, this class of immunotherapeutics was named “Breakthrough of the Year” by Science in 2013. Many stories have been written in the lay press and these medications are now advertised on television, which sadly is the mark of a successful drug in the United States. While clearly these drugs have limitations and certainly not all tumors or classes of malignancies are equally responsive, these constitute a major success in the war on cancer. At the same time, we as clinicians know the principle of balance as virtually no highly effective therapy of such magnitude can be expected to come without adverse effects.

Checkpoint Inhibitors

For checkpoint inhibitors, we can understand the spectrum of AEs through the adage, “There is no such thing as a free lunch.” In economics, this phrase means there is an opportunity cost in every decision or action. In science, it refers to the closed system of the universe and the concept that there is no magic source of anything that does not draw resources from something else. Both interpretations are true in the case of checkpoint inhibitors, which propel effector anti-tumoral immune responses with the “cost” of the frequent appearance of AEs secondary to unregulated inflammation and, at times, organ-directed autoimmune responses.

Indeed, harking back to the TGN1412 disaster, an immunologist who was asked to comment shortly after the trial stated “You don’t need to be a rocket scientist to work out what will happen if you non-specifically activate every Tcell in the body.” That is indeed true.

As the Cover Story in this issue details, in general, the AEs that illustrate the “no free lunch” principle of checkpoint inhibitors are frequent, occurring in more than 50% of patients. These immune-related adverse events (irAEs) are mostly mild and predominately affect the skin and gastrointestinal systems. Other organ systems are less frequently affected. Rheumatic complications have been largely overlooked until recently. Reasons for this are complex but relate, in part, to the fact that musculoskeletal pain is not well tracked and is rarely life-threatening. An increasing number of studies have documented rheumatic complications from checkpoint inhibitors, including inflammatory arthritis, myositis, vasculitis and other connective tissue diseases.

These complications clearly demand aggressive management in the context of an inter-professional team. Furthermore, these challenges will only grow with the spreading use of these new and evolving therapies. I have found in discussing these complications with community rheumatologists that patients are increasingly referred and there is considerable lack of confidence within our community on how to optimally manage them.

Unanswered Questions

In closing, I feel there are numerous unanswered questions to consider. Among the most important are:

Can we define risk factors for irAEs of a rheumatic nature and more readily predict their occurrence?
What pathophysiologic mechanisms are involved in the development of rheumatic irAEs as most observations to date have revealed little? Can such knowledge lead to even more targeted therapies?
What are the optimal therapies for rheumatic irAEs? What are the implications for responding to and continuing cancer immunotherapy?
How will the rheumatologic community become educated and gain confidence in addressing a new field of diseases? Can we build effective bridges with our oncology colleagues in the management of these new diseases?

I hope you enjoy reading our interviews with the key opinion leaders who work in this new area. If you have comments, ideas or experience to share, please reach out to me by email at calabrl@ccf.org or follow me on Twitter @LCalabrese DO.

For more information:
Leonard H. Calabrese, DO, is the Chief Medical Editor, Healio Rheumatology, and Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, and RJ Fasenmyer Chair of Clinical Immunology at the Cleveland Clinic.

Disclosure: Calabrese reports he is a consultant for Genentech, Pfizer, Bristol-Myers Squibb, GlaxoSmithKline, Sanofi, Jansen and AbbVie; and is on the speakers bureau for Genentech, AbbVie and Bristol-Myers Squibb and Crescendo Bioscience