When I started my fellowship in medical oncology in 2009, there were 2 inalienable truths.
First, as we assessed the weaponry we could deploy against cancer, we identified only three angles of attack: surgery, radiation, and chemotherapy. The first two were, in essence, local therapies, effective only where the scalpel or the high-energy beam was directed respectively to excise or ionize a tumor. Chemo was different because it was systemic, diffusely delivered, and the exclusive armamentarium of the medical oncologist, whose expertise lay in administering chemicals to poison malignant cells while trying to limit collateral damage to the host’s normal tissues. If the cancer signified weeds in the garden, this was akin to dispensing pesticides artfully enough to preserve the good plants. But it was hard to avoid a black thumb. Wistfully we hoped for a more discriminating way to stymie the growth of the bad actors, envious of the targeted aim of our colleagues in surgical & radiation oncology.
Secondly, new fellows learned that metastatic melanoma almost always carried a death sentence. All cancers seem scary to the layperson, but only a select few can terrify seasoned oncologists. This upper echelon of intimidating histologies includes acute promyelocytic leukemia, Burkitt’s lymphoma, and extensive-stage small cell lung cancer, all associated with explosive growth rates and dramatic clinical presentations that can be acutely life-threatening, offering little time to intervene and a razor-thin margin of error. Melanoma, while typically not so rapid in its proliferation, is still a fearsome, sneaky adversary, adept at slipping away from sun-damaged skin to sow seeds in the central nervous system, penetrating the blood-brain barrier and often sprouting beyond the reach of chemo.
Now, at the dawn of 2016, there is a fourth arsenal of weaponry in oncology – immunotherapy – and one of its earliest success stories has been, to my shock and delight, the treatment of metastatic melanoma. And while President Nixon declared the War on Cancer in 1971, it is one of his successors in the Oval Office – Jimmy Carter – who has been the most famous beneficiary so far of this exciting therapeutic advance.
President Carter announced in August 2015 that metastases from melanoma had been found in his liver and brain. Mere months later, in December 2015, he proclaimed a complete remission (http://nyti.ms/1Iy9sEi). So what happened in the interim? As before, surgery and radiation still played their roles in local control, but his treating physicians at Emory also awoke the President’s immune system to the presence of his cancer.
The drug pembrolizumab is a humanized antibody that unmasks melanoma as it tries to evade the body’s own search & destroy mission, carried out by a roving army of activated T cells. These T cells have an inhibitory receptor that is designed to regulate the immune system and prevent it from becoming overactive. These checks & balances are important to avoid auto-immunity, e.g. conditions like lupus, so T cells are suppressed by a surface protein with the dramatic name of programmed cell death (PD-1). Melanoma cells can engage this receptor with a protein, or ligand, called PD-L1, that keeps the T cells at bay. Pembrolizumab intervenes to prevent PD-L1 from binding PD-1, essentially removing the brakes on the immune system and letting the disinhibited T cells identify the melanoma as a target to be attacked.
What is particularly exciting about this approach is that these anti-tumor responses can be both dramatic and durable. Just as a vaccine trains the body to recognize a certain pathogen as foreign even years after inoculation, it appears that drugs like pembrolizumab can engender a lasting immune memory by which cancer can be banished and then kept away.
As with chemo, adverse events can arise from immune checkpoint blockade, most worryingly when the T cells start to attack the body’s native tissues, including the endocrine glands and the lungs, but thankfully such side effects are seen in a minority of patients. Doctors dispensing these drugs are increasingly adept at identifying & remedying such auto-immune effects as they emerge, a vigilance that is especially important as immunotherapies are being tested in combination; already PD-1 antibodies are being used in tandem with other mechanisms of inhibition, like antibodies to the cytotoxic T-lymphocyte-associated antigen-4 [CTLA-4], to produce additive, or even synergistic, responses. We owe a debt of gratitude to the patients and researchers who taught us how to manage these toxicities through clinical trials, pushing the field forward and trailblazing the safest path at the frontier of cancer medicine.
I joined the field of oncology a mere 7 years ago, and already some of the textbooks I purchased at the beginning of my training are being rendered obsolete. They cost me a small fortune but I don’t mind. For the benefit of my patients, I’m excited to learn some new tricks. The paradigm shift is making me a better gardener.
Dr. Mark A. Lewis is an assistant professor in general & gastrointestinal medical oncology at the MD Anderson Cancer Center in Houston, Texas. He is double-boarded in hematology/oncology after completing a fellowship at the Mayo Clinic in Rochester, Minnesota, where he was chief fellow in that training program. He has a passionate interest in patient-doctor communication, including online dialogue, and moderates a Facebook group for patients with multiple endocrine neoplasia, a rare tumor syndrome that personally affects him and his son. He is also active on Twitter as @marklewismd. He is co-chair of the Social Media Working Group for SWOG, one of the nation’s largest cancer research cooperative groups, and co-chairs their Adolescent & Young Adult Cancer committee as well.