Tox and Hound – Check Yourself

by Andrew Stolbach

The history of cancer therapy is entwined with the history of the 20th and 21st centuries. Scientific discovery does not occur in a historical vacuum. The swirl of world events does not stop outside the laboratory. In 1910, as Viennese researchers Ernest Freund and Gisa Kaminer published observations that some substance in healthy blood serum suppresses cancer growth, the once-great Austro-Hungarian Empire was very ill. For years, its constituent peoples – Serbs, Macedonians, Slavs, and Magyars – slowly gained independent strength from within. To the aging Austrian Emperor Franz Josef, this must have felt like tumors growing out of control. When Franz Josef’s nephew- and heir to the throne- was murdered by a member of a cell with ties to the Serbian government, Austria launched an attack on Serbia. This remedy, intended to bring a cure to the Empire, triggered the First World War. That conflict expedited the inevitable death of the moribund patient. Neither the Empire nor the Emperor survived the war, but the work of Kaminer and Freund continued. They even reached a mainstream American audience via a mention in Time Magazine in 1924. However, a second cataclysm left them unable follow up on their investigations. In 1938, Austria was annexed by Nazi Germany, and the two scientists of Jewish ancestry were forced to flee.

Cancer therapy turned in another direction. In 1941, the United States found itself at war with Germany. Strategists had legitimate fears that, despite existing prohibitions, that poisonous gases would be used as they had been in the First World War. Alfred Gilman, son of the owner of a small music store, was assigned the role of Section Chief of Pharmacology at the US Army’s arsenal in Edgewood, Maryland. There, with his friend and colleague Louis Goodman, a Portland-born former Johns Hopkins intern, they began a study of the WWI poison agent, nitrogen mustard.^​1​ (The name “mustard” is unfortunate – it is not related to the spice; the two only share a pungent smell.) Goodman and Gilman observed that, in addition to the obvious blistering caused by the chemical, nitrogen mustard also suppresses rapidly dividing cells including intestinal cells, bone marrow, and, auspiciously, tumors. The pair administered nitrogen mustard to animals with cancerous growths and observed the following:

“After just two administrations of the compound the tumor began to soften and regress. I cannot remember exactIy how many doses we gave, but in any case, the tumor compIeteIy regressed to such an extent that we could no Ionger palpate it. We stopped treating the animal and the regression remained for a period of a month or more before a very sIight growth began to appear. We then treated the animal again and a regression occurred again, aIthough it was not as compIete as the first time. In any case, the tumor did decrease and finaIIy began to grow again, at which time further treatment brought about no inhibition of growth.”^​2​

This success led Goodman and Gilman to try it in humans. The medication was labeled “Compound X” for secrecy and administered into the veins of a colleague’s dying lymphosarcoma patient as a last-ditch therapy. The tumor regressed – and then returned. The patient died, but the therapy had extended their life. And so, for the next 50 years, cytotoxic chemotherapy has remained the basis for cancer treatment. Mustards and other similar drugs – platinum analogs (e.g. cisplatin), alkylating agents (e.g. doxorubicin), and antimetabolites (e.g. methotrexate), poison rapidly dividing cells. Of course, malignant tumors are not the only cells with a high turnover rate. Bone marrow (progenitors of blood cells), gastrointestinal cells, and hair follicles are affected, resulting in side effects that can be intolerable and life-threatening. Patients lose hair, suffer nausea, and most consequentially, lose vital immune cells required to prevent infection. Nevertheless, cytotoxic chemotherapy has been the backbone of chemotherapy regimens. In many cases, initial transient control of the disease with cytotoxic therapy can be followed by definitive surgical or medical cure. However, in too many cases, as with Goodman and Gilman’s first patient, a cure cannot be obtained.

Immune Checkpoints

Freund and Kaminer were unable to identify the factors in healthy serum that destroyed cancer cells. Now, it is likely that the phenomenon they observed was a result of T cell activation. The terrible emergence of AIDS in the 1980s renewed interest in immunology. The initial puzzle of HIV was why the immune system’s T lymphocytes do not recognize and destroy the HIV virus. Instead, the virus infects the T lymphocyte. The pursuit of a solution to this conundrum resulted in a growing understanding of how both viruses and cancer cells evade destruction by the immune system. Signals that tell immune cells (like cytotoxic T cells) what to attack and what to leave alone are a basis for immune system responses. A healthy cell is a friend, while a hijacked cell that has been converted into a virus-making factory must be destroyed. How does the T lymphocyte know which is which? Several such signaling receptors were identified during the 1980s and ‘90s immunology boom. A few have become important in cancer immunology. One such discovery, was cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), a T-cell inhibitor.

There exists a network of signals and signal receptors, that control immune cell activity.^​3​ These proteins on immune cells and cancer cells, including CTLA-4, Programmed Cell Death Protein 1 (PD-1), Programmed Death Ligand 1 (PD-L1) can brake, or check T-cell activation. For that reason, they are referred to as immune checkpoints

When the immune system is functioning correctly, pieces of dead cancer cells (antigens) are picked up and processed by antigen-presenting cells (APCs). These APCs deliver the antigen to lymph nodes where T-cell receptors are stimulated. To prevent autoimmune T cell attack on friendly tissue, several receptors exist to limit T cell activation. The activation of CTLA-4 on the T-cell dampens the response. Immune response is also quieted by PD-1, an inhibitory molecule on T-cells. PD-1 is activated by a protein called PD-L1. The apparent purpose of this system is for “good” cells to express PD-L1 as a form of passport, allowing them to be unharmed by the T-cell. Unfortunately, PD-L1 is expressed by tumor cells, tricking the immune system into leaving the cancer cell alone.

The understanding of this system has led to the development of so-called “checkpoint inhibitor” drugs to fight cancer. Investigators can produce monoclonal antibodies that block these inhibitory receptors, allowing T-cells to be primed to produce cytokines in response to cancer cells. A T-cell might attack a cancer cell that would otherwise have been left alone. Ipilimumab (Yervoy®), an inhibitor of CTLA-4, was approved by the FDA for melanoma treatment in 2011. The PD-1 inhibitor nivolumab (Opdivo®) was approved for melanoma in 2014. Many more agents are in the pipeline, undergoing clinical trials. Today, these medications are used in cancers of the kidney, lung, bladder, liver, stomach, skin, and others (Table 1). The checkpoint inhibitors do not produce miracles. However, since the advent of nivolumab for melanoma, median overall survival has increased from 9 to as high as 30 months with more tolerable side effects than traditional chemotherapy.^​4​

What Non-Oncologists Need to Know

Knowledge of this new treatment paradigm is not only important for oncologists. Toxicologists, emergency physicians, and primary care practitioners of all stripes will see patients who are taking these drugs.

The way that we think of cancer drugs should change accordingly. Up until now, neutropenia was the key oncology drug toxicity we needed to know about. We ask our cancer patients when their last chemotherapy session was, check a neutrophil count, and assess them for fever. When we see severe neutropenia, especially when combined with fever, we isolate the patient and antibiotics. These practices are standard of care, tested on board exams, and familiar to clinicians. Cytotoxicity remains a backbone of many cancer treatments, so this paradigm still stands.

However, clinicians must also recognize the new paradigm (Table 2) for patients taking checkpoint inhibitors. The drugs prolong survival, but unfortunately, cause immune-mediated adverse reactions (IMARs). As discussed above, the purpose of immune checkpoints is to prevent T cell attack of healthy tissue. Dialing down T cell inhibition can increase the cell’s ability to attack cancer but also increase the risk of autoimmune attacks on healthy tissue. The affected organ can be anywhere your immune system goes, which is essentially everywhere in your body. Toxicities of checkpoint inhibitors cause hypophysitis (pituitary inflammation), uveitis, mucositis, myocarditis, hepatitis, colitis, encephalitis, vasculitis, nephritis, pancreatitis, diabetes, arthralgias, neuropathies, and more (Table 3).

Diagnosis can be challenging, because IMARs mimic other common conditions and occur in a delayed fashion. IMARs begin weeks to months after therapy, and can occur months after the last dose of the drug. Thankfully, treatment of IMARs is straightforward and similar in all conditions- corticosteroids. For cases that are refractory to corticosteroids, administer infliximab 5 mg/kg.

To Cure, Sometimes

Alfred Gilman and Louis Goodman went on to have productive years together as collaborators on The Pharmacologic Basis of Therapeutics, the most important textbook in pharmacology. “Goodman and Gilman,” in its 13th edition, is still considered the Bible of clinical pharmacology. Alfred Gilman’s other great legacy was his son, Alfred Goodman Gilman. (Yes, named after his father’s friend.) Alfred G. Gilman won the 1994 Nobel Prize in Physics or Medicine for the discovery of the G-Protein receptor, the key to the function of adrenaline and opioids.

Kaminer died in 1940; Freund in 1946. Their work was interrupted by one world war and left incomplete after another. They had been unable to translate their observations into clinical therapies. The development of checkpoint inhibitors has been a collaborative effort of dozens of research teams. These drugs extend lives and cause more tolerable adverse effects. Patients are often not cured, but they live longer and feel less sick. There are more questions that need to be answered about checkpoint inhibitors. Further work is needed to understand biomarkers and genetic markers that will predict response and understand factors that lead to treatment failure.

The treatment of cancer was shaped by catastrophes – AIDS and multinational wars. As physicians, we practice our art while events beyond our control rend the world. But, a cancer diagnosis is a cataclysm in the life of the patient, and in patient care we have a modicum of control. We are compelled by the aphorism ‘To cure sometimes, to relieve often, and to comfort always.’^​5​ Comfort may come in the form of treatment, or the decision not to give a treatment. We may also offer comfort in our recognition of the complications of our treatments.

Disclosure

Andrew Stolbach receives honoraria from PeerView to lecture on immune-related adverse events caused by checkpoint inhibitors.