Immuno-Oncology: A Question of Balance
A SARS-CoV-2 infection precipitates a cascading series of immunological adverse events
The past two months have not been pleasant. In fact, they have been awful.
Julie has struggled with her general health, largely as a result of two viral infections (SARS-CoV-2 and a minor URI) and the resulting sequalae. A lengthy hospitalization occurred and a new complication has arisen.
The irony is that the health issues have not been directly related to GBM, but are clearly related to virus-driven, immuno-inflammatory excursions that drove her finely tuned immuno-oncology (“I-O”) regimen out of balance.
The Immune System: A Potent Anti-Cancer Weapon and a Double-Edged Sword
Cancers erect a number of defenses against attack by the human body. One of the most diabolical is multi-layered immunosuppression, which degrades the normal ability of the immune system to attack cancer cells and kill them.
Over the past 15 years, major advances in I-O science and clinical development have produced breakthrough additions to the oncology arsenal (e. g. checkpoint inhibitors - pembrolizumab, nivolumab, ipilimumab). These medicines often produce miraculous results for patients who respond to I-O treatment.
No drug is without side effects, and I-O drugs are no exception despite being generally well-tolerated (certainly compared to older chemotherapy drugs). In the case of I-O agents, the immune-related Adverse Events (“irAEs”) take the form of immuno-inflammatory attack on otherwise healthy tissue in a manner akin to autoimmune disorders. The most common irAEs are dermatitis, colitis and thyroiditis of varying grades, but the clinical literature also records very serious irAEs such as pneumonitis, pancreatitis and cerebritis.
The key to managing a cancer patient on an I-O regimen is to dynamically maintain the balance between the desired immunological attack on cancer cells and the undesired irAEs that may result if overall systemic immunological activity is too high.
SARS-CoV-2 and the I-O Patient
A spectrum of perturbations can alter an I-O patient’s dynamic immunological balance causing unwanted immuno-inflammatory excursions and serious illness. The SARS-CoV-2 virus is certainly one such perturbation as it is a potent overall activator of the immune system. In fact, COVID patients with the worst outcomes follow clinical paths driven by overwhelming and cascading immune responses to the virus.
In any infected person, SARS-CoV-2 triggers an innate immune response with neutrophils (the immune system’s First Responders) pouring into systemic circulation to attack the virus (see here). Cytokine and chemokine cascades soon follow, and the immuno-inflammatory bonfire burns hot and fast. For the otherwise healthy person, the immune system eventually destroys the virus, but not before unpleasant headaches, myalgia and respiratory symptoms result from the immune response to the virus.
Things can be quite different in an I-O patient. Julie’s infection predictably caused very large elevations neutrophil and cytokine levels [her Neutrophil-to-Lymphocyte Ratio (“NLR”) peaked at 22.5; NLR > 3 is considered pathological]. While her respiratory symptoms were moderate and manageable, the flood of TNFa into her circulation broke through the infliximab prophylaxis that she employs to enable her very successful I-O therapy for GBM. An acute case of ir-Colitis (“irEC”) soon developed, leading to an ER visit and hospital admission. The irEC was confirmed by GI endoscopy. An inpatient infusion of infliximab rapidly began resolving the irEC.
Nearly 10 months of customized, well-tolerated and successful I-O therapy for GBM run into the ditch by SARS-CoV-2. Arrrgh!
A New Complication
As Julie was preparing for hospital discharge, she began reporting sudden onset, acute and severe back pain. The doctors quickly conducted a thorough workup to diagnose the source of the pain. The culprit was a spontaneous, atraumatic and severe compression fracture of her L1 vertebrae, which occurred while she was in the hospital! You read that right: An abdominal CT scan taken during ER presentation on Day 1 showed a normal spine presentation, but the followup CT on inpatient Day 4 showed a pulverized L1 vertebrae. Unbelievable, and very painful!
Spine and Neurology evaluations indicated uncompromised neurological function, and the L1 fracture was considered stable enough to be non-surgically treated…for now. A TLSO back brace was fitted and a multi-modal pain management plan was put in place. Discharge occurred on Day 9.
A Whole Bunch of Tough Questions…and Very Few Answers
What triggered the spontaneous L1 fracture? Could it be an uncommon musculo-skeletal irAE (see here and here)? Or perhaps, it may have been caused by high dose IV steroids administered at the hospital (see here)?
These questions have been the focus of a weeklong discussion within Team Julie. Opinions are divided amongst the Team members. The answers to these questions may have a profound impact on Julie’s ability to restart I-O therapy in the future.
The Path Forward
The Team is unanimous with respect to three topics:
A SARS-CoV-2 infection triggered the immuno-inflammatory excursion that broke through Julie’s infliximab prophylaxis and caused the irEC.
Infliximab-only Maintenance Until the Colon Heals. Inpatient infliximab rapidly improved the irEC. Moreover, concomitant use of outpatient infliximab has prevented any irEC episodes for nearly a year. Therefore, regular infliximab-only infusions will be used for the time being (a) to promote colon healing; and (b) prevent additional irEC episodes. Followup GI endoscopy will be scheduled to assess colonic health.
The L1 Fracture Must Be Closely Monitored. Two goals: (a) Ensure that the spine is stable and the fracture is healing or consider surgical intervention; and (b) manage the pain on an outpatient basis, seeking to avoid additional complications that may result from a prolonged, multi-modal pain management regimen.
Bottom Line: All of the above must be viewed against a sober assessment of Quality of Life. Conservative treatment regimens will be used for the time being until further data can be gathered and Julie makes progress towards regaining the overall health that she enjoyed prior to her recent COVID-driven misadventures.
The Ultimate Irony
Care to guess the source of the SARS-CoV-2 infection that hit Julie? It was brought home undetected by Scott as a result of his attendance and chairing of an Investor panel during the recent GBM Drug Development Summit in Boston. No good deed goes unpunished.
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