Meet the Team: Michael L. Dougan, MD, PhD
Optimizing Immuno-Oncology treatment by overcoming immune-related Adverse Events (irAEs)
Julie and I owe an unretireable debt of gratitude to Michael Dougan, MD/PhD (Massachusetts General Hospital; Dana-Farber Cancer Institute; Harvard Medical School).
Let me explain.
As we have written, Julie experienced Grade 3+ ir-AEs in multiple organ systems on Cycle 1 of pembrolizumab in April 2022. Her thyroid was completely burned out due to acute, inflammatory thyroiditis, and she experienced horrible immune-related sigmoid colitis (irEC). She collapsed on the bathroom floor at home in terrible pain compounded by incessant and unpleasant GI problems.
I drove Julie quickly to the ER of a good local hospital (the same ER that originally diagnosed her GBM in Dec-2021). The ER physicians had not previously seen a severe irAE case, so it took me a frustrating hour to convince them that Julie was experiencing pembrolizumab-induced irAEs. IVs were eventually installed and 2mg/kg of corticosteroids were infused along with hydration fluids and some morphine for the pain. A CT scan of her abdomen revealed pronounced sigmoid irEC, but fortunately, no evidence of pan-colitis. We discovered that Julie’s thyroid was also burned out later when the lab results began to flow.
Julie was admitted from the ER to an in-patient bed, and a full workup was conducted by the GI attending. Liquid diets were initiated and a supportive care plan was designed. After a week in the hospital, Julie was discharged to home care with a taper ladder designed to wean her off oral corticosteroids.
Once the daily dose hit 20mg prednisone (QD, PO), Julie began to experience repeated Grade 2 irEC flares. Oof! Further GI consults resulted in ever-more-complex steroid taper ladders, none of which worked.
Julie was stuck in the Twilight Zone of steroid-refractory irEC.
Who Are You Going Call? Gut Busters
The astute reader is now thinking: There are two simultaneous tough problems here…
Steroid-refractory irEC. We made a mess with the introduction of pembrolizumab into Julie’s GBM treatment regimen, so now we must fix the irEC damage before any other further GBM protocols can reasonably be contemplated.
Keeping the GBM tumor in check. TTF is still active and Julie is still cycling monthly TMZ (even though she is MGMT unmethylated). Is there anything else that can be done to further slow down the tumor while we correct the irEC? More on this in a future post.
Time to hit the scientific and clinical literature and start making calls.
All Roads Lead to Michael Dougan
The general perception of even experienced oncologists is that immune checkpoint inhibitor drugs (ICIs) are generally safe and well-tolerated. Compared to older systemic chemotherapy drugs (e.g. poisons), this perception is very true. However, ICIs do come with a variety of frequent irAEs, which are documented in just about every organ system. Often, these irAEs significantly compromise the ability of the oncology treatment plan to stay on course.
In fact, Dr. Dougan and I have had extensive discussions regarding how many oncologists will essentially panic, and reduce the dose of the ICI or suspend ICI therapy altogether in order to manage the treatment-emergent irAEs.
Research in Mike’s lab combined with his deep clinical experience at MGH in treating and managing irAEs experienced by oncology patients using ICIs has led him to propose an alternative framework.
Instead of reactively reducing ICI dosing or suspending treatment altogether at the first sign of irAEs - both to the detriment of the cancer treatment efficacy - perhaps, the treating oncologist should:
Include irAE mitigation and prophylaxis strategies in the initial design of an oncology treatment plan; and
If irAEs present during ICI therapy, evaluate the clinical case and strongly consider adding non-steroidal irAE mitigation agents to enable continued tolerable dosing of the ICIs.
We cannot emphasize the above framework enough. For Julie, it was both a life-saver, and it ultimately enabled successful rechallenge with pembrolizumab, and some pretty darn spectacular GBM tumor treatment results.
TNFa Prophylaxis and the Path to ICI Rechallenge
Building on Dr. Dougan’s published research and clinical case reports, we designed a plan to (a) fix Julie’s irEC; and (b) build a base of irAE prophylaxis to permit rechallenge with pembrolizumab.
Fixing the irEC. We boiled the ocean with respect to the usual spectrum of immuno-inflammatory pathways: TNFa, IL-6, IL-17, NFkB, JAK/STAT. The finalists for remediation and subsequent prophylaxis were anti-TNFa (e.g. infliximab, adalimumab, golimumab) and anti-IL-6 (tocilizumab) monoclonal antibodies. We chose infliximab (IFX) because:
IFX loading doses can be first infused to remediate the irEC, and potentially permit completion of the oral steroid wean.
IFX can be subsequently co-infused with pembrolizumab (PZB) in a single infusion chair session. Patient Quality of Life matters!
Clinical safety pharmacology reports coupled with Dr. Dougan’s clinical experience indicated that the combination of IFX + PZB is safe and tolerable
Julie’s insurance plan would pay for the IFX to correct the irEC.
We designed a plan to infuse IFX alone as a loading dose at t=0 and 2 weeks, and then clinically evaluate resolution of Julie’s irEC. It worked - spectacularly! Within 3 weeks, Julie’s irEC had resolved and she was able to successfully complete the wean off oral steroids.
We waited an additional 4 weeks with close monitoring of Julie’s hematological, metabolic and immunological parameters to assess whether she was clinically stable enough to contemplate rechallenge with PZB. All systems were GO.
Are You a Fighter Pilot or a Boy Scout?
Sometimes in life one comes to a pivotal juncture at which a scary decision has to be made with imperfect information and no crystal ball (or Magic 8-Ball, if you prefer).
Given Julie’s severe irAEs on Cycle 1 of PZB, do we dare rechallenge…this time with a background of IFX prophylaxis onboard to ameliorate potential irAEs?
Get this wrong, and it could be a Grade 4 (really bad) or Grade 5 (death) irAE.
We reviewed all of the data with Julie; laid out the detailed rationale for the design; summarized the rescue plan if things went wrong…and then admitted that we really were not 100% sure what would happen. Welcome to medicine. There are no guarantees.
The decision was entirely Julie’s. She said, “Go!”
Her rationale was solid: If we could not attack the GBM tumor, it would lead to certain death and possibly rather quickly. When backed into the corner, she wanted to fight her way out.
The Squadron (aka Team Julie) was briefed, and we prepared the Mission combat assets for the initial sortie. On 3-Aug, the Mission was launched.
We have now successfully completed three (3) Cycles of IFX + PZB co-infusion on a Q8W schedule. A fourth Cycle is scheduled for late Jan-2023. The therapy has been both well-tolerated (no recurring or new irAEs) and the MRI scans reveal a remarkable treatment effect and significant regression of the GBM tumor.
None of this would have been possible without the incredible work of Mike Dougan.
Mike and I recently got together at the Liberty Hotel in Boston (aka the MGH Cafeteria) for a breakfast meeting. We discussed immuno-oncology, managing irAEs, innovating exciting new immunotherapies for cancer and building new companies and care delivery organizations to optimize oncology patient outcomes. We both would have kept talking all day were it not for his clinical schedule and my investor meetings.
As our breakfast concluded, I slid a handwritten “Thank You” note to Mike. Julie was very happy to have been around to write that note.
At the recent Society for Neuro-Oncology annual meeting, I hosted a happy hour for the members of Team Julie who were in Tampa. The event was the first time that many of them had a chance to meet each other in-person; to hear the full case debrief and ask questions; and interact as leading physician/scientists to discuss the data. It was also the first time that most of them were seeing the MRI scan time series from irAE-driven despair of Apr-2022 to barely visible GBM tumor in Nov-2022. I asked the question: Given Julie’s severe irAE misadventure on Cycle 1 of PZB, would you have recommended PZB rechallenge against a background of IFX. Half of the physicians admitted that they would not have advised a patient to rechallenge because the risk seemed too high.
I never thought to ask Mike if he was a fighter pilot, but I think I know the answer. If he ever gets the urge to go inverted at 300kts with his hair on fire, it would be my honor to make that happen. Pro Tip: Just tell your wife that you will be wearing a backpack parachute. ;-)
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