Julie Update: Here Be the Dragons

All oncology treatments have Adverse Events (AEs). Sometimes, the AEs are worse than the cancer.
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Dear MissionGBM Community:  You now number more than 215 brain cancer patients worldwide.  Believe me when I tell you that your stories and energy give us wings.  It is heartening to hear of your triumphs, and occasionally, taxing to help you navigate the inevitable setbacks.  It is a Journey.  We are here to help as much as we can.

Also, thank you for your messages inquiring about Julie’s well being.  I have not written on the topic in a while, but here we go.

A Mystery Born of the Long Term Effects of anti-GBM Treatments

As we have written on MissionGBM: Results That Matter, Julie achieved a CR in Dec-2022 and it held for over a year.  Recently, we detected some very small enhancements on her T1 post-contrast scans.  An 18-FDG PET study was done, which was unremarkable.  The tumor bed was quiet.  Further, the MR Perfusion scans showed no evidence of increased CBV/CBF.  Finally, the full MRI series demonstrated no cerebral edema or mass effects.

OK, so why is Julie’s neurological function (principally, speech word-finding and neuromotor coordination/balance/gait) noticeably degrading in the absence of obvious tumor recurrence?  The Team reviewed all the data, and concluded that the most likely cause was the long term effects of her anti-GBM treatments with the primary impact coming from the SoC radiation therapy (RT) that she received almost 2.5 years ago.  Ugh!

Wow! So we successfully contained and regressed the cancer for 28 months only to see evidence of encephalomalacia and gliosis in the resection cavity and RT margins?  Yep.

While we can beat back the cancer, we do not have any methods to regrow healthy neuronal tissue. The treatments can be as challenging as the cancer.  Hold that thought as Julie’s story further unfolds below.

On the positive side, Julie has enjoyed an outstanding QoL for almost 2.5 years (and counting), which has allowed her to travel and commemorate important family events.  When you live for much longer than anyone predicted, the AEs associated with treatment begin to manifest.  Everything has a cost, but when you ask Julie, she will quickly tell you that she is willing to bear the costs as long as she can function as an independent adult.

Julie’s Protocol and Immune-Related AEs (irAEs)

Julie has a hyper-responsive innate immune system, which we have harnessed to hammer her GBM.  In order to deploy Julie’s treatment protocol (see here and here), however, we have had to constantly maintain a delicate balance between enough tumor-directed immunological activity to attack the GBM while avoiding immunological spillover that would cause damage to healthy, non-cancerous tissues.

We chose to use a baseline protocol of Tumor Treating Fields (Optune®; TTF) + Pembrolizumab (Keytruda®) based on the compelling Phase 2 clinical results from David Tran, MD/PhD (see here and here).  We had to add infliximab (Remicade®) as a prophylactic co-infusion with pembrolizumab in order to mitigate irAEs and maintain the immunological balance required to keep Julie on protocol (based on the outstanding work of Michael Dougan, MD/PhD).

Julie’s protocol has worked spectacularly well, and it has been adopted by dozens of MissionGBM families.  In fact, having reviewed hundreds of brain cancer investment opportunities including many with clinical data, we have yet to see a treatment approach that results in more compelling data as evidenced by the percentage of ORs (PRs and lots of CRs) that TTF + Pembrolizumab can yield, if the patient has residual tumor tissue following tumor resection to serve as a basis for in situ TTF-driven anti-cancer vaccination (see here).

Because Julie’s immune system is aggressive, there have been periodic bouts of immune-related enterocolitis (irEC) requiring short hospital stays, which have occurred about once per year and last roughly four days (see here).  An infusion of inpatient infliximab along with supportive care shuts down the irEC damage and allows healing of the colon mucosa to proceed.  Unpleasant, but an acceptable cost for a durable CR in a GBM case.

Until now.

Neutrophils and Runaway Trains

Neutrophils are the First Responders of the innate immune system.  Ordinarily, they remain sequestered at various locations in the body until a pro-inflammatory invader is detected (viral/bacterial infections, wounds, other pathologies).  Then, the neutrophils spring into action; are released into systemic circulation; and rush to battle the invader.  As the battle begins, the neutrophils release cytokines and other pro-inflammatory signals to summon additional immune components to join the fight.  If you are like Julie and have a hair trigger innate immune system, rapid neutrophil demargination can cause pathological conditions to develop rather quickly (her Neutrophil-to-Lymphocyte Ratio rockets from a baseline of 1.7 to as high as >22 in less than 24 hours; an NLR above 3 is considered pathologic and spells trouble).  The pro-inflammatory cascades recruit T-cells that can attack healthy tissues, especially when the T-cells are turbocharged by the presence of a powerful checkpoint inhibitor like pembrolizumab.

One other thing: Corticosteroids are documented to promote neutrophil demargination.  One of the fundamental tools in the Neuro-Oncology toolbox is the steroid dexamethasone to manage cerebral edema.  Recipe for a conundrum…and an accident!

An irEC Train Wreck Caused by Immuno-Oncology and a Neuro-Oncology Experiment Gone Wrong

Julie’s Team had been actively debating potential treatment adjustments to address her neurological decline in the absence of data demonstrating rGBM tumor progression.  A proposal was floated to try a small daily dose of 2mg dexamethasone as a means of observing whether the steroid might help with micro-edema that was not otherwise apparent on the scans.  I was not a fan of the proposal and argued against it with Julie, citing the elevated potential for neutrophil demargination and descent into a spiral of rapid onset irEC based on her medical history and previous steroid non-responsiveness.

Wanting to try “something” to address the increasing neurological degradation that she was noticing, Julie decided to take the dexamethasone.  From the very beginning of her Journey, the final decision on any proposed treatment has always been Julie’s.  We review the biological rationale and potential AEs with her, but it is her body, and therefore, her decision.

Three doses into the dexamethasone experiment, Julie began to experience the telltale symptoms of irEC. We immediately stopped the dexamethasone, and put her on a close monitoring protocol and started a conservative diet in an attempt to avoid hospitalization from advancing irEC.  But, we were already too late.

Julie rapidly progressed into runaway irEC, which resulted in perforation of her sigmoid colon.  This is the definition of an emergency surgical case.  We took her to the local ED, and the imaging confirmed a perforated colon with a pneumo-peritoneum and a large amount of stool spilled into the abdomen.  Within three hours, Julie was in surgery to evaluate the situation and correct the problem.  A sigmoid colectomy had to be performed along with an anastomosis of a portion of her small bowel and an appendectomy.

A stay in the ICU for one day post-surgery was followed by two weeks of hospitalization to restore her bowel function and address any sepsis or abscesses that would likely occur as a result of the ruptured colon.  Julie was discharged just under two weeks ago, and is recovering at home with a large, open abdominal midline incision (necessary to manage the post-operative infection).  She will start using a wound vac soon to hasten wound healing. Given the physical beating that she absorbed, it is amazing that her positive outlook and thirst for life remain intact.

There will be no more pembrolizumab for Julie, but she will continue the infliximab treatments to prevent any further irEC flares as the pembrolizumab effects wash out of her immune system.  When the inevitable cerebral edema eventually presents, it will have to be managed with non-steroidal methods, principally bevacizumab (Avastin®).

The Silver Lining

Because she still enjoys a strong QoL despite the recent setback, Julie has been able to spend time with our children, family and friends doing many of things that make life special.  Over the Holidays, she got to celebrate the engagement of our son Alex to his fiancée.  In the days before Julie underwent emergency surgery, she and our daughter engaged in a couple of cherished Mother/Daughter events.  The children recently visited our house with their partners, and did some activities together, including running the NYC Half Marathon on St. Patrick’s Day.  Finally, both of us got the ultimate “Proud Parents” experience as we watched Surgery resident Stephanie Rakestraw, MD expertly navigate Julie’s emergency surgery and post-operative care at institutions where she is not a member of the house staff.  We are very fortunate, indeed, and look forward to creating more memories.

Onward!

Mission GBM
Mission GBM
Authors
Scott L. Rakestraw, PhD