We collected Alfred the afternoon of the day following surgery. Many dogs return to their owners on the same day, but as Alfred’s operation was more risky than most due to the position of his tumour and the risk of bleeding, he was held back for observation.
The post surgery MRI showed around 97% of the tumour, a 2.5cu cm mass, had been removed. Alfred’s head is about the same size of my fist so you can imagine, the 2.5cm tumour was occupying a significant part of his brain. The remaining 3% of tumour left behind (not intentionally, it is simply a very difficult procedure to remove a tumour like this), will now be treated by immunotherapy; a peptide and vaccine combination made from his own tumour cells. A personalised medicine.
Perhaps because I was aware from his neurology specialist in London, Dr Butterfield, that the surgery was high risk and we’d likely lose him during theater, I had not considered all outcomes associated with brain surgery. Before surgery, all I could think was he would die without it, and that if he did die on the table our decision would have cost him weeks of life at most, and we had to try to do our best for him. I’m all to aware of the impact a bleed on the brain can have on humans; loss of mobility, memory, cognitive function, paralysis. The team had to slice Alfred’s brain open, cut and scoop a large mass with a tail on it, in an area susceptible to bleeding, and put everything back in place.
Sadly, we were told that Alfie had lost vision in one eye, and that it may, or may not return. This was likely caused from an optic nerve being sliced getting to the tumour site. It was a relief knowing Alfred was alive, but our thoughts turned to worrying what he might be like after such serious brain surgery. We already knew he was blind in one eye, but what else? Would he be in pain? Would he be the same Alfie we know? Would he even recognise us?
The University of Minnesota veterinary College is a 15 minute drive from the Canopy Hotel. Arriving early we sat nervously in the Jeep outside. The hospital limiting human visitors inside the building due to the pandemic, we waited for what seemed like forever for him to be carried out to us. Normally when I am waiting somewhere I’m reading something on my iPhone to pass the time, or catching up and replying to emails. Not today, all eyes were on the entrance and every time there was movement at the door I hoped to see him. Eventually I did, and seeing him carried out by Dr Pluhar and Dr Arnold I put out ‘the call’ he and I share – a sort of signature whistle noise. His head started moving to find where it was coming from, he’d definitely heard me, but he’d not yet seen me. And when he did see his humans he was excited. Maybe relieved. A sort of ‘Oh my God you’re here, you won’t believe what has just happened, get me out of here… let’s go’. Or at least that’s my interpretation. Reality closer to being happy to see Renée and me, reunited with his pack.
Playing with him on the grass outside the University was a surreal sight. How could this small animal, who just hours ago had undergone such difficult surgery to his brain, be outside running around and playing fetch with a stick? Interestingly he was more than comfortable to play with Drs Pluhar and Arnold too – a first for our dog who ordinarily runs from any vet. Astonishing. No other word for it.
Getting him back to the hotel was via a much needed coffee shop stop. Caffeine has become the drug of choice the past week. Neither of us have drank any alcohol since Alfred’s first seizure – it didn’t seem right, and we needed to be ready at all times. The two weeks prior to boarding our jet were non-stop days of research and reorganising, as we fought hard against government restrictions on movement put in place alongside the coronavirus pandemic. The knock-on means much catching up needed. A current work project list including UK FTSE annual reports, three US based brand creations, a UK brand creation, a handful of websites, and while I’ve been resident in the hotel another landed from France. On the way here I did not get more than three hours sleep in one go for almost three days. Even now it is sporadic dealing with clients in different time zones. When we were getting knocked-back by airlines and border controllers I was turbo-charged on anger and determination. Now I’m unsure if it’s adrenaline or love pushing us on? But the coffee helps.
While sipping from paper cups and taking a close up look at Alfred’s stitches, we happened to notice he had the most beautifully manicured paws? Clearly Alfred was not just the beneficiary of three talented doctors (there is a Dr Matthew Hunt, another talented neurosurgeon, also involved in this life saving tale), but of the love and care of a team of good people at the University of Minnesota.
For the next couple of weeks we were under direction to keep him calm. Our task to stop him jumping on and off furniture, playing rough, getting over excited. All the things Boston Terriers do when they are not asleep. Not an easy challenge. We were unsure what to expect from him, and what we would witness. We watched him like hawks; looking for signs something could be wrong, a seizure, checking he was breathing, his mood, signals he may be in pain. His medication schedule changed and we were following detailed notes on what to give him, at what times, and when to start reducing doses of the steroid he’d been on since diagnosis.
We were also alerted that he may not poo for a week, possibly two, and that this was nothing to worry over. However, the next day there was poo in the underground car park of the hotel where I’d started walking him while he improved. We are talking post-op poo so more ‘liquid-esque’ than a standard one. Then again in the carpeted business suite corridor of the hotel (this is on the way to the car park), once in the corridor leading to our hotel suite. You have to hand it to him, even after a crainoctomy he was still doing his best not to have an accident in the (temporary) home.
Working from the hotel for over a week now, I’d been a regular popping down to the Starbucks for coffee. Sure, there are better cups a little further walk away in those hipster-type places, but the closest, Northern Coffeeworks, a little sniffy about letting dogs in (perhaps they had heard about the car park and hotel corridor?). Alfred was allowed in twice by campaigning his case for entry; “think of him like a small, furry human”, etc. I liked the coffee there, but no whipped cream (hipsters are sniffy about that too), which in turn meant no pup-cup. So we became friends with the crew in Starbucks, and whenever I went down to get one, Alfred came with. I knew a couple of them had been worried about his surgery so I took him in to be fussed over. A first outing on a leash to the outside world. Nothing wrong with his memory; he knew the way, pulled me toward the door, said hello to his friends, and left with whipped cream on his face.
After a couple of days we started to walk him further. Alfred was keen so why not, and far better than going down to the car park. A reminder all was not as well came quickly, and audibly. Strolling along Alfred crashed straight into a street sign pole despite seemingly looking directly ahead as he trotted along. I can still hear the thunk, and worse the yelping cry. He really couldn’t see at all out of one eye and needed time to adjust. His other eye has always been a weak spot and I’ve long questioned his distance vision, so perhaps he was struggling more than we thought. We would notice more examples like this over the coming days. I adapted a new way of walking where I stayed on his blind side, both on and off leash. I’m Alfred’s eyes on his left now.
With a Frankenstein scar the length of his head, and shaved patches all over his body, he looks a real bruiser. Originally Bostons were bred as fighting dogs but they were all useless, their nature is too gentle, so they became known for being excellent companions for people. Despite his new badass make-over, and any concerns we had that brain surgery could change his personality, he is still the sweet little animal he has always been. Just in need of a little extra help from his humans.
How the science works
Gliomas are highly invasive tumours that carry a grim prognosis in humans, with a median survival of 14 to 16 months, despite intense treatment. Pet dogs diagnosed with these tumors have few options and are often euthanized shortly after diagnosis. Their median survival time is much shorter than in humans at around two months.
Dr Pluhar’s clinical trial focuses on dogs with high grade gliomas. The tumours are surgically removed at the University of Minnesota before cutting edge immunotherapy treatment is given to the dogs in the form of a vaccine based on each individual dog’s tumour. The progress is then monitored by performing magnetic resonance imaging (MRI) on the dogs every four months to assess tumour recurrence or progression.
Unfortunately, although the approach is successful at extending most of the canine patients’ survival, the tumors always recurred. To improve the efficacy of the treatment, Dr Olin who collaborates alongside Dr Pluhar, discovered the tumours were elucidating a protein, CD200, that blocks the body’s natural immune response. To combat this, Dr Olin manufactured peptides of the native CD200 that override the tumour’s efforts to protect itself from the body’s immune response.
1. Cross section of frontal lobes
A healthy, tumor-free dog brain, as seen in cross section of the frontal lobes.
2. Tumor growth and development
Glioblastomas typically develop in the gray matter (represented here in light pink) of the brain. As they grow and expand, the tumors compress normal brain matter and cause the midline to shift away from the tumor mass. Microscopic tendrils of tumor cells often spread along blood vessels and white matter tracts (beige) of the brain, and can extend as far as the opposite lobe. While the tumor (bright red) is visible on the patient’s MRI, the tendrils (dark red) are microscopic and cannot be seen. As such, the tendrils also cannot be removed during surgery. Instead, they are treated by a series of injections, which differ depending on the treatment group within the trial to which the patient is assigned (see figures 3-5).
3. Tumor removal and gene therapy injections
All patients undergo surgery to have the primary tumor mass removed. Afterward, Pluhar and her team use additional therapy to attack any residual tumor mass and the remaining microscopic tendrils. For dogs in treatment groups one and two in the current clinical trial, the surgeons will give 20 injections containing gene therapy (blue) into the brain tissue around where the tumor was removed. The genes stimulate an immune response that kills tumor cells. Patients in group one are finished with treatment after this phase. Meanwhile, patients in group two go on to receive injections of the CD200 peptide (see figure 4).
4. CD200 peptide
After having undergone surgery and receiving gene therapy, patients in group two of the clinical trial will receive a series of injections of the CD200 peptide (green). This peptide is injected into the back of the patient’s neck where it interacts with local immune cells, which circulate to lymph nodes and then, hopefully, the brain. Once there, the peptide-activated immune cells process bits of tumor cells killed by the gene therapy and hunt down and kill any live tumor cells remaining in the tendrils. These vaccines are repeated at regular intervals to boost the immune system. The third and final group of patients also receives these injections but do not receive gene therapy during surgery. They instead go on to also receive a second injection of tumor lysate (see figure 5).
5. CD200 peptide and tumor lysate vaccine
About 24 hours after receiving their first injection of the CD200 peptide, patients in group three receive a second injection of a mixture of peptide (green) and a tumor cell lysate (orange). The peptide activates local immune cells and allows them to process tumor- specific antigens in the lysate. The activated cells move to lymph nodes and prime with other immune cells that can now recognize the tumor cells as “foreign.” These immune cells circulate around the body, including the brain. These vaccines are repeated at regular intervals to boost the immune system.
6. Post-surgery and treatment
In the weeks after the patients in the three treatment groups complete their surgery and treatment, any residual tumor cells in the tendrils have hopefully been killed by the circulating immune cells. The brain relaxes back into the space once occupied by the primary tumor mass.
