October 21, 2021 | by Steve Graff
Donald M. O’Rourke, MD, director of the Glioblastoma Translational Center of Excellence at Penn Medicine, feels energized. After a lot of frustration and too few successes, the cell therapy field has reached a new phase in its pursuit for better treatments for the deadly brain cancer glioblastoma multiforme (GBM).
For decades, treatment approaches using surgery, chemotherapy, and radiation have sometimes helped to slow tumors’ growth, but the disease has almost always recurred
and proved lethal.
For that reason, over the last decade, O’Rourke and others began to explore cellular immunotherapies — similar to cancer immunotherapy developed at Penn Medicine and approved for certain blood cancers — as a potential better option for these brain tumors.
This decade-long focus in the lab and clinic, heightened by President Biden’s Moonshot initiative over the last five years, has helped answer questions about the tumor itself and previous therapies’ shortcomings. Now, researchers are on the cusp of delivering the next generation of chimeric antigen receptor cellular therapies (CARs) that could instill fresh hope for patients with GBM and other types of solid tumors.
Gaining Traction in Cellular Therapy for Glioblastomas.
“The amount and richness of GBM research is dramatically better than it was,” said O’Rourke, who also serves as the John Templeton, Jr., M.D. Professor in Neurosurgery in the Perelman School of Medicine at the University of Pennsylvania.
“And when there is increased work and scholarship being done in the field, it will get clinically translated and there will be an improvement.”
At Penn, a leader in GBM cellular therapies since the early days of this technology,
a new CAR cell therapy could find its way into clinical trials by next year,
In collaboration with Immunity Therapeutics, a Philadelphia-based biotherapeutics developer.
O’Rourke and his team believe this “dual target” CAR could accomplish what its predecessors couldn’t: withstand a hostile tumor microenvironment and more
precisely target and fight the tumor unhindered.
The timing is a tough reminder just how hard that has been for any treatment.
Fifty years after the architects of the National Cancer Act signed it into law and more
than 200 years since GBM was first reported, the median survival time is 15 months,
even after today’s aggressive treatments with chemotherapy and radiation.
The five-year survival rate remains at just 10 percent, and nearly everyone who
battles the disease loses. “This is important for two reasons: for the field, which
is really filled with desperation right now and continued setbacks,” O’Rourke said.
“And for desperate patients who have a disease that still has no standard of care,
which is an illustration of how bad things have been.”
Donald M. O’Rourke, MD
Stubborn, But Not Impossible
GBM patients, many treated at Penn Medicine, have had responses to experimental
CAR T therapies, such as reduction in levels of the CAR T tumor target and proliferation and expansion of CAR T cells in tumor cells.
But the majority of these treatment responses have not been maintained over time.
Brain tumors are notoriously stubborn against nearly everything in the armament, including CAR T cell therapies.
The problem with GBM and other solid tumors is tumor heterogeneity, meaning
not all cells within a GBM tumor are the same or have the same antigen that a CAR T
cell is engineered to attack. On top of that, GBM tumors grow in a microenvironment
that blocks the activity of immune cells that might otherwise fight the tumor.
This includes both engineered CAR T cells and a patients’ innate T cells.
A cellular therapy for GBM, as well as most solid tumors, needs to overcome
those challenges.
Two previous clinical trials at Penn that included 17 patients, along with other trials at fellow institutions, helped tease out the biology to explain how and why some respond better than others.
The first round of CARs used for GBM were designed to target the antigen EGFRvIII,
a known driver of the disease expressed in cancer cells. Studies had proven this was a feasible and safe approach, but when patients with recurrent GBM were infused with EGFRvIII CAR T cells, researchers saw those infused cells diminish in most patients, leading to relapses.
Analyses of their blood and tissue made it clear that expression of the antigen decreased over time and the tumor microenvironment was firing off too many anti-immune-cell soldiers to disable immune cells. All was not lost, though. The studies showed CARs can pass the blood brain barrier and reduce the tumor if they stick around; one patient even had an exceptional response, surviving 36 months post infusion.
That invaluable data joined other research from Penn, including studies led by O’Rourke, Zev Binder, MD, PhD, an instructor of Neurosurgery, and others in Neuro-oncology, that has informed cell therapy approaches up to this point and in the future.
Having infrastructure and expertise from Penn’s Center for Cellular Immunotherapies,
also led by Carl June, MD, the Richard W. Vague Professor in Immunotherapy in the department of Pathology and Laboratory Medicine, only supports this science further. Bold swings that pay off, after all, are what this group excels at.
The CAR T therapy known as CTL019 when it was developed by June and his lab and
is now known as Kymriah, is the first FDA approved CAR therapy, giving patients with advanced leukemias who had little to no options left, another chance.
To move ahead in the GBM space, it was clear CAR T cells had to be engineered to go after more targets than just one. Past studies have shown that targeting interleukin-13 receptor alpha 2 (IL13Rα2), another antigen molecule expressed in GBM tumors, with CARs could elicit responses in animals and patients. It was time to double up.
Combining Forces to Increase Cell Coverage.
Unlike past designs that target one antigen, the newer CAR T cells
expands its abilities by doing just that, targeting two — EGFR and IL-13Rα2.
“Because of the tumor heterogeneity in GBM, there are pockets that will express target A and pockets that will express target B,” O’Rourke said. “We’re hoping we will get more cell coverage by adding a molecule in CAR T cells that express both binding domains so we can hit more cells.”
A significant sponsored research agreement with Tmunity that began last September has fueled preclinical studies and design of a clinical trial to be conducted at Penn Medicine with a multivariant CAR. Anywhere from 15 to 20 patients with recurrent GBM are expected to be enrolled by this time next year or soon after.
It’s just the beginning, O’Rourke said, of a series of collaborative investigations with Tmunity and likely other industry partners that will allow them to expand the number
of patients and try new approaches. One idea is to pair these types of CARs with other therapies to build up the immune system’s defense against the tumors.
The groundwork is there. Past studies from Penn Medicine showed combining a type of immunotherapy called checkpoint inhibitors with CARs in animal models inhibited brain tumors. Another one from June 2021 showed how bispecific T-cell engagers (or BiTEs) redirected T cells to target antigen-expressing tumors, acting as a helping hand
to fight the tumor.
Similar research has been in play across the field, with other institutions
upping their research on brain tumors, pivoting as new information rolls in.
Today, there are about 30 active clinical trials involving CAR T cells and gliomas.
And since the kickoff of Biden’s Moonshot initiative — which was driven by his son’s
death of GBM — at Penn’s Abramson Cancer Center in 2016, additional dollars have
gone toward brain tumor research, including pediatric GBM, and awareness around
the lack of treatments has only increased.
It’s the kind of momentum O’Rourke and other neuro-oncology teams at Penn wants
to keep up. “There is a lot of incredible science going on that has broad scientific impact beyond GBM,” O’Rourke said. “We want to work with many groups, both in industry and academia, to supercharge that into clinical translation. It will take time, but we hope to shorten that lag time by starting off with this new study, which I think is going to be a big advance over the previous work.”
Editor’s Note: O’Rourke is a scientific collaborator with Tmunity. He receives sponsored research funding from Immunity and, as an inventor of licensed technology, he may receive additional future financial benefits under licenses granted by Penn to Immunity. The University of Pennsylvania also holds equity and licensing interests in Immunity.
Donald M. O’Rourke, MD – Neurosurgeon, Penn Medicine.
Donald M. O’Rourke, MD, – Search (bing.com)
I was diagnosed with brain cancer at 25. I try to be resilient when things are uncertain.
The author. Courtesy of Kelsey Day© Provided by INSIDER
Story by insider@insider.com (Kelsey Day)
I was diagnosed with brain cancer when I was 25.
At first, I had to come to terms with the loneliness of the diagnosis and treatment.
I moved past the pressure of wanting to be perfect or having it all together.
I’ll never forget the morning I unenrolled from my 401(k) as a 25-year-old.
In retrospect, I laugh at the absurd symbolism of this seemingly minor act of acceptance.
The “American dream” of retirement was swept under the rug for me as I contemplated my likelihood of living past 12 months. I had been diagnosed with brain cancer three weeks earlier, and uncertainty filled me as I waited for the pathology results.
My brain cancer, a pandemic, the climate crisis — they’re all rooted in uncertainty. Uncertainty is inevitable. So is disruption. Despite this, resilience is possible.
Here’s how I’ve learned to be resilient amid the disruption.
First, I made friends with my loneliness
During personal challenges, it’s often said that “you’re not alone.”
This statement is meant to be consoling, but I’d like to counter that
during some life events, such as a cancer diagnosis, we are, in fact, deeply alone.
I don’t say this to strike fear. When I feel the pulsating sting in my skull where the surgeons operated, it’s me and only me who feels the sensation.
When I sit in a room full of cancer patients who are all 40 years older than me,
I have only myself to bear witness. I let my loneliness take up space, and in return,
I have learned to trust myself in the process.
Related video: How to make cancer treatment more bearable – YouTube
With this process, however, I try to keep in mind that resilience is not isolation,
quite the contrary. Making friends with my loneliness hasn’t meant denying help
or support in times of change — believe me, I’ve needed it.
It means I’ve found peace with my unique circumstances.
It means I’ve kept inside jokes to myself to find humor in the worst of times.
And above all, it means I see my aloneness as a superpower.
I found comfort in my routine, and then I broke it
Two weeks after I had brain surgery, I went back to work part time.
Looking back, I’m astounded at how quickly I pushed myself to return.
But now, almost a year later, I see my desire to return to work so quickly as an attempt to restore my daily rituals. Returning to my routine allowed me to experience the pleasure of the mundane. I felt grounded in my simple tasks — even though nothing was quite the same.
Carrying on with small activities I could control helped me mitigate the overwhelming uncertainty of what was not in my control. These early stages of healing helped me be more resilient by building habitual, manageable intentions.
After holding on to the familiar, I leaned into the disruption and severed that routine.
For me, after the first few months postoperative, I started to feel stagnant. I had just experienced this extraordinary life event, but with the change, I felt as if I had to change, too.
To me, being resilient also means unraveling the familiar. For me, this meant leaving my environment and traveling alone. It also meant doing things as simple as going to a new restaurant, making friends, or finding creative hobbies. When I stepped out of the familiar, I allowed room for transformation. Leaning into change has grown my self-confidence and improved my resilience when life doesn’t go as planned.
Finally, I redefined and released
Everyone has a story, and we all have opportunities in life to redefine those stories.
I decided I was the narrator of my own life. Even when the plot twisted and turned,
I shifted my perspective and saw the challenges or traumas I’d faced as the climax
of another chapter. But I also remembered more chapters were possible if I had the
courage to take ownership of those stories.
When I sought resiliency, redefining the stories helped
me affirm my experiences without keeping me stuck in them.
Once I took control of the narrative, I released my desire to be perfect and
the pressure to have it all together. I wanted to be known as strong and resilient,
but being strong and resilient doesn’t mean I won’t feel the pain of uncertainty.
I allow myself to hold these experiences kindly and just be.
I know my path to resilience may not be the same as someone else’s.
Healing, as commonly stated, is not linear. Despite my eventual positive prognosis —
we are still in the watch and wait period to see if it grows — fighting my way back from
a cancer diagnosis in my 20s has been life-altering. I don’t know what healing will look
like for others, but I do know we have the power to be resilient.
Woman correctly diagnoses herself with leukemia – using GOOGLE | Bing video
Chloe-Leigh Todd, 22, pictured above, was told she had tonsillitis by her GP after suffering with a sore throat (pictured bottom inset). The stay-at-home mum from Gateshead, Tyne and Wear, was diagnosed with leukaemia in June 2020 and underwent six rounds of chemotherapy before getting a transplant in October 2020 (pictured right)
The stay-at-home mum from Gateshead, Tyne and Wear, was concerned her symptoms were not getting any better and managed to have a face-to-face appointment in June where she went for a blood test.Her results came back abnormal and she went straight to the hospital where she was told she had leukaemia and was just ‘weeks away from death’. Now she has been cancer-free for two years and is no longer having treatment, although still suffers with some side effects.
Miss Todd said: ‘Everyone knows their own body and I just knew it was something serious. ‘The doctors were putting it down to other things but I was adamant they were wrong.
‘I googled my symptoms – night sweats, fatigue, bruising and so on – and leukemia came up as the first search result.
‘I checked and saw I had every symptom on the whole website –
everyone had thought I was crazy when I said it, but I knew I wasn’t.
‘When the doctor confirmed it, I thought I was going to die.
‘I was happy to have the diagnosis, but I went numb, hearing it is a big difference.
‘The doctors told my mum in a different room; she broke down and I could hear
my mum screaming.’
Chloe-Leigh Todd, pictured receiving treatment (left) Googled her symptoms,
A woman who was told she had tonsillitis correctly diagnosed herself with leukemia – using Google. – Search (bing.com)
Chloe-Leigh Todd started experiencing a sore throat and general illness. One month after starting to feel unwell Chloe had a telephone appointment with her GP and was told she had tonsillitis. After googling her symptoms – which included vomiting, night sweats, and weight loss – Chloe realized she was suffering from textbook leukemia symptoms.
Chloe managed to have a face-to-face appointment where she went for a blood test.
Her results came back abnormal and she went straight to the hospital where she was told she had leukaemia. Now she has been cancer-free for three years and is no longer having treatment, although still suffers with some side effects.
Chloe Todd, 22, a stay-at-home mum from Gateshead, Tyne and Wear said:
“Everyone knows their own body and I just knew it was something serious.
“The doctors were putting it down to other things but I was adamant they were wrong.
“I googled my symptoms – night sweats, fatigue, bruising and so on – and leukemia came up as the first search result. “I checked and saw I had every symptom on the whole website – everyone had thought I was crazy when I said it but I knew I wasn’t.
“When the doctor confirmed it, I thought I was going to die. In June 2020 after being told she had tonsillitis; Chloe managed to get herself a face-to-face appointment with a doctor because she thought they were wrong.
The mum of one had been suffering from a sore throat, night sweats, vomiting and
weight loss since February and was getting concerned so searched online for answers. After having a blood test, Chloe was called by the doctors and told her results were abnormal and called into the hospital where she was told she had leukemia and was “weeks away from death”.
The following day Chloe was sent to the Newcastle Freeman Hospital to start treatment. She said: “I had a bone marrow biopsy and told I was weeks away from death.
“The cancer was everywhere in my blood. Doctors told me they didn’t know if chemotherapy would help but they were willing to give it a try.”
Chloe endured six rounds of chemotherapy which eradicated most of the cancer, leaving her more optimistic. In September 2020, Chloe was put on the Anthony Nolan register in search for a bone marrow donor. Straight away the hospital found a 100% match in a 27-year-old boy, and she had the transplant in October 2020.
This is done by transferring stem cells from one person to another, replacing damaged blood cells with healthy ones. After a successful operation, Chloe underwent another bone marrow biopsy to make sure her new cells had worked – later receiving the news she was cancer free.
Leukemias symptoms – skin looking pale or “washed out” – tiredness – breathlessness – losing weight without trying – frequent infections – having a high temperature, and feeling hot or shivery (fever) – night sweats – easily bruised skin, I was told I had tonsillitis — I correctly diagnosed myself with leukemia (nypost.com)
BONUS: The Best Diet for Healthy Aging – YouTube
Her belly was getting bigger and bigger – doctors were
shocked when they saw what came out (msn.com)
A dermatologist went viral on TikTok for sharing why airline pilots have a higher
risk of skin cancer. Here’s how to protect yourself from UV rays in the sky. (msn.com)
When I heard my son had a benign brain tumor at 11,
I thought that meant it was harmless. I was wrong. (msn.com)
College student got a headache on spring break. She was hemorrhaging from a tumor.
Doctors dismissed a 28-year-old’s chest pain as a pulled muscle.
She had a rare terminal cancer growing in her heart. (msn.com)
CNN Anchor Kasie Hunt’s Brain Tumor Removed at Penn Medicine
Woman Declares Her Surgeon ‘Wasn’t Paying Attention’ As She Realised –
Her Brain Tumour Had Grown Back Under Their Watch | Media Drum World