Vulnerability Identified for Subtypes of Glioblastoma

Excerpt:

“Glioblastoma, the most common and aggressive form of brain cancer, typically fails to respond to treatment or rapidly becomes drug resistant. In a paper published online in the journal Cancer Cell on November 30, University of California San Diego School of Medicine researchers identified a strategy that pinpoints a genetically distinct subpopulation of patients with glioblastoma that is particularly sensitive to drugs like cilengitide that target a cell adhesion receptor known as integrin αvβ3.

“Cilengitide was developed based on early studies by David Cheresh, PhD, Distinguished Professor of Pathology at UC San Diego School of Medicine, and colleagues who demonstrated that αvβ3 expression was linked to the progression of glioblastoma. The  was tested in clinical trials but production was halted in 2014 when it failed to show significant improvement in overall survival among participants during phase III trials.”

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Cancer Drug Starts Clinical Trials in Human Brain-Cancer Patients

Excerpt:

“A drug that spurs cancer cells to self-destruct has been cleared for use in a clinical trial of patients with anaplastic astrocytoma, a rare malignant brain tumor, and glioblastoma multiforme, an aggressive late-stage cancer of the brain. This phase Ib trial will determine if the experimental drug PAC-1 can be used safely in combination with a standard brain-cancer chemotherapy drug, temozolomide.

“The trial is approved for patients who have seen their cancer progress after first-line therapy. This is an extension of an ongoing human phase I clinical trial of PAC-1 alone in patients with various late-stage cancers. Phase I  are designed to test the safety of new drugs in human patients.”

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Super Caregiver: Allison Brighton Tracks Down the Best Treatment Possible for Her Husband’s Brain Tumor


California resident Allison Brighton is the founder of a Facebook group that unites people dealing with glioblastoma (GBM) so they can discuss their experiences and receive support from each other. Here, she shares her husband’s GBM story.

Bill and I met on June 19, 1993. We fell in love at first sight, got married 5 months later, and had our first son on June 19; one year after we met. On February 16, 1997, our second son Austin was born, then on June 3, 1999, our last son Tyler was born. Happy times; we were so happy.

We decided we were done having children; three sons was enough. We had them in tee-ball, football, bowling, Disney drawing classes, and more—anything that a boy could do. They were like three little munchkins, and we couldn’t love them enough!

The years passed by, and in 2001 Billy said his eyes were giving him problems. “Huh,” I thought, “then go to an optometrist.” So he went, and they found nothing. “Ok,” we both thought, “weird.”

Then, two months later, Bill said again that his eyes were acting strange, and he was getting headaches at this point. So he went back to the optometrist and told the doctor, “something is not right.”

The doctor examined Billy again and said, “There’s nothing wrong with your eyes, so I recommend you get an MRI.” So, our primary care doctor ordered an emergency MRI. At this point Bill and I were starting to get worried. We went to get his MRI and then headed home to wait for the results, which would be days away.

Bam! The phone rang at about 7:30 that night, and it was Bill’s doctor. The doctor went on to tell Bill that he had a tumor the size of a baseball…and needed to have it removed immediately. We both were in shock. There are no words to describe the feeling.

A couple days later, Bill went in for a craniotomy to remove the tumor tissue, with our family and friends joining us at the hospital.

Now, Billy’s grandmother had brain tumors, but they were never cancerous, so she continued to lead a pretty normal life. And we all assumed that Bill’s tumor was the same kind as his grandma’s—not cancer.

Well, Bill was in surgery for hours; I can’t even remember how long his surgery was. But when the surgeon comes out with a nurse at his side, you know something’s not right.

The doctor started telling us how well Bill did in surgery and how he was now resting in the ICU. “Ok,” I thought, “but what was the tumor?” The doctor went on to tell us that Bill had a malignant brain tumor, grade 4 GBM. (They later sent a tumor sample out for a second opinion to a location in San Francisco, which confirmed it was GBM).

The doctor told us that Bill had about six months to live. I fell on the floor, literally, started vomiting, and my two sisters-in-law had to help me to the bathroom. At that point, I blacked out.

When I came to, I had to go see Billy. I had told Billy I would be the first face he’d see when he came out of surgery. But I just couldn’t; his parents went in first, then my father, and then me.

When I entered the room to see Bill, he stared at me with his blue eyes and asked, “do I have cancer?” We had been told by the doctor not to tell Billy he had cancer because he needed his strength to recover from the surgery.

I tried lying, but I just couldn’t. I told him that, yes, he had brain cancer, and I crawled up into his bed and cried with him.

Three days later, Bill was sent home with hospice services. At this point, he didn’t seem to need hospice care because he was walking and talking just like normal. So, I didn’t call them.

With all of this happening so quickly, there was no time for any extra research. Bill had his surgery at St. Bernardine’s in San Bernardino, California. They took out 90 percent of the tumor and said it was deep-seated. But we were lucky to have a great doctor, Dr. Rowe, perform the surgery.

When we got home from that surgery, my mother, my dad, Bill’s dad, and I began researching like mad. On the internet, making phone calls—anything we could do to find a doctor to ensure that Billy would live. We researched and researched! As you could imagine, we had never heard of GBM until Bill was diagnosed. But we weren’t going to settle for anyone, and we wanted the best for Bill.

My research lead me to three other doctors, and I made appointments with the two that were here in Los Angeles. Dr. Cloughesy at UCLA wanted to reopen Billy’s tumor site and place chemo wafers inside. Dr. Black at USC wanted to reopen his brain and take out more tissue. We didn’t want to do another surgery, so neither of these options would work for us.

Next, we wanted to see the third doctor I had found: Dr. Friedman at the brain tumor center at Duke in North Carolina. So our friends started raising money for us to travel to help save Bill’s life. They did raffles, car washes, silent auctions, and even had a softball tournament with all the bells and whistles! So many people reached out; it was incredible. We raised so much money, and it was put into a Fight For Life Fund for Bill. We’re very thankful for everyone’s help.

Then, thanks to the fundraising efforts, Bill’s dad, myself, and Billy boarded the plane, and off we went, not knowing what to expect. We touched down in North Carolina, and then we were off to meet Dr. Friedman.

As we waited for the doctor to meet with us, we were all nerves, of course. But when he walked in, I swear I knew that second that he was the doctor for us. He was so passionate and caring, and he seemed absolutely concerned for Bill. He was the first doctor to say, “let’s kill this beast before it grows back.” And that was all it took.

We decided that Dr. Friedman would prescribe Bill his chemo and radiation. Then we would fly home and go to Bill’s oncologist to administer what Dr. Friedman prescribed. Our two doctors worked beautifully together. Bill was bombarded with Temodar, CPT-11, some additional chemo drugs, Celebrex, and radiation.

Dr. Friedman said that Bill was as healthy as a horse and could handle the amounts of the chemo drugs he was prescribing. So Bill went through the whole chemo and radiation process with almost no symptoms. He did have some vomiting and sickness, and he took some time off when needed. But he was so young, at age 30, and very fit, so the doctor had no problem with him continuing to work, for the most part.

At one point, I did have to put my foot down and tell the doctor that Bill couldn’t take the last treatment of CPT-11 because he was on death’s door; he had lost 40 lbs. in one week. So we didn’t do it.

See, doctors work for patients, not the other way around, and I made sure that our doctors knew this. I was very young (28 years old) and very aggressive and pushy when it came to Bill’s life. He had to see our boys grow up.

As you can imagine after all those treatments, Billy’s first MRI after treatment showed necrosis—dead tissue at the site of the removed tumor. But the tumor hadn’t grown back, so they did not put Billy on any more treatments, but scheduled an MRI every 3–6 months.

The idea of no more treatments was scary. “Yikes,” I thought, but I had to believe in the doctor and in Billy. Billy never complained about being sick; as a matter of fact, he said he knew he would beat it. He was very positive never negative. That’s just Bill’s nature. He did have some eye issues that remained, but nothing that he couldn’t adjust too. He’s a miracle to me.

So we just continue life as normal as normal was, and after 2.5 years, Dr. Friedman said he was in remission (cancer free). Wow, we couldn’t have asked for anything better in life. We were so happy. But the doctor did say Bill would be sterile after all that chemo. Fine with us.

Well, on April 5, 2004, I gave birth to a beautiful baby girl. She was a miracle baby. We couldn’t believe we finally had a girl. She was so precious and beautiful it was undeniable to me that Bill’s cancer was gone and he would live to see our four kids grow up.

As the years passed, the anxiety started to go away, the MRIs stopped, and we were just a normal family again. Don’t get me wrong; it was the hardest thing I have ever had to go through. Over the years, I have had a few midlife crises myself from PTSD, but Billy continues to support me in any way he can. In some ways I feel I’m not good enough for him. He beat the hardest cancer in the world, and I have midlife crisis on my plate. Life is not easy!

It sucks when a loved one becomes sick with cancer. I lost my dad to lung cancer seven years ago. Life throws so many obstacles at you, but if you take it with a grain of salt and stay positive, things always work out—except if cancer is involved.

For a patient and loved one, you need to remember it’s two individuals going through a different process. Bill’s path was much different from my path of being his wife.

You also need to take all the available information in account. We learned so much through our journey, and I wanted to share this story with others to give them hope. There is always hope.

P.S. Our boys are now 23, 20, and 18, and our girl is 13. Bill and I live in Murrieta, California, and have been married almost 24 years. I work part time, and Bill has been with the same company for 30 years. We live a peaceful life and are enjoying watching our children grow into adulthood.

***

Super Patients are cancer survivors who learned to be more engaged in their own care. Cancer Commons believes every patient can be a Super Patient or benefit from a Super Caregiver or Super Advocate. We hope these stories will provide inspiration and hope for your or your loved one’s own treatment journey.


Reengineering Immune System Cells to Fight Glioblastoma


Glioblastoma multiforme (GBM) is a diagnosis to fear. The search for better treatments is ongoing, but with little to show since the U.S. Food and Drug Administration (FDA) approved the use of the chemotherapy drug temozolomide with concurrent radiation 12 years ago, based on data showing modest improvement in patients’ survival.

By now, a new cancer treatment approach known as CAR T-cell therapy is famous for its remarkable success in certain blood cancers. But there is not yet much to report for CAR T-cell therapy in solid tumors such as GBM. Still, the treatment may hold promise, and this post will discuss the possible applicability of CAR T-cell therapy in GBM.

What is CAR T-cell therapy?

CAR T-cell (chimeric antigen receptor-engineered T-cell) therapy is based on early work of Israeli scientist Zelig Eshhar conducted in the laboratory of the renowned T-cell treatment pioneer Steven Rosenberg at the National Institutes of Health (NIH). They first prepared CAR T cells to target melanoma, and the treatment has since been shown to work amazingly well in certain types of blood cancer, including B-cell leukemia, and lymphoma. Continue reading…


Reengineering Immune System Cells to Fight Glioblastoma

Glioblastoma multiforme (GBM) is a diagnosis to fear. The search for better treatments is ongoing, but with little to show since the U.S. Food and Drug Administration (FDA) approved the use of the chemotherapy drug temozolomide with concurrent radiation 12 years ago, based on data showing modest improvement in patients’ survival.

By now, a new cancer treatment approach known as CAR T-cell therapy is famous for its remarkable success in certain blood cancers. But there is not yet much to report for CAR T-cell therapy in solid tumors such as GBM. Still, the treatment may hold promise, and this post will discuss the possible applicability of CAR T-cell therapy in GBM.

What is CAR T-cell therapy?

CAR T-cell (chimeric antigen receptor-engineered T-cell) therapy is based on early work of Israeli scientist Zelig Eshhar conducted in the laboratory of the renowned T-cell treatment pioneer Steven Rosenberg at the National Institutes of Health (NIH). They first prepared CAR T cells to target melanoma, and the treatment has since been shown to work amazingly well in certain types of blood cancer, including B-cell leukemia, and lymphoma.

Many improvements in CAR T-cell engineering have been made since its initial development, but the concept remains, in essence, the same: There are many types of immune cells collectively named T cells, but some of them are of the “cytotoxic” variety. Cytotoxic T cells have the useful function of killing cells that possess some proteins (antigens) perceived as foreign, like viral or bacterial proteins. Cancer cells may express some antigens (neoantigens) that are not found on normal cells, and should, in principle, be recognized and killed by cytotoxic T cells. However, this does not always happen because cancers have many different ways to either avoid recognition by T cells, or to inactivate T cells by creating an immune system-suppressing tumor microenvironment.

The general idea behind CAR T-cell therapy is to equip T cells taken from patients’ blood with a specific receptor that recognizes a particular neoantigen on cancer cells. These modified T cells are then infused back into the patient in the hope that they will destroy cancer cells that express that specific neoantigen.

Challenges for CAR T-cell therapy in solid tumors

There are several reasons why the CAR T-cell approach presents a formidable problem when it comes to solid tumors. First, it is difficult to find antigens that are expressed in cancer cells but not in normal tissues. A protein present in a solid tumor is most often also present in normal tissues and organs. To target it with CAR T cells would be really dangerous; normal tissue could be destroyed along with the tumor, without a chance to be replaced (most solid tissues are not continuously renewed like blood cells).

So what about neoantigens or mutated proteins found on cancer cells only? This is a good idea that has so far produced some promising results in tumors that express certain viral proteins, like HPV in cervical cancer. However, a lot of neoantigens do not present good targets for T cells for reasons that have to do with the details of how immune recognition works.

Lack of good targets for CAR T cells is just the first obstacle. The second one is the fact that T cells often cannot travel to tumors due to impaired tumor vasculature (blood vessel arrangement), and/or heavy tumor stroma (non-tumor cells encasing and blocking access to tumor cells). The third problem is that tumors actively develop mechanisms to avoid T-cell attack, like new mutations that prevent antigen presentation and immune recognition. Fourth, even if cytotoxic T cells do manage to infiltrate tumors, cancer cells often express certain proteins that directly inhibit them. Cancers also produce proteins that attract inhibitory immune cells of several types, such as regulatory T cells or myelosuppressive cells. Myelosuppressive cells repel and inhibit cytotoxic T cells, including CAR T-cells that have been infused into the body.

Why GBM?

Due to the known problems described above, few clinical trials are actively developing CAR T-cell strategies for treatment of solid tumors. However, among those that are, GBM seems to be disproportionally represented. This is possibly due to the simple fact that nothing else has really worked in GBM. It is also hoped that GBM may have some “unique” antigens that could be targeted safely.

Current CAR T-cell trials in GBM

Late last year, researchers described a case of successful treatment of a GBM patient with CAR T cells targeting a protein known as IL13Rα2, which is found in GBM cells. The patient, who had several tumors in the brain, received multiple injections of CAR T cells into the cavity left by a resected (surgically removed) tumor, and also into the brain ventricular system to ensure delivery to un-resected tumors. This worked remarkably well for over 7 months, but new tumors unfortunately developed and were successfully treated with more CAR T-cell infusions, this time also into the cerebrospinal fluid. Responses to treatment were also observed in some other patients enrolled in the same ongoing clinical trial, which is run by City of Hope in California (NCT02208362).

Other GBM CAR T-cell trials target EGFRvIII, a particular version of the EGFR protein that is found in GBM. EGFRvIII is not a universal target in GBM because it is expressed in less than a third of patients’ tumors. The other problem is that even if it is found in a given tumor, its presence within that tumor may not be uniform; some (many?) of the cancer cells in a tumor that tests positive for EGFRvIII overall do not have the protein, and will therefore avoid recognition by CAR T cells directed towards EGFRvIII.

Recently published results document these anticipated problems, as well as new problems with EGFRvIII-targeting CAR T cells. In a study conducted at the University of Pennsylvania (NCT02209376), 10 patients with EGFRvIII-positive tumors received one intravenous infusion of CAR T cells targeting EGFRvIII (versus direct injection into the tumor used in the City of Hope trial mentioned above). Seven of the patients had their tumors resected after infusion of CAR T cells, which allowed for analysis of changes induced by the modified T cells. Loss of the EGFRvIII antigen after CAR T-cell treatment was seen in five of the seven resected tumors. This could be due to successful killing of EGFRvIII-positive cells, or it could be the result of loss of EGFRvIII expression by tumor cells.

Unfortunately, CAR T-cell treatment also created an immune system-suppressive environment in the tumors of the treated patients. This manifested as increased expression of some proteins known to dampen immune response (including IDO and PD-L1) and recruitment of cells that inhibit cytotoxic activity of T cells. However, it should be possible to overcome this type of resistance by adding a relevant immune checkpoint drug to CAR T-cell treatment.

One of the 10 patients in this trial was alive at 18 months post-treatment. Overall, these data indicate that CAR T cells infused intravenously do travel to GBM tumors, but also that the tumors employ a variety of mechanisms to repel the immune attack.

At least three more ongoing clinical trials are investigating CAR T cells that target EGFRvIII. Additionally, a new target for CAR T cells in GBM is now being explored: CMV, a virus thought to be associated with and suspected to contribute to development of GBM. One trial (NCT02661282) will administer up to four intravenous infusions of CMV-specific CAR T cells to patients receiving temozolomide.

However, there is a potentially serious problem with CMV-directed CAR T cells: Even though many publications have reported that CMV is found in practically all GBM tumors, a number of publications have failed to confirm this. While some GBM patients are seropositive for CMV antibodies in their blood (meaning that they have been infected with the virus at some point in their lives, as have many healthy people), the potential absence of CMV from tumor tissues may spell failure for CAR T cells targeting CMV. Time will tell.


These Experimental Treatments Target Brain Cancer Like John McCain’s

Excerpt:

“For patients, like Sen. John McCain (R-Ariz.), who develop aggressive brain cancer, the first-line treatment is almost always radiation and chemotherapy. But if the glioblastoma recurs, and it almost always does, what then?

“The answer could be one of the many experimental treatments being tested in clinical trials across the country. Depending on how you count them, there are dozens or hundreds of trials, many of which are focused on immunotherapy, a new approach designed to spur the immune system to attack cancer.”

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Brain Cancer Like McCain’s Has Hundreds Of Experimental Therapies (With Little Success)

Excerpt:

“The type of brain cancer John McCain was diagnosed with July 14, glioblastoma, is among the most difficult cancers to beat. The reasons it’s so hard to treat, as I discussed previously, include its location, its genetic diversity within and across patients, and its aggressiveness. Glioblastoma (GBM) is also among the most devastating cancers in its effects since it attacks the brain, the control center for the body’s functions and the essence of an individual’s personality. Even people who survive rarely remain the same person after their treatment.”

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Combining CAR T Cells With Existing Immunotherapies May Overcome Resistance in Glioblastomas

Excerpt:

“Genetically modified “hunter” T cells successfully migrated to and penetrated a deadly type of brain tumor known as glioblastoma (GBM) in a clinical trial of the new therapy, but the cells triggered an immunosuppressive tumor microenvironment and faced a complex mutational landscape that will need to be overcome to better treat this aggressive cancer, Penn Medicine researchers report in a new study this week in Science Translational Medicine.”

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“Trojan Horse” Tested in EGFR-Amplified Glioblastoma

Excerpt:

“Investigators are seeking to determine whether the addition of ABT-414, an antibody–drug conjugate, to concomitant radiotherapy and temozolomide will improve the survival of patients with newly diagnosed glioblastoma multiforme (GBM) with epidermal growth factor receptor (EGFR) amplification.

“The phase IIb/III Intellance1 trial (NCT02573324), which is currently recruiting participants, seeks to randomize approximately 720 patients to a 2-phase experimental arm with ABT-414 or to a placebo comparator arm. Participants in the experimental arm will receive intravenous ABT-414 combined with standard therapy of oral temozolomide and radiation in a chemoradiation treatment phase, followed by ABT-414 plus oral temozolomide during an adjuvant treatment phase. The comparator arm will follow the same regimens, with an intravenous placebo to replace ABT-414.”

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