New Guidelines Aim Treat Brain Tumors More Effectively

Excerpt:

“A University of Portsmouth academic has helped to develop European guidelines to treat brain tumours more effectively.

“Geoff Pilkington, Professor of Cellular and Molecular Neuro-oncology and one of the UK’s leading brain tumour specialists, was one of only three UK academics who devised the European Association for Neuro-Oncology (EANO) guidelines on the diagnosis and  of  with astrocytic and oligodendroglial gliomas, including glioblastomas.”

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FDA Awards Orphan Status to Brain Cancer Vaccine Developed at Roswell Park Cancer Institute

Excerpt:

“The U.S. Food and Drug Administration has awarded orphan drug status to a promising immunotherapy vaccine developed at Roswell Park Cancer Institute. The FDA notified MimiVax LLC, a Roswell Park spinoff company, on Aug. 3 that its application for orphan status for SurVaxM as treatment for glioblastoma, a type of brain cancer, had been approved.

“Orphan status is a special designation awarded to encourage innovation and exploration of approaches to treat rare diseases that affect relatively few people. SurVaxM, also known as DRU-2017-5947, is an immunotherapy drug that targets survivin, a cell-survival protein present in most cancers.”

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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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McCain May Benefit from Glioblastoma Tx Advances

Excerpt:

“The announcement that Sen. John McCain (R-Ariz.) has glioblastoma brought to mind the parallels with his longtime colleague and friend, Sen. Edward M. Kennedy (D-Mass.), who also developed a malignant glioma while major healthcare legislation was being considered.

“But treatment options for Kennedy were more limited than they are today. New drugs and devices, and especially new diagnostics and surgical procedures, have become available in the years since Kennedy was diagnosed in May 2008. He survived about 15 months after undergoing surgery followed by chemotherapy and radiation treatments.”

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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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