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.


Vaccines Based on Immunotherapies Being Tested in Phase 2 Trials in Brain Cancer

Excerpt:

Immunomic Therapeutics has entered an exclusive licensing agreement with Annias Immunotherapeutics for the rights to use Annia’s intellectual property regarding an immunotherapy based on antigens of cytomegalovirus (CMV). Both companies are developing new approaches for generating vaccines for cancer.

“Under the new licensing agreement, Immunomic will be able to combine LAMP-Vax, its investigational nucleic acid-based immunotherapy platform, with Annia’s CMV immunotherapy platform. Duke University’s John H. Sampson, MD, PhD, and Duane A. Mitchell, MD, PhD, developed this platform, which was later licensed to Annias.”

Go to full article.

If you’re wondering whether this story applies to your own cancer case or a loved one’s, we invite you to use our ASK Cancer Commons service.


Vaccine/Chemotherapy Combination Improves Survival in Glioblastoma

Excerpt:

“Cytomegalovirus (CMV)-targeted vaccination plus high-dose chemotherapy with temozolomide can lead to long-term progression-free survival (PFS) and overall survival (OS) in patients with newly diagnosed glioblastoma (GBM), according to a new study published in Clinical Care Research.

“Despite surgical resection, high-dose radiation, and chemotherapy with temozolomide, GBM patients typically survive a median of 15 months. CMV proteins are expressed in more than 90% of GBM. ‘Recent evidence has also demonstrated that CMV-specific T-cell immunity can be generated to recognize and effectively kill autologous GBM tumor cells expressing endogenous levels of the immunodominant pp65 antigen, providing compelling support for the development of CMV-directed immunotherapy for the treatment of GBM,’ stated the researchers, led by Kristen A. Batich, MD, PhD, a researcher in the departments of neurosurgery and pathology at Duke University Medical Center in Durham, North Carolina.”

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If you’re wondering whether this story applies to your own cancer case or a loved one’s, we invite you to use our ASK Cancer Commons service.


Study Finds No Evidence of Common Herpes Type Virus in Aggressive Brain Cancer Tissue

Excerpt:

“In a rigorous study of tumor tissue collected from 125 patients with aggressive brain cancers, researchers at Johns Hopkins say they have found no evidence of cytomegalovirus (CMV) infection and conclude that a link between the two diseases, as claimed by earlier reports, likely does not exist.

“The Johns Hopkins team cautioned that studies to confirm this finding are needed to absolutely rule out any role for the common CMV in glioblastoma and other cancers that arise in neurological support cells called glial cells. But they say their study substantially weakens the likelihood of that role.

” ‘We have found no evidence of CMV in these tissues, and if there is no virus, targeting that virus to affect cancer using antiviral drugs or tailored vaccines doesn’t make biological sense,’ says Angelo M. De Marzo, M.D., Ph.D., professor of pathology, oncology and urology at the Johns Hopkins Kimmel Cancer Center.”

Go to full article.

If you’re wondering whether this story applies to your own cancer case or a loved one’s, we invite you to use our ASK Cancer Commons service.


TCR-Ligand koff Rate Correlates with the Protective Capacity of Antigen-Specific CD8+ T Cells for Adoptive Transfer

“Adoptive immunotherapy is a promising therapeutic approach for the treatment of chronic infections and cancer. T cells within a certain range of high avidity for their cognate ligand are believed to be most effective. T cell receptor (TCR) transfer experiments indicate that a major part of avidity is hardwired within the structure of the TCR. Unfortunately, rapid measurement of structural avidity of TCRs is difficult on living T cells. We developed a technology where dissociation (koff rate) of truly monomeric peptide–major histocompatibility complex (pMHC) molecules bound to surface-expressed TCRs can be monitored by real-time microscopy in a highly reliable manner.”


TCR-Ligand koff Rate Correlates with the Protective Capacity of Antigen-Specific CD8+ T Cells for Adoptive Transfer

“Adoptive immunotherapy is a promising therapeutic approach for the treatment of chronic infections and cancer. T cells within a certain range of high avidity for their cognate ligand are believed to be most effective. T cell receptor (TCR) transfer experiments indicate that a major part of avidity is hardwired within the structure of the TCR. Unfortunately, rapid measurement of structural avidity of TCRs is difficult on living T cells. We developed a technology where dissociation (koff rate) of truly monomeric peptide–major histocompatibility complex (pMHC) molecules bound to surface-expressed TCRs can be monitored by real-time microscopy in a highly reliable manner.”


TCR-Ligand koff Rate Correlates with the Protective Capacity of Antigen-Specific CD8+ T Cells for Adoptive Transfer

“Adoptive immunotherapy is a promising therapeutic approach for the treatment of chronic infections and cancer. T cells within a certain range of high avidity for their cognate ligand are believed to be most effective. T cell receptor (TCR) transfer experiments indicate that a major part of avidity is hardwired within the structure of the TCR. Unfortunately, rapid measurement of structural avidity of TCRs is difficult on living T cells. We developed a technology where dissociation (koff rate) of truly monomeric peptide–major histocompatibility complex (pMHC) molecules bound to surface-expressed TCRs can be monitored by real-time microscopy in a highly reliable manner.”