Research Corner

Using The Immune System to Target Brain Cancer: Are We There Yet?

          In honor of brain cancer awareness month, this post will discuss a recent study published in Frontiers in Immunology, entitled “Genetically Engineered T-Cells for Malignant Glioma: Overcoming the Barriers to Effective Immunotherapy.” Here is the article and some related content. In the last decade, there have been several public figures with gliomas such as Senator John McCain, Senator Ed Kennedy, and the son of former Vice President Joe Biden, Beau Biden. Recently, there has been greater attention focused on finding novel therapies by using the immune system to improve or bolster the current standard of care. One of the ideas surmised in recent years of research is that combination therapies targeting the complex biology of cancer will give us the greatest chance of successful treatment.

          So what is a glioma? A glioma is a type of brain tumor. In the brain, there are several types of cells. For instance, neurons are the cells that will conduct the electrical impulses in the brain that allow for communication between cells. There are also glial cells, which serve an important role of supporting neurons with nutrients and electrical insulation, thereby nourishing them and protecting them from harm.

glial-cells.gif

          Gliomas arise from these supporting cells, and these cancers are often aggressive in nature (in that they grow quickly), although they tend not to spread to other parts of the body.

A: Magnetic resonance image (MRI) showing a Glioma.  B: Positron emission tomography (PET) image, showing relatively increased cell  metabolism in red and yellow areas. For information on when and how PET scans are used, read more  here.

A: Magnetic resonance image (MRI) showing a Glioma.

B: Positron emission tomography (PET) image, showing relatively increased cell

metabolism in red and yellow areas. For information on when and how PET scans are used, read more here.

          What makes gliomas so problematic? One of the notable aspects of gliomas is their tendency to recur following treatment due to the cancer’s adaptability. There are changes at the genetic level that allow the cell to fly under the radar of the immune system by creating an immunosuppressive environment surrounding the tumor and camouflaging itself--this makes it so that the immune system cannot respond appropriately. Because of the uniqueness of these tumors’ immune behavior and their tendency to recur, many therapies have been aimed at bolstering the role of the immune system in fighting this cancer and keeping patients cancer-free.

          This article discusses how researchers are engineering patients’ own immune cells to target the tumor cells, and how to improve delivery of these cells to the brain, which has been thought to be an immunologically privileged space (while we know that the brain has an immunologic response that differs from other tissues in the body, there is currently much debate in the field about the exact parameters of immune privilege in the brain and spinal cord).

          Let’s get right into some of the interesting questions the article discusses.

          1. What are CAR T-cells and how do they work in treating cancers?

          CAR T-cells are Chimeric Antigen Receptor T-cells. One group of your body’s immune cells is the T cells, which function to coordinate and direct the immune response towards things in your body that should not be there, and thereby eliminate them.

white-blood-cell-formation.png

          A chimeric antigen receptor is an external feature that we engineer into a group of a patient’s immune cells that we gather from a blood sample. After gathering and modifying these immune cells, we grow them into a large quantity and reintroduce them into the patient’s body, with the new receptors allowing them to target the tumor cells. The important idea to keep in mind is that the chimeric antigen receptor that we design in the T-cell is specific for the cancer. Think of this like a lock and a key. For more information, watch this video.

A schematic highlighting the differences between a normal T-cell vs. a CAR T-cell.

A schematic highlighting the differences between a normal T-cell vs. a CAR T-cell.

          2. What are the CAR T-cells looking for on the glioma cells?

          Glioma cells are able to hide themselves using a form of camouflage. In other words, the cancer cells lack immunogenicity. Immunogenicity is the ability to provoke the body to launch an immune response. This presents a problem of selecting the right antigens (or signals) for designing the chimeric antigen receptor. The article summarizes several targets in the Glioma cells. One group looked at targeting a protein that is involved in cell-to-cell adhesion. Another looked at targeting a growth factor receptor called Her2, which is also found in some types of breast cancer. Lastly, a promising trial targeted a molecule called EGFRvIII, which can be thought of as a double edged sword for the Glioma cells as it is only expressed in glioma and not in other tissues, yet it permits the cell to divide uncontrollably and resist the urge to die from radiation and chemotherapy.

          3. What is challenging about getting the CAR T-cells into the brain?

          As previously mentioned, there are difficulties moving certain types of cells and molecules across the blood brain barrier (BBB). The BBB seals the brain off from the rest of the body by having adjacent cells hold on tightly to one another, thereby in most circumstances, it only permits small or fat soluble guests in. An analogy to help understand this would be to think of the brain as a castle and the BBB as its moat. Only in the right conditions will we lower the drawbridge to allow passage inside. The condition that allows our CAR T-cells through is the engineering step we do outside of the body to activate them and allow them to home in to the brain.

This diagram demonstrates how the blood brain barrier allows for selective transport of molecules. Some molecules move using channels and transporters and others are small enough to slip through the tight cell-to-cell adhesions that prevent large molecules and certain cells from crossing from the blood into the brain.

This diagram demonstrates how the blood brain barrier allows for selective transport of molecules. Some molecules move using channels and transporters and others are small enough to slip through the tight cell-to-cell adhesions that prevent large molecules and certain cells from crossing from the blood into the brain.

          4. How effective have the CAR T-cell therapies been in treating cancers and preventing recurrence?

          Selecting the right patients has been shown to influence the success of using the immune system to treat the cancer. The potential for these therapies in early phase trials to improve the care of patients has been demonstrated, not only in terms of survival time, but also in terms of quality of life scores. However at a macro level, the effectiveness of these therapies has been less evident in solid tumors such as gliomas as compared to the successes seen in blood cancers.

          5. What are the safety considerations for immune therapy for glioma?

          The current standard of care of maximal surgical resection, chemotherapy, and radiation, discussed more at length here, results in massive cell death in the tumor AND a non-trivial amount of healthy cell death as well. The brain generally does not respond well to irreversible damage, which forces researchers to balance reaching an effective dose and not causing additional side effects such as brain swelling or excessive cell death. For our immune based therapies, there is a concern for off-target effects as the tighter our T-cells bind to the glioma cells, the increased likelihood that they will also bind tightly to other, non-cancerous tissues. This is a problem that demands creative solutions.

          Looking towards the future of CAR T-cell therapy for gliomas, there are several important areas that warrant future study, such as increasing the T-cell numbers that make it into the brain, accounting for diversity of proteins expressed in glioma cells, and overcoming the immunosuppressive environment of the tumor itself. In conclusion, there is encouraging data from the early phase clinical trials and from animal models that is directing us closer toward therapies to treat the cancer and preventing recurrence.

          Disclaimer : This disclaimer informs readers that the views, thoughts, and opinions expressed in the post belong solely to the author and contributors and not necessarily to the author’s employer, organization, committee, or other affiliations. The content in this post is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read in this post.