Brain cancer is the growth of abnormal cells, or tumors, in the brain that can disrupt neurological functions. These tumors may originate in the brain or spread from cancers elsewhere in the body. While treatment has traditionally involved surgery, radiation, and chemotherapy, immunotherapy offers a different strategy. Immunotherapy is a treatment that uses the body’s immune system to fight cancer. It enhances the immune system’s ability to recognize and eliminate cancerous cells, overcoming the tactics they use to hide from or deactivate immune cells.
The Unique Challenge of the Blood-Brain Barrier
The brain is protected by a highly selective border called the blood-brain barrier (BBB). This barrier consists of tightly packed endothelial cells lining the brain’s capillaries. It creates a physical obstruction that regulates the passage of substances from the bloodstream into the brain, shielding it from toxins and pathogens.
The BBB acts as a security system, screening all incoming traffic from the blood. It allows necessary molecules like glucose to pass through while denying entry to most others. This is achieved by tight junctions that seal the space between cells and transport proteins that act as gatekeepers, moving nutrients in and waste out.
This protective mechanism poses a substantial obstacle in treating brain tumors. Many chemotherapy drugs cannot cross the BBB to reach the tumor in sufficient concentrations. The barrier also restricts the movement of immune cells, such as T-cells, from the bloodstream into the brain.
The BBB complicates the delivery of therapeutic agents to brain cancer cells. Researchers are exploring strategies to bypass this barrier, such as designing drugs to trick transport proteins or using focused ultrasound to open it temporarily. Overcoming this challenge is a focus in developing effective treatments, including immunotherapies that require immune cell access to the tumor.
Types of Brain Cancer Immunotherapy
Checkpoint Inhibitors
Cancer cells can exploit natural “checkpoints” that regulate immune activity to survive. These checkpoints are molecules on immune cells that must be activated or inactivated to start an immune response. Cancer cells produce proteins that bind to these checkpoints, applying a brake on the immune system. Checkpoint inhibitors are drugs that block these suppressive signals. By binding to checkpoint proteins on T-cells (like PD-1) or corresponding proteins on tumor cells (like PD-L1), these drugs release the brakes, allowing T-cells to recognize and attack the cancer.
CAR T-cell Therapy
Chimeric antigen receptor (CAR) T-cell therapy is a personalized treatment. The process begins by collecting a patient’s T-cells from their blood. In a lab, these cells are genetically engineered to produce specific receptors on their surface, known as CARs, designed to recognize a specific protein (antigen) on the patient’s tumor cells. After millions of these modified T-cells are grown, they are infused back into the patient. The newly equipped CAR T-cells then seek out, attach to, and destroy cancer cells throughout the body.
Cancer Vaccines
Unlike preventative vaccines, cancer vaccines are therapeutic, designed to treat an existing cancer. A therapeutic brain cancer vaccine stimulates the patient’s immune system to recognize and attack tumor cells by introducing tumor-associated antigens into the body. These antigens can be proteins from the tumor’s surface or the patient’s own deactivated tumor cells. One approach involves isolating a patient’s dendritic cells, which present antigens to T-cells. These dendritic cells are exposed to tumor antigens in a lab before being re-injected to teach the immune system what the cancer cells look like, triggering a targeted response.
Oncolytic Virus Therapy
Oncolytic virus therapy uses viruses modified in a lab to selectively target and kill cancer cells while leaving healthy cells unharmed. Once inside a cancer cell, the virus replicates, causing the cell to burst and die. The destruction of the cancer cell releases new virus particles to infect other nearby tumor cells. This process also alerts the immune system, as the bursting cells release tumor antigens. This helps the immune system recognize and attack the remaining tumor, creating a broader anti-cancer response.
Immune-Related Adverse Events
Activating the immune system to fight cancer can sometimes lead to it mistakenly attacking healthy tissues, known as immune-related adverse events (irAEs). Because immunotherapy boosts the overall immune response, it can disrupt the normal checks that prevent autoimmunity. This can result in inflammation in various parts of the body.
Common irAEs can affect different organ systems, including skin toxicities like rashes and itching. Colitis, or inflammation of the colon, can cause diarrhea, while hepatitis is inflammation of the liver. Endocrinopathies, problems with hormone-producing glands, can also occur, and all events require careful monitoring.
For brain cancer patients, neurotoxicity, which is inflammation in the brain and nervous system, is a concern and can cause confusion, headaches, or seizures. Another serious condition, especially with CAR T-cell therapy, is cytokine release syndrome (CRS). This happens when immune cells release a flood of inflammatory molecules called cytokines, causing high fevers and blood pressure drops. Medical teams manage these side effects with medications like steroids to suppress the immune system.
Patient Selection and Treatment Considerations
Determining if a patient is a candidate for immunotherapy involves evaluating several factors. The specific type and subtype of the brain tumor are primary considerations. For example, the characteristics of a glioblastoma differ from a metastatic tumor, influencing how each interacts with the immune system.
Biomarkers help predict a patient’s response to certain immunotherapies. For checkpoint inhibitors, the level of PD-L1 expression on tumor cells is an indicator; higher expression can make the tumor a better target. Another biomarker, tumor mutational burden (TMB), measures the number of mutations in a tumor’s DNA. A high TMB can make the cancer more visible to the immune system.
Many advanced immunotherapies for brain cancer are available primarily through clinical trials, which determine the safety and effectiveness of new treatments. Participation may provide access to therapies not yet widely available. The decision to pursue immunotherapy is made with a medical team, considering the patient’s health, tumor characteristics, and the risks and benefits.
Combination Therapy Approaches
To improve patient outcomes, researchers are combining immunotherapy with other standard cancer treatments. The rationale is that different therapies can work synergistically, where the combined effect is greater than the individual treatments. This allows for a multi-pronged attack on the tumor.
A common combination is immunotherapy with radiation therapy. Radiation damages the DNA of cancer cells, causing them to die and release tumor antigens. These antigens act as a signal, making the tumor more recognizable to T-cells. When followed by a checkpoint inhibitor, the immune system can mount a more effective attack on remaining cancer cells.
Immunotherapy is also combined with chemotherapy and targeted therapies. Some chemotherapy drugs can kill cancer cells and reduce suppressive immune cells in the tumor microenvironment. Combining this with an immunotherapy that boosts T-cell activity can create a more favorable anti-tumor response. The goal of these strategies is to overcome treatment resistance and improve long-term survival.