Cancer Immunotherapy: Principles and Practice

Cancer immunotherapy is a treatment that utilizes a patient’s own immune system to combat cancer by overcoming the defenses cancer cells develop against immune attack. This approach shifts the focus from directly targeting the tumor to empowering the body’s natural defensive capabilities.

The Immune System and Cancer: A Complex Relationship

The immune system performs immune surveillance, a process of identifying and destroying abnormal cells before they become cancerous. This defense involves specialized cells like T cells, which directly kill cancerous cells, and Natural Killer (NK) cells, which provide a rapid response to cellular abnormalities.

For cancer to develop, it must outmaneuver this surveillance. Cancer cells can become invisible to the immune system by reducing or losing the surface proteins, or antigens, that T cells use for identification.

Cancer cells can also actively suppress the immune response. They release signals that inhibit immune cells or express proteins on their surface that act as “off switches” for T cells. This creates an immunosuppressive tumor microenvironment, filled with cells that dampen defensive actions and barriers that block T cells from reaching their targets.

Mechanisms of Action: How Immunotherapies Empower the Immune System

Immunotherapies disrupt the methods cancer cells use to evade the immune system. One strategy releases the natural “brakes” on T cells, which have checkpoint proteins to prevent them from attacking healthy tissue. Cancer cells can exploit this by displaying proteins that bind to these checkpoints, deactivating the T cells. Checkpoint inhibitor therapies use antibodies to block this interaction, allowing the T cells to recognize and attack the cancer.

Another approach involves engineering a patient’s immune cells to be more effective cancer fighters. In CAR T-cell therapy, T cells are extracted from a patient’s blood and genetically modified in a laboratory. They produce specialized Chimeric Antigen Receptors (CARs) designed to recognize and bind to a specific antigen on the patient’s cancer cells.

Therapeutic vaccines work differently from preventative ones. Instead of preventing disease, they treat an existing cancer by introducing cancer-specific antigens to the immune system. This process helps T cells mount a more targeted attack against tumor cells carrying those antigens.

A separate class of therapies uses laboratory-produced molecules called monoclonal antibodies to mark cancer cells for destruction. These antibodies attach to specific proteins on cancer cells, acting like a flag. This makes the cancer cell more visible to other components of the immune system, such as NK cells, which can then eliminate the flagged cell.

Major Categories of Cancer Immunotherapy in Practice

The most widely used immunotherapies are immune checkpoint inhibitors. These drugs, which target proteins like PD-1, PD-L1, and CTLA-4, are approved to treat a wide range of cancers, including melanoma, non-small cell lung cancer, kidney cancer, and bladder cancer.

Adoptive cell therapy is a more personalized approach, with CAR T-cell therapy being the most prominent example. This “living drug” is primarily used for certain blood cancers, such as some types of leukemia and lymphoma, that have not responded to other treatments. Research is ongoing to expand its use to solid tumors.

Therapeutic cancer vaccines are another category. While many are still in clinical trials, one approved example is Sipuleucel-T, used for some men with advanced prostate cancer. It is custom-made by exposing a patient’s immune cells to a protein found on prostate cancer cells.

Monoclonal antibodies are a broad class of therapy. Beyond those used as checkpoint inhibitors, others are designed to target proteins like CD20 on lymphoma cells or HER2 on some breast and stomach cancer cells. This helps the immune system identify and destroy them.

Oncolytic virus therapy uses viruses modified in a lab to preferentially infect and kill cancer cells while sparing healthy ones. As the virus replicates, it bursts the cancer cell, releasing new viral particles and cancer antigens, which can stimulate a broader immune response. One such therapy, T-VEC, is approved for treating certain types of melanoma.

Navigating Immunotherapy Treatment

A patient’s suitability for immunotherapy depends on the specific type and stage of cancer. This evaluation involves biomarker testing, where doctors may measure the level of the PD-L1 protein on tumor cells or assess the tumor’s mutational burden (TMB). Higher levels of either can predict a better response to checkpoint inhibitors in some cancers.

Most checkpoint inhibitors and monoclonal antibodies are given as an intravenous (IV) infusion in an outpatient clinic. These infusions can last from 30 minutes to several hours, with a treatment schedule ranging from every two to six weeks. The duration of therapy can last for months or years, depending on the patient’s response.

Monitoring the effectiveness of immunotherapy can be different from traditional chemotherapy, as responses can be delayed for several months. In some cases, a tumor may appear to grow on an initial scan before it shrinks. This phenomenon, known as pseudoprogression, is thought to be caused by immune cells infiltrating the tumor.

Doctors use a combination of imaging, blood tests, and assessment of the patient’s overall health to gauge the treatment’s success. The goal is to achieve a durable response, where the cancer is controlled for a long period, even after treatment has been discontinued. This reflects the immune system’s ability to “remember” and suppress the cancer.

Understanding and Managing Side Effects of Immunotherapy

Immunotherapy’s side effects differ from those of chemotherapy because they arise from an overstimulated immune system attacking healthy organs and tissues. These reactions are known as immune-related adverse events (irAEs). Their presentation can vary greatly from patient to patient.

Common irAEs can affect almost any part of the body and range from mild to life-threatening. Examples include:

• Skin issues, such as rashes and itchiness
• Gastrointestinal problems like diarrhea or colitis (inflammation of the colon)
• Inflammation of the lungs (pneumonitis), liver (hepatitis), or hormone-producing glands
• Conditions like hypothyroidism or adrenal insufficiency

Early detection and communication are important for managing these side effects. Patients are educated to report any new or worsening symptoms to their healthcare team immediately. Prompt intervention can prevent side effects from becoming severe.

The management strategy for irAEs depends on their severity. For mild reactions, treatment might involve topical creams or simple medications. If side effects are more serious, the healthcare team may pause immunotherapy and prescribe corticosteroids to suppress the immune system. In severe cases, immunotherapy may be stopped permanently and stronger immunosuppressive medications might be required.