Cancer immunotherapy is a treatment approach that harnesses the body’s own immune system to fight cancer. Unlike traditional methods such as chemotherapy or radiation, immunotherapy empowers the immune system to recognize, target, and eliminate cancerous cells. It works by boosting or modifying immune function, allowing for a more effective and precise attack against the disease.
Understanding How Immunotherapy Works
The immune system acts as the body’s defense, constantly surveying for and eliminating abnormal cells, including those that could develop into cancer. This recognition relies on immune cells, such as T cells and B cells, identifying specific markers, known as antigens, on foreign or abnormal cells. T cells, for instance, can detect mutations in cancer cells and destroy them, leaving healthy cells unharmed.
However, cancer cells develop mechanisms to evade this immune surveillance. They can suppress immune cell activity by releasing inhibitory factors or by downregulating tumor-associated antigens, making them harder to recognize. Cancer cells also exploit natural “checkpoint” processes within the immune system, which normally prevent overactivity, by activating these checkpoints to stop immune attack. Tumors can also create an immunosuppressive environment that hinders immune cell activity.
Immunotherapy aims to overcome these evasive tactics. It works by boosting the immune response or by removing the “brakes” cancer cells place on immune cells. This allows the immune system to recognize and attack cancer cells more effectively, leading to tumor destruction.
Key Types of Immunotherapy
Immunotherapy encompasses several distinct strategies, each designed to manipulate the immune system to fight cancer. These approaches leverage different components and pathways to achieve anti-tumor effects.
Checkpoint Inhibitors
Immune checkpoint inhibitors are drugs that block proteins, or “checkpoints,” on immune cells or cancer cells that normally act as “brakes” on the immune response. Two examples are Programmed Death-1 (PD-1) and Cytotoxic T-Lymphocyte-Associated protein 4 (CTLA-4).
PD-1 is a protein on T cells that, when bound by its ligands (PD-L1 or PD-L2) on tumor cells, leads to T cell exhaustion and allows cancer cells to evade detection. Blocking PD-1 or PD-L1 restores the activity of anti-tumor T cells, enabling them to attack cancer.
CTLA-4, another inhibitory receptor on T cells, dampens T cell activation by competing for binding to proteins on antigen-presenting cells. CTLA-4 inhibitors block this negative regulation, promoting more robust T cell activation and proliferation, particularly in the early stages of an immune response.
CAR T-Cell Therapy
Chimeric Antigen Receptor (CAR) T-cell therapy is a personalized treatment that involves genetically modifying a patient’s own T cells to enhance their cancer-fighting abilities. T cells are collected from the patient’s blood and engineered in a laboratory to express a specialized receptor called a chimeric antigen receptor (CAR). This CAR is designed to recognize a particular antigen found on the surface of cancer cells, such as CD19 in certain leukemias and lymphomas.
Once modified, these CAR T cells are grown in large numbers and infused back into the patient. The re-infused CAR T cells seek out and bind to cancer cells through their engineered receptors. Upon binding, CAR T cells activate, proliferate, and release factors that directly destroy the cancer cells. This therapy provides a long-term supply of specialized T cells that target and eliminate cancerous cells.
Monoclonal Antibodies (Non-Checkpoint)
Monoclonal antibodies (mAbs) are laboratory-produced proteins designed to bind to specific targets, often found on cancer cells. These antibodies can directly induce cancer cell death by blocking growth factor receptor signaling pathways needed for tumor cell survival and proliferation. For example, some mAbs bind to epidermal growth factor receptor (EGFR), disrupting signals that promote tumor growth.
Beyond direct targeting, mAbs can also engage the body’s immune effector cells. They can trigger Antibody-Dependent Cellular Cytotoxicity (ADCC), marking cancer cells for destruction by immune cells like Natural Killer (NK) cells. This process releases tumor-specific proteins, which can be presented to T cells, enhancing the anti-tumor immune response. Some mAbs can also activate the complement system to directly lyse cancer cells.
Cytokine Therapy
Cytokines are naturally occurring proteins that act as messengers within the immune system, orchestrating its response to infections and diseases, including cancer. In cancer therapy, synthetic versions are administered to boost the immune system’s ability to recognize and attack cancer cells. Interferons and interleukins are two types of cytokines used.
Interferon-alpha (IFN-α) has been used to treat certain cancers, such as hairy cell leukemia and melanoma, by enhancing the immune response and potentially exerting direct anti-proliferative effects. Interleukin-2 (IL-2) can promote the activation and proliferation of various immune cells, including T cells and NK cells, enhancing their anti-tumor activity. These therapies aim to overcome tumor-induced immunosuppression.
Oncolytic Viruses
Oncolytic viruses are viruses naturally identified or genetically engineered to selectively infect and destroy cancer cells while sparing healthy tissues. They exploit defects in cancer cells’ antiviral defenses, such as impaired interferon signaling, making tumor cells more susceptible to viral infection and replication.
Once inside a cancer cell, the virus replicates, using the cell’s machinery to produce more viral particles. This replication leads to the lysis of the infected cancer cell, releasing new viral particles that can infect other tumor cells. The destruction of cancer cells also triggers an immune response by releasing tumor-associated antigens and “danger signals” that alert the immune system. These signals activate immune cells, such as dendritic cells and T cells, to recognize and attack both infected and uninfected cancer cells.
Cancer Vaccines
Therapeutic cancer vaccines are designed to train the patient’s immune system to recognize and attack existing cancer cells. Unlike preventive vaccines, therapeutic vaccines are administered after cancer has developed. These vaccines expose the immune system to specific molecules, called tumor antigens, which are present on cancer cells. These antigens can be unique to the tumor (neoantigens) or overexpressed versions of normal proteins.
By presenting these antigens, often with an immune-triggering adjuvant, the vaccine stimulates the production of anti-tumor T cells and other immune cells. These activated immune cells then identify and destroy cancer cells throughout the body. Examples include cellular vaccines, where a patient’s own immune cells or tumor cells are modified and reintroduced, or nucleic acid-based vaccines (DNA or RNA) that instruct the body’s cells to produce tumor antigens.
Immunotherapy in Cancer Treatment
Immunotherapy has significantly advanced cancer treatment, offering new strategies often integrated into comprehensive plans. It can be used alone or combined with other immunotherapies or traditional treatments like chemotherapy, radiation, or surgery to enhance efficacy. For instance, combining checkpoint inhibitors such as nivolumab and ipilimumab has shown improved response rates and progression-free survival in metastatic melanoma.
The selection of immunotherapy involves a personalized approach, considering tumor type, biomarkers, and patient health. Biomarkers, such as PD-L1 expression or tumor mutational burden, provide insights into how a patient might respond. High PD-L1 expression or tumor mutational burden, for example, can indicate a greater likelihood of response to immune checkpoint inhibitors. These factors guide clinicians in tailoring treatment decisions.
When evaluating treatment response, clinicians consider unique patterns like pseudo-progression. This describes an initial apparent increase in tumor size or new lesions on imaging scans, which is not true disease progression. Pseudo-progression occurs due to immune cell infiltration into the tumor or inflammation. Subsequent scans show tumor shrinkage, and modified response criteria (e.g., irRECIST) differentiate this from actual disease worsening, allowing patients to continue therapy.
Patient Experience and Side Effects
Patients undergoing immunotherapy may experience a unique set of side effects, distinct from those associated with chemotherapy or radiation. These are known as immune-related adverse events (irAEs), occurring because immunotherapy activates the immune system, which can sometimes attack healthy tissues and organs. The incidence and severity of irAEs vary depending on the specific agent and whether it is used alone or in combination.
Common irAEs can affect various organ systems, including the skin (e.g., rash, itching), gastrointestinal tract (e.g., diarrhea, colitis), and endocrine glands (e.g., thyroid dysfunction). While most irAEs are mild to moderate (Grade 1-2), some can be severe (Grade 3-4) and, rarely, life-threatening, such as inflammation of the lungs (pneumonitis), heart (myocarditis), or nervous system (neurotoxicity). The onset of these side effects can range from weeks to many months after starting treatment, or even after treatment concludes.
Management of irAEs typically involves corticosteroids, such as prednisone, which suppress the overactive immune response. The dose and duration depend on the irAE’s severity. Patients should report any new or worsening symptoms promptly to their healthcare team, as early detection and intervention are important for effective management and to prevent complications. If irAEs do not respond to corticosteroids, other immunosuppressive agents may be considered. Ongoing monitoring for potential long-term immune effects is also part of patient care.