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KEY CONCEPTS
Immune checkpoint therapy (ICT) targeting cytotoxic T lymphocyte antigen-4 (CTLA-4) or programmed cell death protein 1 or programmed cell death ligand 1 (PD-L1) has changed the clinical course of many cancers, with some patients achieving survival benefit and durable responses lasting for years.
The most commonly used biomarkers for ICT are tissue PD-L1 expression, tumor mutational burden, and mismatch repair deficiency or microsatellite instability.
Significant efforts are underway to discover biomarkers for optimal patient selection and develop combinatorial strategies to improve response.
Immune-related adverse events (irAEs) can affect any organ and require prompt recognition and early intervention is critical.
Chimeric antigen receptor (CAR) T-cells are engineered with a synthetic antigen receptor with high affinity for a tumor antigen coupled with a T-cell signaling domain. There are now three CAR T-cell (CAR T therapeutics approved by the Food and Drug Administration for patients with hematologic malignancies). CAR T-cells have unique toxicities, including cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome, which require a high index of suspicion.
Future areas of investigation in cancer immunotherapy include rational targeting of other immune checkpoints, refinement of CAR T-cell therapies and other cellular therapies, testing of immunotherapy earlier in the disease state (eg, neoadjuvant), combinatorial strategies, improved understanding of irAEs, and development of predictive biomarkers for toxicities and response.
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THE PROMISE OF IMMUNOTHERAPY
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Although the ability of the immune system to recognize and eradicate cancer was first postulated in the 19th century, proof of principle remained elusive until the 20th century. As early as 1884, Anton Chekhov observed in a letter that: “It has long been noted that the growth of malignant tumors halts for a time when this disease [erysipelas] is present.”1 Beginning in the 1890s, William Coley developed a mixture of heat-killed bacteria (Coley's toxin) that was found to induce complete tumor regression in certain patients with sarcoma and subsequently studied in various types of cancer through the 1960s with mixed clinical benefit.2 The concept of stimulating the immune system using bacterial elements was further validated with the development of intravesical bacillus Calmette–Guérin (BCG) for superficial bladder cancer, which promotes a nonspecific inflammatory immune response and clinical benefit.3 Over time, the discovery of the major histocompatibility complex (MHC) and T-cell receptor (TCR) in the 1980s provided insight into T-cell function that led to a number of clinical trials.4,5 Unfortunately, many early clinical trials failed because an incomplete understanding of T-cell function. As further research led to deeper understanding of mechanisms of T-cell function, including co-stimulation and co-inhibition, the field of cancer immunotherapy has expanded rapidly with the emergence of treatments that have yielded survival advantages for many patients, such as immune checkpoint therapies (ICTs) and chimeric antigen receptor T-cell (CAR T) therapy. Immunotherapy is now firmly established as a pillar of cancer treatment, alongside chemotherapy, radiation, and surgery.
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The basic principles that guide cancer immunology are (1) immune surveillance, (2) ...