Cancer Immunotherapy: How the Immune System Fights Tumors

A Nobel Prize and a Treatment Paradigm Shift

In 2018, James Allison of the University of Texas MD Anderson Cancer Center and Tasuku Honjo of Kyoto University shared the Nobel Prize in Physiology or Medicine for their discovery of cancer therapy through inhibition of negative immune regulation. Their work — Allison on the CTLA-4 pathway and Honjo on the PD-1 pathway — underpins what became a revolution in oncology. Drugs targeting these pathways, now called checkpoint inhibitors, have produced durable remissions in cancers that were previously considered near-universally fatal, including metastatic melanoma and certain lung cancers. The five-year survival rate for metastatic melanoma was approximately 5% before immunotherapy; with nivolumab and ipilimumab, it now approaches 50% in some patient populations.

Immunotherapy refers to treatments that work by modifying the immune system's ability to recognize and destroy cancer cells, rather than directly attacking cancer cells with cytotoxic chemotherapy or radiation. Multiple distinct mechanisms and drug classes fall under this umbrella.

How Tumors Evade the Immune System

Understanding immunotherapy requires first understanding why the immune system doesn't naturally destroy all cancers. Immune evasion is real. Cancer cells exploit several mechanisms:

• Downregulation of MHC-I molecules: Tumors reduce expression of major histocompatibility complex class I proteins, making cancer cells less visible to cytotoxic T cells
• Checkpoint exploitation: Tumor cells express the ligand PD-L1, which binds to the PD-1 receptor on T cells and delivers an "off" signal — essentially applying the brakes to the T cell's attack
• Immunosuppressive tumor microenvironment: Tumors recruit regulatory T cells (Tregs) and secrete cytokines like TGF-beta and IL-10 that suppress anti-tumor immune activity
• Antigen loss: Tumor cells can mutate to lose the specific proteins (neoantigens) that T cells were targeting

Immunotherapy approaches work by countering one or more of these evasion mechanisms.

Checkpoint Inhibitors

Checkpoint inhibitors are monoclonal antibodies that block immune checkpoints — molecular "brakes" that normally prevent excessive immune responses. By blocking these checkpoints, the drugs release inhibition and allow T cells to attack tumors more effectively.

Pembrolizumab (Keytruda) has become the first cancer drug approved based on a biomarker — microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) status — regardless of which organ the cancer originated in. This "tumor-agnostic" approval, granted in 2017, was a first in oncology history.

CAR-T Cell Therapy

Chimeric antigen receptor T-cell (CAR-T) therapy involves collecting T cells from a patient's blood, genetically engineering them to express an artificial receptor that targets a specific protein on cancer cells, multiplying them in a laboratory, and infusing them back into the patient. The results in blood cancers are remarkable.

• Kymriah (tisagenlecleucel), approved in 2017 for pediatric ALL, achieved a complete remission rate of 81% in patients who had failed all prior therapies in the pivotal trial
• Carvykti (ciltacabtagene autoleucel), approved for multiple myeloma in 2022, showed an overall response rate of 98% in its pivotal trial — remarkable for a disease with limited options after multiple prior therapies
• CAR-T therapies come with serious potential toxicities: cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) require specialized management and hospitalization
• Manufacturing takes 3–4 weeks; patients must be stable enough to wait; bridging therapy is sometimes needed

CAR-T cells targeting solid tumors remain a major research challenge because solid tumors present physical and immunological barriers that blood cancers do not.

Cancer Vaccines

Cancer vaccines take two forms: preventive (prophylactic) and therapeutic. The HPV vaccines (Gardasil, Cervarix) and hepatitis B vaccine are preventive cancer vaccines — they protect against viruses that cause cervical, oropharyngeal, and liver cancers respectively.

Therapeutic cancer vaccines aim to stimulate an immune response against existing tumors. Sipuleucel-T (Provenge), approved in 2010 for metastatic prostate cancer, was the first therapeutic cancer vaccine approved — but it extends survival by an average of only about 4 months and has largely been displaced by other agents. The field saw renewed excitement with Moderna and Merck's mRNA-based personalized neoantigen vaccine (mRNA-4157/V940) combined with pembrolizumab, which showed a 44% reduction in risk of recurrence or death compared to pembrolizumab alone in resected melanoma in a phase 2b trial published in 2023.

Side Effects and Immune-Related Adverse Events

Immunotherapy toxicity differs fundamentally from chemotherapy toxicity. Immune-related adverse events (irAEs) result from non-specific immune activation affecting normal tissues.

Combination checkpoint inhibitor therapy (anti-CTLA-4 plus anti-PD-1) produces higher response rates but also substantially higher rates of severe irAEs — approximately 55% grade 3–4 toxicity with ipilimumab/nivolumab versus roughly 20% with either agent alone.

This article is for informational purposes only. Consult a qualified healthcare professional before making medical decisions.