History of Immunotherapy: Key Milestones and Breakthroughs

Harnessing the immune system to fight disease has long intrigued scientists, but only in recent decades has immunotherapy emerged as a transformative medical tool. This approach has reshaped cancer treatment, offering hope where conventional therapies fall short.

Tracing its history reveals breakthroughs that shaped modern immunotherapy. From early observations of immune responses against tumors to laboratory experiments and clinical applications, each milestone brought it closer to integration into standard oncology care.

Early Observations Of Immune Responses To Tumors

The idea that the body might recognize and attack abnormal growths dates back centuries, but early evidence remained anecdotal. In the 18th century, physicians noted that some cancer patients who developed infections occasionally experienced tumor regression. Though poorly understood, this hinted at a link between immune activity and tumor control.

A more structured investigation emerged in the late 19th century with William B. Coley, an American surgeon who observed that bacterial infections sometimes led to tumor shrinkage. Inspired by case reports, he injected cancer patients with live Streptococcus bacteria, later refining the approach into “Coley’s toxins.” While his methods lacked modern scientific rigor, some patients exhibited tumor shrinkage, suggesting immune stimulation played a role. Despite skepticism, Coley’s work laid the groundwork for future immune-based cancer therapies.

As microscopy and pathology advanced in the early 20th century, researchers identified immune cells infiltrating tumors, raising questions about their function. Some hypothesized these cells attempted to eliminate cancerous growths, while others believed they were bystanders. The discovery of lymphocytes and macrophages within tumors fueled speculation that the immune system might naturally recognize malignancies, though definitive proof remained elusive.

Initial Lab Demonstrations Of Immunotherapy Potential

The transition from theory to laboratory validation marked a turning point in immunotherapy research. As scientific techniques advanced in the mid-20th century, researchers sought measurable evidence of immune-based interventions. One of the earliest breakthroughs came in the 1950s with the identification of interferons by Alick Isaacs and Jean Lindenmann. These signaling proteins, initially recognized for antiviral properties, also showed potential in cancer treatment.

By the 1970s, laboratory experiments revealed mechanisms for manipulating immune components to target malignant cells. A major step forward was the isolation of interleukin-2 (IL-2) by Robert Gallo and colleagues. IL-2, a cytokine that promotes T-cell proliferation, was among the first molecules investigated for enhancing immune responses against cancer. Early experiments in cell cultures and animal models demonstrated its ability to stimulate immune cells to attack tumors. Around the same time, César Milstein and Georges Köhler developed hybridoma technology, enabling the production of highly specific monoclonal antibodies and opening new possibilities for targeted cancer therapies.

In the 1980s, attention shifted to adoptive cell transfer techniques, particularly tumor-infiltrating lymphocytes (TILs). Steven Rosenberg and his team at the National Cancer Institute demonstrated that TILs, when expanded ex vivo and reinfused into animal models, could mediate tumor regression. This laid the groundwork for later advancements in personalized immunotherapy. Researchers also explored immune checkpoint regulation, identifying molecules such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) as potential therapeutic targets. These discoveries set the stage for future checkpoint inhibitors, though practical applications would take decades to refine.

First Clinical Implementations

Bringing immunotherapy from the lab to clinical practice required overcoming challenges, from establishing safety protocols to demonstrating efficacy. Early attempts focused on cytokine-based therapies. IL-2, which had shown promise in preclinical models, was among the first to undergo rigorous human trials. In the 1980s, clinical studies led by Steven Rosenberg explored high-dose IL-2 for metastatic melanoma and renal cell carcinoma. While some patients achieved durable remissions, severe toxicities limited its widespread use. Despite these challenges, IL-2 demonstrated that immune-based treatments could produce meaningful outcomes in advanced cancers.

Monoclonal antibodies emerged as a more targeted alternative. Rituximab, approved by the FDA in 1997 for B-cell non-Hodgkin lymphoma, marked a milestone as the first monoclonal antibody for cancer treatment. By selectively binding to the CD20 antigen on malignant B cells, Rituximab enabled targeted tumor destruction with fewer systemic side effects than earlier cytokine therapies. Its success paved the way for subsequent antibody-based treatments, including trastuzumab for HER2-positive breast cancer and bevacizumab for colorectal and lung cancers. These therapies demonstrated that immunotherapy could be integrated into standard oncology protocols, often in combination with chemotherapy or radiation.

Checkpoint inhibitors represented the next major advancement. The FDA’s approval of ipilimumab in 2011 for metastatic melanoma signaled a paradigm shift in cancer treatment. By blocking CTLA-4, ipilimumab enhanced T-cell activation, leading to prolonged survival in some patients. This breakthrough was followed by PD-1 inhibitors, such as pembrolizumab and nivolumab, which offered improved safety profiles and broader applicability across multiple cancer types, including non-small cell lung cancer and Hodgkin lymphoma. These therapies showed that immune modulation could produce long-lasting responses, even in cancers historically resistant to conventional treatments.

Integration Into Oncology Treatments

As immunotherapy gained regulatory approval and demonstrated efficacy across multiple cancers, its role evolved from an experimental approach to a standard treatment option. Oncologists incorporated checkpoint inhibitors, monoclonal antibodies, and adoptive cell therapies into clinical guidelines, often tailoring their use based on tumor biomarkers and genetic profiling. The introduction of PD-L1 testing allowed for more precise patient selection, ensuring therapies like pembrolizumab and nivolumab were administered to those most likely to benefit. This biomarker-driven approach improved response rates and minimized unnecessary exposure to immune-related adverse effects, which ranged from mild skin reactions to severe autoimmune complications.

The impact of immunotherapy extended beyond individual drug approvals, reshaping treatment sequencing and combination strategies. In previously untreatable malignancies such as metastatic melanoma, combining checkpoint inhibitors like ipilimumab and nivolumab significantly extended survival, with some patients achieving long-term remission. Similarly, the integration of CAR-T cell therapy for refractory B-cell malignancies provided a curative option for patients unresponsive to chemotherapy or stem cell transplantation. These advancements prompted updates in clinical practice guidelines from organizations such as the National Comprehensive Cancer Network (NCCN), which now recommend immunotherapy as a first-line or adjunct treatment in various cancers, including lung, bladder, and head and neck cancers.