History of Immunotherapy: Key Milestones and Breakthroughs

Immunotherapy’s roots stretch back more than a century, to a time when a New York surgeon deliberately infected a cancer patient with bacteria and watched the tumor shrink. That 1891 experiment by William B. Coley is widely considered the first deliberate attempt to harness the immune system against cancer, and the field has unfolded in dramatic, often surprising leaps ever since. What connects Coley’s crude bacterial injections to today’s engineered cell therapies and checkpoint drugs is a single idea: the body’s own defenses, properly directed, can recognize and destroy disease.

Serum Therapy and Coley’s Toxins

The late nineteenth century produced two foundational threads of immunotherapy almost simultaneously. In 1890, Emil von Behring demonstrated that serum from animals immunized against diphtheria could protect other animals from the disease, establishing serum therapy and earning the first Nobel Prize in Physiology or Medicine in 1901.¹ Behring’s work proved that something in the blood itself could neutralize a pathogen, a revelation that laid the conceptual groundwork for antibody-based medicine.

Meanwhile, William B. Coley took a radically different approach. After observing that some cancer patients who developed severe infections saw their tumors regress, Coley began injecting streptococcal organisms directly into patients with inoperable cancer. Over the next four decades, as head of the Bone Tumor Service at Memorial Hospital in New York, he treated more than a thousand patients with bacteria or bacterial products that became known as Coley’s Toxins.² The results were inconsistent, and the medical establishment largely dismissed Coley’s work as the age of radiation and chemotherapy dawned. But his central insight, that immune activation could destroy tumors, preceded contemporary immunotherapy by decades.³

Allergy Immunotherapy and the Idea of Desensitization

While Coley pursued cancer, other researchers were applying a parallel principle to allergic disease. In 1911, Leonard Noon and John Freeman published pioneering work on injecting patients with small, increasing doses of grass pollen extract to reduce hay fever symptoms.⁴ Their approach, now called allergen-specific immunotherapy, remains the only treatment that modifies the underlying disease process in allergic conditions rather than simply suppressing symptoms.⁵

The classical protocol involves repeated injections of increasing amounts of allergen extract, followed by maintenance injections over roughly three years. The result is a form of allergen-specific tolerance that provides clinical benefit for years after the injections stop.⁶ The principle of training the immune system to tolerate something it previously attacked would echo, in very different forms, across the next century of immunotherapy research.

BCG and Non-Specific Immune Stimulation

Bacillus Calmette-Guérin, or BCG, is best known as a tuberculosis vaccine. But researchers noticed early on that BCG provoked a broad immune response that could inhibit tumor growth in animal models. That observation eventually led to clinical trials showing that BCG delivered directly into the bladder could eradicate superficial bladder tumors and prevent their recurrence.⁷ First used clinically in the 1970s, intravesical BCG became one of the earliest cancer immunotherapies to enter routine practice and remains a standard treatment for non-muscle-invasive bladder cancer today.

The mechanism involves BCG attaching to and being internalized by both normal bladder cells and cancer cells. This triggers a cascade of immune signaling that recruits a broad army of immune cells, including T cells, natural killer cells, and macrophages, which then kill bladder cancer cells. Both the fast-acting innate immune response and the slower, more targeted adaptive response contribute, providing lasting protection against tumor recurrence.⁸ BCG was a proof of concept that a blunt immunological tool, one not specifically designed to recognize cancer, could still produce durable anti-tumor effects.

The Cytokine Era and Interleukin-2

The 1980s brought a new approach: instead of introducing foreign organisms to wake up the immune system, researchers tried amplifying the immune system’s own signaling molecules. Interleukin-2, or IL-2, is a protein the body naturally produces to expand and activate T cells. Steven Rosenberg and colleagues at the National Cancer Institute showed that administering high doses of IL-2 could cause established tumors to shrink in some patients with metastatic melanoma and kidney cancer.⁹

The effect was real but far from universal. In a large series of 652 cancer patients who received high-dose IL-2, objective tumor shrinkage occurred in roughly 20 to 35 percent of patients with selected advanced cancers. Among the 18 who achieved a complete response, more than half had no recurrence at follow-up periods stretching beyond a year and a half.¹⁰ IL-2 became the first effective immunotherapy for human cancer, demonstrating that a purely immunological manipulation, without surgery, radiation, or chemotherapy, could mediate durable and sometimes apparently curative regressions.¹¹ The treatment was harsh, though, with severe side effects that limited its use to carefully selected patients in specialized centers.

Monoclonal Antibodies Enter the Clinic

A separate technological revolution made a different kind of immunotherapy possible. Hybridoma technology, developed in the 1970s, allowed scientists to fuse antibody-producing immune cells from mice with immortal cell lines, creating factories that churned out identical copies of a single antibody, a monoclonal antibody, targeted against a specific molecule.¹² The concept earned a Nobel Prize in 1984, but turning it into usable cancer drugs took another decade of engineering to make mouse-derived antibodies safe enough for repeated use in humans.

The breakthrough came in 1997 with the approval of rituximab, a monoclonal antibody targeting the CD20 protein found on the surface of B cells. Rituximab was the first monoclonal antibody approved for cancer treatment and transformed outcomes in non-Hodgkin lymphoma.¹³ Non-Hodgkin lymphoma was also the first cancer where treatment success with antibodies could be reproduced at scale, making rituximab a proving ground for the entire class of drugs.¹⁴ Dozens of therapeutic antibodies for various cancers followed in the years after.

Immune Checkpoint Inhibitors Change Everything

If monoclonal antibodies were precision tools aimed at cancer cells, checkpoint inhibitors flipped the strategy entirely. Rather than targeting the tumor, these drugs target the brakes on the immune system itself. Cancer cells often exploit natural “off switches” on T cells, proteins like CTLA-4 and PD-1, to shut down the immune attack before it can do real damage. Checkpoint inhibitors block those off switches, freeing T cells to recognize and kill tumor cells they would otherwise ignore.¹⁵

PD-1 was originally discovered in 1992 as a molecule associated with T cell death. Over the next three decades, researchers found that it plays a critical role in preventing the immune system from overreacting and causing autoimmune damage, but that blocking it can unleash powerful anti-cancer immunity.¹⁶ The clinical validation came when ipilimumab, which blocks CTLA-4, was approved in 2011 for metastatic melanoma, a disease that had been essentially untreatable. Drugs targeting PD-1 and its binding partner PD-L1 followed shortly after and proved effective across a far wider range of cancers.

The impact was enormous. James Allison and Tasuku Honjo shared the 2018 Nobel Prize in Physiology or Medicine for their foundational work on CTLA-4 and PD-1, respectively.¹⁷ Checkpoint inhibitors are now used to treat lung cancer, kidney cancer, bladder cancer, head and neck cancers, and many others, and they have produced durable remissions in patients who had exhausted all other options.

CAR-T Cells and Engineered Immune Armies

While checkpoint inhibitors remove the brakes from existing T cells, chimeric antigen receptor T cell therapy, or CAR-T, builds entirely new weapons. The approach involves extracting a patient’s own T cells, genetically engineering them in a lab to recognize a specific protein on cancer cells, then infusing them back into the patient. The first-generation CAR constructs appeared in 1993, but they lacked the staying power to produce meaningful clinical results. Second-generation designs added a co-stimulatory signal that kept the engineered cells alive and active much longer.¹⁸

The clinical turning point came in 2011, when Carl June’s team demonstrated responses in patients with chronic lymphocytic leukemia using second-generation CAR-T cells targeting CD19, a protein on B cells. That success led to the FDA approving the first two CAR-T cell therapies in 2017: tisagenlecleucel for pediatric acute lymphoblastic leukemia and axicabtagene ciloleucel for certain lymphomas. As of 2023, six CAR-T products have been approved, showing strong results in B cell cancers and multiple myeloma.¹⁹

Oncolytic Viruses and Cancer Vaccines

Some of immunotherapy’s more creative strategies involve using modified viruses or the patient’s own immune cells as treatment. Talimogene laherparepvec, commonly called T-VEC, was the first oncolytic virus therapy approved by the FDA. It is a genetically modified herpes simplex virus engineered to selectively replicate inside tumor cells while sparing normal tissue.²⁰ When injected into a tumor, T-VEC kills cancer cells directly and also stimulates a broader immune response by increasing the infiltration of cancer-killing T cells into the tumor while reducing the regulatory T cells that suppress immunity.²¹

Therapeutic cancer vaccines represent yet another angle. Unlike preventive vaccines for infections, these are designed to teach a patient’s immune system to attack a cancer that already exists. Sipuleucel-T, approved in 2010 for castration-resistant prostate cancer, was the first. In its pivotal trial, patients who received the vaccine lived a median of about four months longer than those who received placebo, with the three-year survival probability rising from about 23 percent to roughly 32 percent.²² The benefit was modest by some measures, but it established that a personalized immune-based vaccine could extend survival in cancer.

Bispecific Antibodies and T Cell Engagers

A newer class of immunotherapy solves a problem that monoclonal antibodies and checkpoint inhibitors cannot always address: getting T cells physically close to cancer cells. Bispecific T cell engager, or BiTE, molecules are engineered proteins with two binding sites. One grabs onto a protein on cancer cells, and the other grabs onto T cells, essentially acting as a molecular bridge that forces the two into contact.²³

Blinatumomab was the first approved BiTE molecule. It targets CD19 on B cells and CD3 on T cells, redirecting the patient’s own immune cells to destroy cancerous B cells. When blinatumomab binds to both a B cell and a T cell, the T cell releases its killing molecules and the B cell dies.²⁴ Because the approach works through a surface protein rather than through genetic mutations inside the tumor cell, it can potentially sidestep some of the resistance mechanisms that undermine other therapies.²⁵ The modular nature of BiTE technology means new versions targeting different tumor proteins can be generated relatively quickly, opening the door to off-the-shelf immunotherapies across many cancer types.

Managing the Side Effects of Unleashed Immunity

Every advance in immunotherapy has come with a corresponding challenge: the same immune activation that destroys cancer can also damage healthy tissue. The specific toxicity profiles differ by treatment type, and managing them has become its own subspecialty.

CAR-T cell therapy is associated with cytokine release syndrome, or CRS, a potentially life-threatening inflammatory reaction that occurs when the engineered cells activate en masse and flood the body with immune signaling molecules. A related complication, immune effector cell-associated neurotoxicity syndrome (ICANS), can cause confusion, seizures, or other neurological symptoms.²⁶ Tocilizumab, an antibody that blocks the IL-6 receptor, became the standard treatment for CRS, though newer agents like siltuximab, which directly neutralizes IL-6 rather than blocking its receptor, have shown faster resolution times in early comparisons.²⁷

Checkpoint inhibitors carry a different set of risks called immune-related adverse events. Because these drugs broadly release the brakes on immune activity, the immune system can turn against virtually any organ. Skin reactions like rash are the most common and usually appear first, but inflammation of the gut, thyroid, liver, lungs, and even the heart or nervous system can occur.²⁸ Clinical guidelines generally recommend continuing treatment with close monitoring for mild reactions, pausing the drug for moderate ones, and starting high-dose steroids and potentially stopping the drug permanently for severe reactions.²⁹ Recognizing and grading these side effects quickly is critical, and the learning curve on how to do so has been steep for oncologists worldwide.

Why Immunotherapy Does Not Work for Everyone

For all the dramatic success stories, a stubborn reality persists: only a fraction of cancer patients respond to immunotherapy. Understanding why has become one of the most active areas of research. Some tumors are considered immunologically “cold,” meaning they have few immune cells infiltrating them and little of the inflammatory signaling that checkpoint inhibitors depend on. The tumor microenvironment, the ecosystem of cells and molecules surrounding the tumor, can actively suppress immune responses through metabolic changes, suppressive immune cells, and physical barriers that keep killer T cells out.³⁰

To help predict who will benefit, researchers have focused on biomarkers. The three most studied are PD-L1 expression on tumor cells, microsatellite instability (a sign of defective DNA repair that produces many mutations), and tumor mutational burden (the total number of mutations in a tumor’s DNA). All three have been validated to some degree as predictors of response to checkpoint inhibitors.³¹ But none is reliable enough on its own. PD-L1, for instance, was the first biomarker incorporated into prescribing guidelines for the PD-1 inhibitor pembrolizumab, but its levels can shift during treatment in response to immune signaling, undermining its predictive value.³² Finding better biomarkers, or better combinations of existing ones, remains a major unmet need.³³

The Gut Microbiome as an Unexpected Variable

One of the more surprising discoveries in recent immunotherapy research is that the bacteria living in a patient’s gut can influence whether checkpoint inhibitors work. In animal studies, gut microbes have been shown to directly affect the therapeutic response to these drugs. In human patient cohorts, people who respond to checkpoint therapy tend to have a different gut microbiome composition compared to those who do not.³⁴

The evidence goes further than simple correlation. In mouse experiments, fecal microbiota transplants from patients who responded to immunotherapy could transfer that responsiveness to the mice, while transplants from non-responders did not. In human trials, fecal transplants from patients who had achieved a complete response have sometimes overcome resistance in patients whose cancers had progressed on treatment, though the results remain variable.³⁵ This line of research suggests that the natural variation in people’s gut bacteria could partly explain the wide differences in how patients respond to the same drug, and it opens the possibility that manipulating the microbiome could improve treatment outcomes.

mRNA Platforms and the Next Frontier

The COVID-19 pandemic pushed mRNA vaccine technology into the global spotlight, and cancer researchers were already exploring the same platform. The idea is to use lipid nanoparticles, tiny fat-based delivery capsules, to ferry mRNA encoding tumor-specific proteins into the body. Once inside cells, the mRNA instructs them to produce those proteins, which the immune system then recognizes as foreign and mounts an attack against.

Recent work has focused on engineering lipid nanoparticles that preferentially deliver their cargo to lymph nodes, where immune responses are initiated. One such nanoparticle system showed significantly stronger CD8+ T cell responses, the type of immune cell most important for killing cancer, compared to the lipid nanoparticle formulation used in a widely distributed COVID-19 vaccine. In a mouse melanoma model, this lymph-node-targeting approach combined with PD-1 blockade produced complete tumor clearance in 40 percent of animals.³⁶ These are still preclinical findings, and the gap between mouse models and human patients is wide. But the modularity of mRNA technology, its ability to be quickly redesigned for different tumor targets, makes it one of the most watched platforms for personalized cancer vaccines in coming years.