Immunotherapy: What It Is, How It Works, and Current Research

Medically reviewed by F. Stephen Hodi, MD

Immunotherapy refers to treatments that use the body’s immune system to combat diseases. Immuno-oncology focuses on efforts to use the immune system as a weapon against cancer.

The immune system is a collection of organs, tissues, specialized cells, and substances that protect the body against infection and disease. While the immune system can often handle very small tumors on its own, either by destroying them or keeping them from growing, it can sometimes fail – either because a tumor grows too large, the cancer cells are too well camouflaged, or the tumor cells are able to stave off an immune system attack.

There are several types of immunotherapy for cancer:

  • Some help train the immune system to better recognize and attack cancer cells.
  • Others harness specific agents of the immune system, such as antibodies, to become cancer fighters.
  • Still others work by releasing the molecular “brakes” on the immune system’s attack on cancer.

From the 1880s to today

The immune system’s promise as a cancer fighter was first recognized well over a century ago.

In the late 1880s, German physician Rudolph Virchow discovered that tumors are often laced with immune system cells, suggesting a connection between cancer and the inflammation produced by the immune response to disease.

In the early 20th century, American physician William Coley observed that when patients with cancers on or near the surface of the body became infected, the tumors sometimes disappeared after the infection cleared. Coley theorized that the immune system’s reaction to infectious bacteria was driving the tumors into remission. He developed a technique for deactivating the bacteria that were causing those infections, and then injecting the disarmed bacteria into patients. Some of the patients saw their tumors shrink, providing the first evidence of a potential immune system therapy for cancer.

checkpoint inhibitors, immunotherapy
How immune checkpoint inhibitors work.

In the past half-dozen years, immunotherapy has become one of the hottest areas of cancer research, fundamentally changing the way the disease is treated in many patients and setting the stage for an even more extensive role in cancer treatment in the future. The key discovery, made by Dana-Farber’s Gordon Freeman, PhD, and others, was that the immune system’s attack on cancer often falls short because many cancer cells display proteins, called immune checkpoint proteins, that bring the attack to a halt. Drugs known as immune checkpoint inhibitors prevent tumor cells from sending a “stand down” message to immune system attackers have had striking success in many types of cancer.

Hodgkin lymphoma

In Hodgkin lymphoma (HL), for example, a clinical trial led by Dana-Farber’s Margaret Shipp, MD, and Philippe Armand, MD, PhD, found that the checkpoint inhibitor nivolumab drove the disease into full or partial remission in 69 percent of patients, all of whom had drug-resistant forms of the disease. The findings led the Food and Drug Administration to approve the drug for patients with classical HL that has come back or progressed after a stem cell transplant.

Melanoma

Clinical trials led by Dana-Farber’s F. Stephen Hodi, MD, showed that the checkpoint inhibitor ipilimumab could slow advanced melanoma in a significant number of patients and prolong their survival. The trial marked the first time a drug – any drug – had improved survival rates for patients with advanced melanoma. 

Checkpoint inhibitors have shown exceptional promise in laboratory studies and clinical trials involving:

One of the most exciting aspects of checkpoint inhibitor drugs is that, although they tend to work in a relatively small percentage of patients with certain cancers, when they do work, their effects are often lasting. The majority of patients who benefited from ipilimumab in the advanced melanoma trial are alive today.

Combination therapy

Recent trials have shown that combining checkpoint inhibitors with other drugs can produce impressive results, particularly in types of cancer that don’t respond to checkpoint inhibitors alone. A Dana-Farber-led trial found that pairing a checkpoint inhibitor with a drug known as a PARP inhibitor was significantly more effective than either drug alone in women with hard-to-treat ovarian cancer.

Types of immunotherapy

Cancer vaccines are substances given to people to prevent cancer from developing, or to treat existing cancers by strengthening and optimizing the body’s immune response against the tumors.

An example of a preventive vaccine is one that protects against infection with the human papilloma virus (HPV), which causes cervical cancer and some other cancers, including cancers of the mouth and throat.

The first therapeutic cancer was approved by the Food and Drug Administration in 2010. Called Provenge, it is designed to stimulate an immune response against metastatic prostate cancer. Provenge is customized to each individual patient.

Researchers are testing experimental treatment vaccines in a variety of cancers, including:

Cancer vaccines can be combined with other types of therapies.

Monoclonal antibodies are synthetic copies of antibody proteins that exist in the immune system. Their job is to identify foreign invaders by binding to specific proteins called antigens, which dot the surface of cells. After they bind, antibodies recruit other cells and substances of the immune system to attack the foreign cells.

Researchers can make large numbers of identical (monoclonal) synthetic antibodies in the laboratory and give them to cancer patients. Monoclonal antibodies are used as checkpoint inhibitors to block checkpoint proteins such as CTLA-4, PD-1, and PD-L1. Other monoclonal antibodies attach to and block antigens that cancer cells use to grow and spread.

An illustration of a monoclonal antibody drug—a type of immunotherapy—attacking cancer cells.
An illustration of a monoclonal antibody drug attacking cancer cells.

In agents known as conjugate drugs, monoclonal antibodies are bonded to chemotherapy drugs. This enables the antibody to carry the chemotherapy agent directly to cancer cells, maximizing chemotherapy’s effectiveness.

CAR T-cell treatments

Another exciting entry into the immunotherapy world, known as CAR T-cell therapy, had had early success in trials with hard-to-treat cancers.

CAR stands for chimeric antigen receptor. CAR T cells are T cells that have been extracted from the patient’s blood and “trained” in the laboratory to recognize and kill tumor cells; they’re then returned to the patient as supercharged cancer-killers. CAR T cell treatments have achieved unprecedented response rates in stubborn forms of leukemia. They’re now being tested in other blood cancers and in some solid tumors, such as glioblastoma brain tumors.

Potential side effects

Like virtually all cancer therapies, immunotherapies carry the potential for side effects. Such effects vary depending on which type of cancer a patient has, how advanced it is, the type and dosage of immunotherapy used. The most common side effects are skin reactions at the needle site:

  • Pain
  • Swelling
  • Soreness
  • Itchiness
  • Rash

Some patients experience flu-like symptoms, such as:

  • Fever
  • Chills
  • Weakness
  • Dizziness
  • Nausea or vomiting
  • Muscle or joint aches
  • Fatigue
  • Headache
  • Changes in blood pressure

Other effects can include:

  • Swelling and weight gain from retaining fluid
  • Heart palpitations
  • Sinus congestion
  • Diarrhea
  • Risk of infection
  • Organ inflammation

Some of these symptoms result when the immune system, mobilized to fight cancer, mistakenly attacks health, normal tissue.

Most immunotherapy-related side effects appear in the first few weeks or months of treatment. With proper management, they generally lessen or go away in a few weeks.

Current research

A major focus of current research involves finding ways to make tumors immunologically “hot,” or more likely to provoke an immune system attack on the cancer. “Hot” tumors tend to have large number of mutations or other genetic abnormalities draw T cells to the site of cancer. All too often, however, these T cells are stymied by checkpoint proteins such as PD-L1 or CTLA4. By combining therapies that make tumors “hot” with drugs that block checkpoint proteins, researchers hope to generate a more potent and precise attack on cancer.

Investigators are exploring several such combinations. In one clinical trial, Hodi injected a specific type of human herpes virus directly into tumors in 21 patients with advanced melanoma. The patients then received the checkpoint inhibitor pembrolizumab. The two-part therapy shrank tumors in a remarkable 62 percent of patients. Other studies have shown that radiation therapy can strengthen immune responses unleashed by checkpoint inhibitors.

Another approach was tested by Dana-Farber’s Catherine Wu, MD, and Patrick Ott, MD, PhD, in a six-patient clinical trial. Patients received the NeoVax vaccine, which is created using pieces of cancer-related proteins from patients’ melanoma tumors. When injected into patients, the vaccine spurred T cell responses. Four of the six patients had no recurrence of the cancer at a median of 25 months. The two who did have recurrences were treated with pembrolizumab and had a complete disappearance of the cancer.

Catherine Wu, MD (right), and Patrick Ott, MD, PhD, are testing a vaccine, NeoVax, that is personalized for each patient and contains “neoantigens” that stimulate an immune response.
Catherine Wu, MD, and Patrick Ott, MD, PhD, testing a vaccine, NeoVax, that is personalized for each patient and contains “neoantigens” that stimulate an immune response.

Other Dana-Farber researchers have used nanoparticles to deliver immune-stimulating drugs into tumors with pinpoint accuracy. Scientists have also found that cells under stress can create changes in their immediate surroundings – their microenvironment – that prevent a T-cell invasion of tumors. Silencing this process in ovarian cancer-related dendritic cells reprogrammed them into immune-activating cells.

Researchers are increasingly coming to recognize that drugs designed to incapacitate cancer cells from the inside can also spark an immune response that menaces them from the outside. One study led by Dana-Farber’s David Weinstock, MD, found that large doses of the chemotherapy drug cyclophosphamide not only kills cancer cells directly, but also spurs an immune attack on them.

In addition, Dana-Farber researchers have shown that drugs known as CDK4/6 inhibitors, which undermine cancer cells by halting their division, can spark an immune assault on the cells as well. And scientists led by Dana-Farber’s Geoffrey Shapiro, MD, recently showed that targeted drugs known as PARP inhibitors, which hamper cancer cells’ ability to repair damage to their DNA, can also incite an immune system response to the cancer.

11 responses to “Immunotherapy: What It Is, How It Works, and Current Research

  1. Enjoyed this! My wife was a participant in clinical trials with ipilimumab approximately 9-10 years ago. It prolonged her life by one year beyond the original prognosis. At that time she was hoping that others would benefit by her participation.

    1. We have benefited! Thank you for your continued interest and your sacrifices as a care giver. So wonderful that your wife enjoyed one more year, a blessing and a gift.

  2. I had advanced melanoma with metastasis to brain and bowel in 2010. My oncologist strongly suggested that I get on immunotherapy medicine Leukine. That was in 2010, my health is excellent, still on the drug.

  3. Car T Cell Therapy at Dana Farber has put me into complete remission for over a year now from Follicular NHL. A real life saver.

  4. I was just enrolled in a Phase 1 clinical trial for colon cancer, MSS with zero genetic mutations, for immunotherapy using a two-drug combination. One is supposed to make the tumor “hot” like the article talks about and the other is the immunotherapy drug. I will know by next week if I am accepted. The trial is testing a multitude of cancers, not just CRC.

    Drugs used:
    Cabozantinib
    Atezolizumab

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