Why Does Immunotherapy Work for Some but Not for Others?

Immunotherapies expose cancer cells to the immune system so it can attack them. Read about why these drugs work so well in some patients but in others the immune system doesn’t respond to these very promising drugs.
June 2017 – Cancer Immunotherapy
Maurie Markman, MD
President of Medicine & Science
Cancer Treatment Centers of America

When an immunotherapy drug is given to a patient with cancer but the cancer does not respond, doctors and researchers may not always know why. Did the patient’s immune system simply not respond to this treatment, but the cancer of another patient does respond?

“Not everyone responds to these drugs right now,” says Pamela Crilley, MD, Chair, Department of Medical Oncology, Cancer Treatment Centers of America, and Medical Oncologist at Eastern Regional Medical Center in Philadelphia. “There’s ongoing investigation into understanding why that is, and what can be done to increase the response rate.”

Checkpoint Inhibitors

Immunotherapy drugs, known mainly as checkpoint inhibitors, continue to generate buzz, for a good reason. Since 2010, when the first immunotherapy drug, Yervoy (ipilimumab), was approved by the FDA for the treatment of patients with advanced melanoma, many patients have seen positive results with immunotherapies, and some only had few significant side effects.

These drugs work by unmasking cancer cells and exposing them to the immune system for attack. Now researchers and oncologists are trying to unravel the mystery behind why in some cases—in about half the time that immunotherapy is used in most cancer types—the patient’s immune system doesn’t respond at all.

Some patients who have little or no response to immunotherapy drugs may be suffering from T-cell exhaustion, the scenario where there are not enough available or functioning T-cells to mount a response. “The T-cells may already be busy with other tasks, or they may not be in the right location, or something else may be preventing them from reacting,” says Dr. Markman.

Researchers are exploring how so-called co-stimulators may work in jump-starting the production of T-cells, to ensure that these cells are hardy and plentiful enough to launch an immune response.

Resistance to Immunotherapy

Meanwhile, researchers in London, England, are exploring the role that neoantigens may play in preventing immunotherapy from doing its job. An antigen is a molecule on a cell that attracts immune cells. Neoantigens are new antigens that develop on cancer cells. In some cases, researchers found, cancer cells did not produce enough neoantigens to summon T-cells to attack the tumor, even after they were exposed by an immunotherapy drug.

“The tumors that we think will respond the best [to immunotherapy drugs] have a certain neoantigen burden, but those neoantigens have to be in almost every tumor cell,”1 said Charles Swanton, MD, a cancer geneticist at Francis Crick Institute in London.

Researchers are also trying to determine why the disease relapses (returns) in some patients after initially responding to immunotherapy.

Genetic Mutations

In separate studies, researchers have discovered specific genomic mutations (changes) in cancers that developed resistance to immunotherapy drugs.

In one study, for example, researchers concluded that certain mutations develop resistance to Yervoy, a CTLA-4 checkpoint inhibitor.2

In another study, the researchers concluded that the JAK1 and JAK2 proteins are resistant to the immunotherapy drug Keytruda (pembrolizumab), a PD-1 checkpoint inhibitor, in patients with melanoma whose disease relapsed after early responses to the drug.3

In both studies, the researchers concluded that genetic mutations (alterations) disrupted the interferon-gamma (IFN-y)–signaling pathway, a critical immune system function. IFN-y molecules are cancer-fighting cytokines that attack cancer cells directly and also act as messenger molecules that help to direct the body’s immune response to a drug.

“This is one additional piece of the puzzle of how we could overcome resistance to checkpoint inhibitors,” James Gulley, MD, of the National Cancer Institute (NCI)’s Center for Cancer Research, told NCI staff.3

According to Dr. Markman, disease relapse (return of the cancer) and resistance to checkpoint inhibitors are expected and are not unique to immunotherapies. We also see this with other therapies, he says. “You can have a patient that responds for a period of time, and then ultimately, the cancer develops some form of resistance.”

New Immunotherapy Combinations

New immunotherapy drugs and combinations of immunotherapies are being developed and explored in clinical trials. The hope is that these new therapies will open the door to better responses of different types of cancer and improve patient outcomes.


  1. Begley S. The newest cancer therapies don’t work on everyone. Now, doctors have a clue why. STATnews. March 3, 2016.
  2. MD Anderson Cancer Center. Melanoma tumors use interferon-gamma mutations to fight immunotherapy. MD Anderson News Release. September 22, 2016.
  3. NCI Staff. Mutations linked to immunotherapy resistance. National Cancer Institute blog. August 5, 2016.

This article is based on a blog prepared by Cancer Treatment Centers of America, with clinical oversight by Maurie Markman, MD.

Key Points

  • Relapse and resistance to checkpoint inhibitors are not unique to immunotherapies
  • An antigen is a molecule on a cell that attracts immune cells, and neoantigens are new antigens that develop on cancer cells
  • Sometimes, cancer cells don’t produce enough neoantigens to get the T-cells to attack a tumor, even with immunotherapy
  • Some patients have genetic mutations that may resist the immunotherapy drug
  • New immunotherapies are being developed that may improve outcomes for patients with different types of cancer

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Last modified: June 22, 2020

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