Who Is Likely to Benefit From Immune Checkpoint Blockade?

Exploring Biomarkers That May Predict the Likelihood of Your Cancer Shrinking

Cancers That Cannot Repair Damaged DNA May Respond Better to Immunotherapy
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The idea of using a person's own immune system to fight off cancer is not novel, but getting this concept to translate into medical practice has been an uphill battle.

The good news is that with the recent success of drugs called immune checkpoint inhibitors, the use of immunotherapy to treat cancer has been revitalized. Now, in addition to developing more immune checkpoint inhibitors, researchers are finding ways to better identify the best candidates for such drugs.

In other words, experts want to piece together which patients are most likely to benefit from this type of immunotherapy, meaning whose cancer is most likely to shrink or even vanish as a result of this treatment.

The answers are not straightforward, so it's worth taking some time to understand the basics of this advancing research.

Response to Immune Checkpoint Blockade: Biomarkers

Researchers are investigating ways to identify which immunotherapies will be most effective for each patient. Ideally, an oncologist (a doctor who specializes in treating cancer) would like to test the cancer cells of a person for a biomarker (or multiple biomarkers).

These biomarkers would predict a person's likelihood of responding to a specific immunotherapy. This way, time and the potential for adverse effects are not wasted on a drug that is already known to be less effective for that type of cancer cell.

Three examples of cancer biomarkers that may help predict a person's response to immune checkpoint inhibitors include:

  • PD-L1 expression (whether cells within a tumor express a protein called programmed death-ligand 1)
  • Mutational load (whether cells within a tumor carry high rates of genetic mutations)
  • Mismatch repair status (whether cells within a tumor are mismatch repair deficient or proficient)

Let's explore these three biomarkers in more detail.

This way you can grasp a bit of the science behind why an immune system checkpoint inhibitor may work for one person and not another.

PD-L1 Expression

PDL-1 is a protein expressed on the surface of some cancer cells. Its purpose is to trick the immune system into thinking those cancer cells are healthy or "good." This way the tumor avoids an immune system attack—a sneaky, yet sophisticated and evasive tactic.

However, there are now drugs that block PD-L1. This way the cancer is detected by the immune system because the cancer cells have lost their mask, so to speak. Drugs that block PD-L1 are called immune system checkpoint inhibitors and include:

  • Tecentriq (atezolizumab): blocks PD-L1
  • Bavencio (avelumab): blocks PD-L1
  • Imfinzi (durvalumab): blocks PD-L1

These drugs have been helpful in treating a number of different cancers like bladder cancer, non-small cell lung cancer, and Merkel cell skin cancer.

There are also immune checkpoint inhibitors that block PD-1 (which binds to PD-L1 and can also be expressed by cancer cells), and these include:

  • Opdivo (nivolumab): blocks PD-1
  • Keytruda (pembrolizumab): blocks PD-1

Research shows that these drugs are useful in treating cancers like melanoma, non-small cell lung cancer, kidney cancer, bladder cancer, head and neck cancers, and Hodgkin lymphoma.

In searching for biomarkers that would determine the likelihood of a person responding to one of the above drugs, researchers have begun testing cancer cells for PD-L1. Indeed, while research shows PD-L1 expression is the one factor most closely linked with response to a PD-L1 or PD-1 blocker, more research still needs to be done.

In other words, PD-L1 expression alone may not be a sufficient indicator of whether a person's cancer will shrink or vanish with one of the drugs mentioned above. It's not a perfect biomarker, but a good one thus far.

Mutational Load

Besides PD-L1 expression on cancer cells, researchers have studied the link between a tumor's mutational load and its response to an immune checkpoint inhibitor.

First, in order to understand what a mutational load is, you have to understand what a mutation is and how this relates to cancer.

What Is a Mutation?

A mutation is a change in the DNA sequence that makes up a gene. Mutations can be hereditary (meaning they were passed on from your parents) or acquired.

With acquired mutations, the mutation is only present in the somatic cells (all the cells in the body, but the egg and sperm cells), so they cannot be passed on to the next generation. Acquired mutations may occur from environmental factors, like sun damage or smoking, or from an error that occurs when a cell's DNA is copying itself (called replication).

As in normal cells, acquired mutations also occur in cancer cells, and certain types of cancers have higher rates of mutations than others. For instance, two cancer types that have a high number of somatic mutations are lung cancer, from exposure to cigarette smoke, and melanoma, from exposure to the sun.

What Is a High Mutational Load?

There is research that suggests that tumors with high rates of somatic mutations (higher mutational load) are more likely to respond to immune checkpoint inhibitors than tumors with lower rates of genetic mutations.

This makes sense because, with more mutations, a tumor would theoretically be more recognizable to a person's immune system. In other words, it's hard to hide with all those gene sequence abnormalities.

In fact, these new gene sequences end up creating new tumor-specific proteins called neoantigens. It's these neoantigens that are hopefully recognized by the immune system and attacked (called immunogenic cancer neoantigens because they provoke an immune response).

Mismatch Repair Status

The human body goes through a constant repair process for fixing DNA errors made during cell replication. This process for repairing DNA errors is called mismatch repair.

Research into immune checkpoint inhibitors has revealed that a tumor's mismatch-repair status may be used to predict a person's response to immunotherapy. Specifically, tumors that are mismatch repair deficient (meaning both copies of the mismatch repair gene are mutated or silenced) cannot repair DNA mistakes.

If cancer cells have a decreased ability to repair DNA damage, they can accumulate lots of mutations that make them recognizable to the immune system. In other words, they start to look more and more different from normal (noncancerous) cells.

Research shows that cancers with mismatch-repair deficiencies contain lots of white blood cells that have left the bloodstream to enter the tumor—a sign of a robust immune response and an indication that this cancer is much more vulnerable to immunotherapy.

This is in contrast to mismatch-repair proficient cancers, with show little white blood cell tumor infiltration.

Cancer and the Immune System: A Complex Interaction

The emergence of immunotherapies that target checkpoint proteins has brought excitement and hope to those treating and enduring cancer. But given the imperfect biomarker of PD-L1 expression, other reliable biomarkers need to be identified and investigated. While mutational load and DNA repair mismatch are great starts, tests still need to be validated for use in patients.

With that, determining a person's chance of responding to a specific immunotherapy will likely come from an analysis of multiple types of data—the tumor's genetic profile, so to speak.

A Word From Verywell

On a final note, it's important to not get too bogged down with the complex details presented here.

Rather, please understand that while promising and extremely exciting, immune checkpoint inhibitors are only FDA approved to treat specific types and stages of cancer. They may or may not be the answer for you or a loved one but demonstrate tremendous progress in the development of new treatments for cancer. Either way, stay hopeful and continue your resilient journey.

Sources:

Farkona S, Diamandis EP, Blasutig IM. Cancer immunotherapy: the beginning of the end of cancer? BMC Med. 2016 May 5;14:73.

Le Dt et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Eng J Med. 2015 Jun 25;372(26):2509-20.

Masucci GV et al. Validation of biomarkers to predict response to immunotherapy in cancer: Volume 1 - pre-analytical and analytical validation. J Immunother Cancer. 2016 Nov 15;4:76. eCollection 2016.

Mouw KW, Goldberg MS, Konstantinopoulos PA, D'Andrea AD. DNA damage and repair biomarkers of immunotherapy response. Cancer Discov. 2017 Jul;7(7):675-93.

Shoushtari AN, Wolchok J, Hellman M. (2017). Principles of cancer immunotherapy. Atkins MB, ed. UpToDate. Waltham, MA: UpToDate Inc.

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