Will My Cancer Respond to Immunotherapy?

Radio-immunotherapy, drawing
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Wouldn’t it be great if doctors could take a look at your cancer, look at the various new therapies that are emerging, and make a determination about which options are most likely to succeed?

Although oncologists may, in many instances, have good tools and data to sort out and compare different treatments, newly emerging therapies can sometimes be difficult to predict, in the absence of clinical experience.

Advances in knowledge come from clinical trials, in which patients agree to enter studies with research drugs that have shown some promise; but, as the term ‘trial’ implies, there is always a degree of uncertainty about how well a drug will perform and who will benefit most—that is, which patient types and which subsets of cancer.

What Is Cancer Immunotherapy?

Cancer immunotherapy is a treatment that involves certain parts of an individual’s immune system to fight the malignancy. One example of immunotherapy is the use of monoclonal antibodies such as rituximab and obinutuzumab. Monoclonal antibodies are man-made antibodies, or immune system proteins. These antibodies can attack a very specific part of a cancer cell in what is known as targeted therapy.

Other forms of cancer immunotherapy include immune checkpoint inhibitors, which take the ‘brakes’ off the immune system to help it recognize and attack cancer cells.

The world of cancer immunotherapy is by no means limited to the above examples, however, and new ideas for using your body's own immune system to fight the cancer cells continue to be developed and tested.

Does Immunotherapy Work for All Cancers?

Each person is unique, and each person’s cancer is unique; not everyone responds in the same way to the same immunotherapy.

Effectively gauging, in advance, which people are most likely to respond to an immunotherapy would be advantageous from several angles. For the patient, it could save crucial time, which could translate into clinical benefit.

In other words, you wouldn't waste your time or risk side effects trying something that is likely to have a minimal effect when there may be a 'bigger gun' or more effective therapy available. But how might one know this type of thing in advance? One story relating to how oncologists and cancer researchers are going about doing this begins with something called neoantigens.

Neoantigens: Cancer’s Achilles Heal?

Cancer cells can be sneaky. They often have a number of changes in their genes, some of which may correspond to their ability to do bad things that normal, healthy cells cannot. Some of these changes actually result in physical differences in or on the outside of the cancer cells that can be detected by the immune system. These parts of cancer cells that the immune system can recognize as foreign are called “neoantigens.”

Neo, meaning new, because they arise newly from our own cells, gone amuck with cancer, as opposed to the regular antigens scientists usually talk about in contagious diseases, for example. Regular antigens may be found on the outside of bacteria, or virally infected cells, for instance. In contrast, neoantigens are like red flags that can signal the immune system that our own cells are misbehaving.

Neoantigens lead to the activation of white blood cells known as T-cells—the immune system’s soldiers. These soldier T-cells then travel the blood vessels, much like the cobblestone roads of Ancient Rome, to reach the site of the unruly malignant cells, infiltrate the tumor and help decimate the local population of malignant cells.

So, neoantigens are one of the keys to immune-based anti-cancer therapies. That said, winning the battle seldom involves immunotherapy alone, and a more scorched-earth type of approach is usually needed; immunotherapy is often used in conjunction with cytotoxic chemotherapy and/or and other immunotherpies, depending on the malignancy and the individual patient.

Will Immunotherapy Work For Me?

This is an important question in modern oncology, and one that is being actively worked on. Toward that end, two characteristics of your cancer cells may help doctors predict how well available immunotherapies will work: TMB and MSI.

Tumor mutational burden, or TMB, can be thought of as an index of all those changes in genes in the cancer cells that have gone awry—genes, for instance, that used to code for all the normal things a cell might need—but that have changes or mutations in the case of the cancerous cells. TMB is sometimes also referred to as total mutational burden or mutational load.

Tumors that have high TMB are believed to have more neoantigens and therefore may respond better to immunotherapy. Cancer cells can end up with high TMB through exposures linked to cancer, including to tobacco or UV light. Another way is through microsatellite instability, or MSI, a technical term that refers to a problem with your body’s natural mechanisms for DNA repair—a problem that results in highly changing and inconsistent lengths of repetitive DNA gene sequences.

One company called Foundation Medicine now offers the first fully-integrated, validated assessments of TMB as part of its FoundationOne assay, which may help predict a person’s potential response to immunotherapy.

“Faulty genomes are the common denominator of all cancers,” explains Vincent Miller, MD, chief medical officer at Foundation Medicine. “Tumors with an especially high number of mutations are more likely to produce new, abnormal proteins called neoantigens. The immune system recognizes these neoantigens as foreign and goes on high alert, initiating a complex series of steps to attack the tumor.”

Will an Immune Checkpoint Inhibitor Work for Me?

The plot thickens in that some cancers have developed extremely sneaky ways of evading the immune system—by making proteins that actually inactivate certain types of your immune cells. A biologic cloaking device, if you will.

To prevent the cancer from cloaking itself in this way, some immunotherapies have been designed to block these immune-suppressing proteins. These immunotherapies, known as immune checkpoint inhibitors, include those termed anti-PD1 and anti-PDL1 antibodies. And, as with other types of immunotherapy, there is evidence that suggests higher levels of neoantigens in the cancer cells are associated with better responses to immune checkpoint inhibitors.

The response to check point inhibitors varies from approximately 20 percent in lung cancer to 80 percent in Hodgkin lymphoma. The reason why certain tumors respond to check point inhibitors and others don`t is not clear.

Importance of Predicting Clinical Response

These predictive tools and their success was a topic of conversation at this year’s meeting of the American Society of Clinical Oncology, or ASCO.

TMB has been shown to predict a greater likelihood of response and longer duration of response to cancer immunotherapies in patients with bladder cancer, lung cancer, melanoma and other advanced cancers. In addition to TMB, FoundationOne also measures microsatellite instability, representing a single test to guide therapeutic decisions for targeted therapies, clinical trials and FDA-approved cancer immunotherapies using a single biopsy.

“Cancer immunotherapies are at the forefront of cancer treatment, and new, quantitative approaches are needed to predict clinical responses to this important, but also expensive, class of therapies,” said Dr. Miller.

“The ability to accurately measure multiple biomarkers simultaneously, including TMB and MSI, is an important advance for the field of cancer immunotherapy, and one that is unique to Foundation Medicine,” said Thomas George, M.D., GI oncology program director, University of Florida. “Foundation Medicine’s combination of advanced sequencing platforms and highly-specific algorithms gives me access to all relevant genomic biomarkers for my patients at once, helping to save both time and tissue.”

“We were encouraged by the findings presented at ASCO, including the possibility of identifying patients more likely to benefit from checkpoint inhibitor immunotherapy,” said Dr. Miller. “Our goal is to empower doctors and patients with a full range of relevant, actionable genomic information, and we’re excited to offer our distinctive solution to estimate TMB and MSI simultaneously and with exceptional accuracy, supported by sophisticated algorithms and rooted in contextual insights from our knowledge base FoundationCORE. This is something no other next-generation sequencing platform offers.”

Independent of the FoundationOne and FoundationOne Heme assays, Foundation Medicine also offers testing for PD-1 and PD-L1 protein expression, providing, in combination with the FoundationOne assays, a full suite of cancer immunotherapy assays for oncologists.

Sources:

Foundation Medicine presents new data at ASCO 2016 demonstrating that FoundationOne may help predict response to cancer immunotherapy across a variety of advanced cancers.

Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 Blockade with Nivolumab in Relapsed or Refractory Hodgkin’s Lymphoma. N Engl J Med. 2015;372(4):311-319.

Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252-64.

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