Every case of cancer is unique. Two patients with the same cancer type can have tumors with vastly different characteristics, and each patient’s immune system may react differently to their cancer. As a result, each treatment journey is unique and different from the moment of the first diagnosis.
It is an oncologist’s role to help navigate their patients through a complex maze of treatment decisions. For example, who should be recommended for which treatment? How long should they receive the treatment? In the era of precision medicine, healthcare providers rely on biomarker testing to give individual recommendations for each patient rather than using a one-size-fits-all approach.
This precision medicine approach, however, has had minimal impact on drugs used for cancer immunotherapy. Treating a patient with an immune checkpoint inhibitor (ICI) recruits their immune system to find and fight the cancer. However, ICIs do not work for most people, and typically less than 25 percent of patients experience a significant change to their long-term prognosis. Doctors have had limited, imprecise tools for assessing who is likely to be a good candidate for immunotherapy with these ICIs.
UK-listed Anglo-American precision medicine company Oxford Biodynamics has a proprietary blood test in clinical use today, called EpiSwitch CiRT (Checkpoint inhibitor Response Test), which identifies a patient’s most likely response to ICIs. The straightforward, noninvasive test evaluates eight 3D genomic markers – also called a chromatin-conformation signature (CCS) – and is the only test that returns a binary result to the ordering physician with high accuracy: “low probability” or “high probability” of response to an ICI.
In this interview, Thomas Guiel, chief operating officer of Oxford BioDynamics, talks about how the test is changing patient treatment.
What standard tools have clinical oncologists relied upon, until now, when deciding about ICI treatment?
Tom: Immunotherapy with an ICI gives some cancer patients a real boost to their recovery and survival, but there have been no good biomarkers to guide doctors on who may or may not benefit. Several imperfect tools rely on retrieving a biopsy of the cancer from a patient or resecting the tumor and then looking for specific genetic or protein markers, such as the expression of PD-L1.
Although this type of testing is now widely used, only about one in four patients put on ICI therapy will see an overall anti-cancer benefit. Of the remaining three, many will be kept on the therapy despite the risk of serious side effects, with significant expense and lack of positive outcome.
What is also worrying is that recent literature suggests that a significant fraction of patients who test negative for PD-L1 expression, and are subsequently denied ICI therapy, would have benefited from these drugs. For example, over 18 percent of PD-L1 negative patients had an observed cancer regression after being treated with an ICI in a hepatocellular carcinoma clinical trial.
It is important to have more immunotherapy patients on an appropriate treatment path, but established tests can give a false sense of confidence. Therefore, we feel it is necessary to provide doctors with a better tool to guide their decision on whether ICIs could be an effective therapy for their patients. This is why we developed the EpiSwitch CiRT.
What potential do you see for EpiSwitch CiRT in changing the clinical decision-making process?
Tom: We are delighted by the initial positive reaction from the oncology industry. We believe that the transformation could be multifold. Firstly, in treatment planning, if the CiRT indicates a high likelihood of response, a doctor may recommend ICI therapy with confidence for their patient, building on the understanding that the molecular immune profile is associated with clinical benefit to ICIs, regardless of their PD-L1 status. Even if the patient does not initially respond to therapy, they will likely benefit later from continuing therapy for longer, acknowledging a slow immune response. On the other hand, a low-likelihood result is a strong indication that the patient will not respond to ICI treatment. In this case, a doctor may limit the ICI therapy to a shorter duration before re-imaging and/or evaluating other options.
ICIs are not benign, and it is crucial to know that a patient’s situation can quickly change with immunotherapy. As many as 40 percent of those treated will face a cascade of treatment-related toxicity, called an immune-related adverse event (irAE), that can occur at any time when the immune system is re-engaged. As a result, often, the treatment must be stopped, and without adequate tests, such as the CiRT, it is very difficult to know whether to recommend resuming therapy. Interestingly, emerging evidence suggests that patients with strong irAEs may have better chances of achieving a durable response to ICIs if they are reset by continuing their treatment course.
CiRT is initially being used as a complementary test, giving doctors additional guidance to make a balanced therapy recommendation. However, as adoption grows, we are confident that CiRT will significantly impact how immunotherapy is administered.
Can you provide any examples of how this test is useful in managing treatment with ICIs?
Tom: Understanding a patient’s likely response to ICI therapy is a fundamental benefit of using CiRT to help guide treatment planning. But there are additional compelling benefits.
Recently, we ran CiRT on a young, 34-year-old woman diagnosed with late-stage colorectal cancer that had also metastasized to the liver. Her biopsy was PD-L1 negative, and her microsatellite instability (MSI) was low, which usually means she is not even considered for ICI therapy. However, the CiRT test indicated that she had a high probability of responding to ICIs. Based on this new information, her oncologist has recommended her a second-line treatment with ICIs.
In another case, a 90-year-old female patient with recurrent squamous cell carcinoma tested positive for PD-L1 protein by IHC. She had a tumor proportion score of 90 percent, which would generally warrant ICI treatment, yet her CiRT profile returned a low probability of response. When treated with the ICI, the patient did not respond – confirming our prediction.
These are not isolated cases. In some of the most widely treated cancers, more than one in six patients with a negative PD-L1 result are still likely to respond to ICI therapy if given a chance. This means that there is another major use opportunity where CiRT can significantly impact and potentially change anti-cancer care.
You mentioned that markers from tumor biopsies have not provided an adequate solution for predicting response to ICIs. What are CiRT’s benefits as a blood test?
Tom: Cancer does not exist in isolation, but is tied heavily to the unique biochemistries our body possesses and utilizes. The most successful approaches must consider the larger systemic picture and capture the interactions between a tumor, its surrounding microenvironment, the immune system, and a patient’s genetics. Blood is an ideal medium to sample this complete biological picture. A blood test allows for a noninvasive approach to collect a snapshot of the complex interplay of cellular systems within a human. Traditional tests that only rely on a tumor specimen collected with a needle biopsy or surgery are inherently limited as they cannot capture any molecular information beyond the tumor’s expression patterns.
EpiSwitch CiRT is a first-of-its-kind test that taps into the powerful modality of three-dimensional (3D) genomics. The genome is purposefully organized in a compact 3D shape that serves a vital role in biological regulation. With the advent of the EpiSwitch platform, we can reliably and sensitively measure stable, conserved 3D architectures common across a clinical phenotype in a standard clinical lab for the first time. From the blood, we see a clear signal that is universal across both responders and non-responders to ICIs.
How universal? There are many types of cancer and diverse treatment options out there.
Tom: CiRT has demonstrated best-in-class performance from validated clinical work assessing several ICIs regimes from multiple pharmaceutical companies and more than 15 of the broad, key oncological indications, including melanoma, lymphoma, pancreatic, and lung cancer. Therefore, the CiRT result is not specific to a particular drug or type of tumor. Almost every cancer patient being considered for ICIs can benefit from the guidance the CiRT diagnostic provides to their doctor.
Are there any hurdles before CiRT can deliver this promise of personalized medicine?
Tom: The test is already in clinical use in the US and UK. We have partnered with a high-complexity CLIA-certified laboratory, NEXT Molecular Analytics in Virginia, to ensure that we can make the test widely available and meet the demand from clinicians as quickly as possible. CIRT is a simple blood test, and doctors can order it like any other routine lab test. Therefore, there are no barriers for a doctor to start using CiRT today for patient management strategies in the oncology setting. Once the lab receives the blood, a secure report is returned in days with fast, accurate results. Currently, the test is already helping guide doctors and patients to navigate more clearly the most effective pathway of treatment.
What’s next after CiRT? You talked about the unique opportunities unlocked with the EpiSwitch platform. There must be other diseases where this will make a major clinical impact.
Tom: Over the last decade, we have built the world’s largest database of regulatory 3D genomic signatures in blood across many indications. CiRT was made possible by our deep understanding of predictive biomarkers in oncology. Leading pharma companies in this arena are well aware of this, and we have publicly discussed some of our other projects in this space. Beyond cancer, the EpiSwitch platform was also selected for use in an ongoing Phase IV clinical trial in amyotrophic lateral sclerosis (ALS), led by Mitsubishi Tanabe Pharma America and Massachusetts General Hospital, where it is driving successful patient stratification in conjunction with Mitsubishi’s ALS drug Radicava.
What’s just as exciting, last year we introduced our high-throughput EpiSwitch biomarker discovery platform as a kit via a partnership with Agilent Technologies. We call it the EpiSwitch Explorer Array Kit. Thanks to this, now any lab can easily explore high-quality 3D genomic biomarkers in blood at scale for research purposes. We are very pleased to have assets being utilized in the clinic, basic science laboratories, and in the clinical trial setting for major biopharma.