Isaac S. Kohane, MD, PhD ©Cassandra Perry

Once dismissed as rare medical miracles that overcame overwhelming odds to thwart cancer, exceptional responders to cancer treatment are now the subject of intense study. In 2015, the National Cancer Institute (NCI) announced the launch of its Exceptional Responders Initiative, with the goal of understanding the molecular underpinnings of patients with cancer who experience dramatic and long-lasting responses to treatments that were ineffective for most other patients, to learn how to advance cancer treatment.

For this initiative, exceptional responders are defined as patients who received a treatment in which fewer than 10% had a complete or durable partial response lasting at least 6 months based on clinical trial data; achieved either a complete or partial response lasting at least 6 months as defined by Response Evaluation Criteria in Solid Tumors (RECIST) or response criteria as defined where RECIST is not commonly used; or sustained a complete or partial response for at least three times longer than the median duration of response from literature resources for a specific treatment.

On November 21, 2017, the NCI announced its study accrual goals had been met and that tissue samples from more than 100 cases had been received and are undergoing molecular analysis. Once completed, controlled access to the data will be made available via the National Center for Biotechnology Information database for Genotypes and Phenotypes (www.ncbi.nlm.nih.gov/gap).¹

This past June, Harvard Medical School took an even broader approach to studying these patient outliers with the launch of the Network of Enigmatic Exceptional Responders (peoplepoweredmedicine.org/neer), a national registry of exceedingly rare patients with all cancer types who had a unique response to treatment. In this study, in addition to patients having genomic sequencing performed on their tumor tissue, blood, and stool material to look for the genetic keys that made their tumor more responsive to treatment, the Network of Enigmatic Exceptional Responders is also compiling data on patients’ diet and lifestyle habits, medical history, and information in their electronic medical records to look for health and environmental clues and pinpoint patterns that might explain the constellation of events that turned these patients into exceptional responders. Just 1 month after the launch of the Network of Enigmatic Exceptional Responders, over 100 patients have already enrolled in the registry.

To qualify as an exceptional responder in the Network of Enigmatic Exceptional Responders, participants must have been among a small percentage of patients who responded to treatments being tested in early-phase clinical trials; patients treated in later-phase clinical trials of single agents or combinations of therapies or treated with established therapies; or patients treated with drugs not found to be generally effective for their cancer type.

To learn more about the goals of the Network of Enigmatic Exceptional Responders, The ASCO Post talked with Isaac S. Kohane, MD, PhD, Chair of the Department of Biomedical Informatics and Marion V. Nelson Professor of Biomedical Informatics at Harvard Medical School and Cofounder of the Network of Enigmatic Exceptional Responders.

Defining Exceptional Responders and Patient Outliers

What is your definition of an exceptional responder, and is there a difference between an exceptional responder and an outlier?

Exceptional responders are patients who respond to therapies in ways that are dramatically and unexpectedly positive. What that means is going to vary from cancer type to cancer type and from treatment protocol to treatment protocol.

For instance, a child who survives acute lymphocytic leukemia and lives many years into adulthood and beyond is not an exceptional responder, because we have been blessed with outstanding survival outcomes in this childhood cancer. Conversely, a patient diagnosed with stage IV lung cancer who is living a full and comfortable life, regardless of any evidence of cancer, for years after the initial diagnosis is considered a remarkable outcome—and an exceptional responder. So, the definition of exceptional responder is a measure of how unlikely a positive outcome is in a patient relative to the disease.

Exceptional responders are fortunate individuals who are unusual. We are trying to figure out what makes them unusual.

— Isaac S. Kohane, MD, PhD

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Exceptional responders are outliers going in a positive outcome direction, but outliers can also be patients with unusually poor outcomes as well. Exceptional responders are fortunate individuals who are unusual. We are trying to figure out what makes them unusual. Is there something special about their treatment that was different from that of other patients? Is there something different about their genetic makeup or their immune system? Has their immune system been reprogrammed differently by their genetics or the environment and infections to which they have been exposed?

Obviously, we don’t yet know the answers to these questions. We do know that these individuals have miraculous responses to therapy, whether they constitute a full remission or not, and we’ve never before studied them as a group. This is why our study and the NCI’s Exceptional Responders Initiative are so important to complete.

Possible Reasons Behind Exceptional Responses

Do you have a theory about what makes exceptional responders exceptional? Are there some emerging patterns that increase their response to therapy, such as tumor biology or lifestyle uniqueness?

We just started our study, so I have to be careful how I answer that question. There are hints from other studies showing that certain molecular features of some exceptional responders’ tumors made them uniquely respond to therapy. So far, that is our best evidence indicating there is something different about these patients’ gene mutations that cause a particularly good response to treatment. But that finding represents only a tiny fraction of exceptional responders, so the jury is still out on the exact reason or reasons.

There is some evidence demonstrating that patients who have tumors with a higher degree of microsatellite instability are more likely to respond to checkpoint inhibitors than patients who do not have cancer with a higher degree of microsatellite instability. That is exactly the type of pattern we are hoping to find. What is the mechanism that makes a difference in these patients? Is it genetics, lifestyle, or the sequence in which patients receive their therapies?

We want to stoke the culture of open access and get an interdisciplinary look at our data from as many fresh perspectives as possible….

— Isaac S. Kohane, MD, PhD

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For example, it may be that receiving an alkylating agent as first-line treatment may damage the immune system and reduce its ability to respond effectively to treatment. It may be that the order in which medications are given is making the difference in exceptional responders. Or it may be that these patients have immune systems that are “revved up” and can go after the cancer.

We have examples in other diseases, such as HIV, in which patients had the virus for years and never developed AIDS (even without treatment), because there was something different and special about their immune system. That insight allowed research in HIV to move forward, and we’re hoping to find similar insights in cancer to advance research.

Statistically, how many patients do you have to enroll in the Network of Enigmatic Exceptional Responders to start to see emerging patterns?

We don’t know for sure. My feeling is that if we can sequence the tumors of 100 patients and obtain their immunoprofiles, that might be enough to start seeing some patterns as to why these patients responded so well to therapy. We have a lot of work ahead, but we should have some results in the next year or two.

Qualifying What It Means to Be an Exceptional Responder

Most of the patients enrolled in the Network of Enigmatic Exceptional Responders have been treated with chemotherapy. Since some patients treated with chimeric antigen receptor (CAR) T-cell therapy experience durable remissions, how might the therapy impact what qualifies as an exceptional responder?

The answer is we don’t know yet. Currently, some patients who have undergone CAR T-cell therapy look like exceptional responders in the sense that they are doing much better than you would expect because they have advanced-stage disease. Certainly, not everyone on CAR T-cell therapy does well, and we don’t know what percentage of patients will experience a durable response. Is the number 10%, 20%, 30%, or higher? The answer isn’t clear yet, so the definition of what is an exceptional responder might change over time.

Sharing Data

Please talk about your plans to make all the clinical and genomic data gathered from patients enrolled in the Network of Enigmatic Exceptional Responders available to outside investigators through a controlled-access database housed at Harvard Medical School.

From the outset of planning this study design, we decided that we would make all the data available to participants in the study, so they can offer this information to other researchers and interested researchers could also access the data from our database and perform their own analyses. The idea is to get as many eyeballs on our data as possible. We want to stoke the culture of open access and get an interdisciplinary look at our data from as many fresh perspectives as possible to learn what makes these patients so exceptional.

‘Turning Every Patient Into an Exceptional Responder’

Isn’t the goal of personalized medicine to make every patient with cancer an exceptional responder?

Yes, that’s right. I hadn’t thought of exceptional responder in that context before, but it is the intention of personalized medicine to provide long-term remissions, even cures, for patients with cancer, essentially turning every patient into an exceptional responder. That could be our campaign slogan.

To learn more about the Network of Enigmatic Exceptional Responders project and to enroll patients, visit peoplepoweredmedicine.org/neer.■

DISCLOSURE: Dr. Kohane reported no conflicts of interest.

REFERENCE

1. National Cancer Institute: Exceptional Responders Initiative: Questions and Answers. Available at www.cancer.gov/about-cancer/treatment/research/exceptional-responders-initiative-qa. Accessed August 3, 2018.