April 28, 2020

Jim Heath: On a Mission to Learn Why COVID-19 Patients Have Drastically Different Outcomes

Michele Cleary, PhD

This post is a first in a series highlighting a selection of The Mark Foundation for Cancer Research’s scientific partners who have rapidly mobilized resources to confront the great challenges posed by COVID-19. Dr. Heath is a recipient of the foundation’s ASPIRE Award for a project titled “Using Blood Biomarkers to Aid App-Based Cancer Monitoring”

In my last post, I aimed to lay to rest misconceptions that scientific productivity will grind to a halt during this challenging period. Scientists are deeply wedded to the research they have put on pause, and abandoning efforts poised for breakthroughs has been heartbreaking. While this is true, the essence of science is problem solving. For most scientists, there is just as much exhilaration in trying to solve an unexpected problem that has arisen anew today as there is in making steady progress on problems that they may have been tackling for years.

We are witnessing this phenomenon in action within our own network of funded investigators, many of whom have pivoted to research aimed at solving problems with COVID-19. Thankfully, this type of research, deemed “essential”, can continue as time is of the essence. In this post I want to share one example, although many of our researchers have taken similar steps in deploying their skills and capabilities for the greater good.

An immediate pivot in Seattle, the U.S.’s first COVID-19 hot spot

In 2019, we awarded a grant to Jim Heath from The Institute for Systems Biology (ISB) to study blood markers that would give insight to the disease trajectories of glioblastoma patients. In response to the current situation, Heath is redirecting the application of these platforms and others with the help of Dr. Jason Goldman of the Swedish Medical Center in Seattle and a team of collaborators to samples from COVID-19 patients from several hospitals within the Swedish healthcare network. The battery of experimental approaches they are deploying will allow them to holistically probe the effects of the virus on patients looking at features such as cardiac physiology, oxygenation, lung tissue damage, blood clotting and more. As patients enroll in the study, Heath and team are tracking timed responses of the immune system to better understand the disease and, more importantly, optimize treatments and design the best vaccines.

ISB-Swedish study participant tee shirt

Along with the sheer depth of analysis that this study will undertake, there are two other unique features of the study that are remarkable. First, the team received internal review board (IRB) approval in 24 hours. This process usually takes weeks to months; however, the urgency in this case is undeniable. Second, unlike many studies that offer payment to participants, the ISB–Swedish team has designed an apropos tee shirt that will no doubt become an envied souvenir. The design of the tee shirt, showing a patient slashing a model of the virus with a sword, makes it clear that these patients are being viewed as warriors in the fight against this deadly disease.

Patients are consented for the study when a participating physician suspects a diagnosis of COVID-19, and blood is taken upon confirmation by testing. The team aims to recruit roughly an equal number of patients within 4 categories of severity:

· asymptomatic but confirmed presence of the virus;

· at home with symptoms, without the need for hospital admission;

· in the hospital but not in the ICU;

· in the ICU most likely on a ventilator.

Initially, the team envisions a 200-patient study, but it could be bigger. So far 50 patients have been enrolled, most of whom are in the hospital. To track patients convalescing at home, the team has deployed a mobile phlebotomy unit to access samples across multiple time points throughout the trajectory of each patient’s disease. In addition to blood, the team will acquire nasal swabs, and when outcomes are grim, tissue samples.

With the wide variability in response among patients to SARS-CoV-2 infection, we don’t know what may be special about the immune responses of those whose symptoms are mild versus those who suffer severe effects or ultimately succumb to the disease. Two key questions will be addressed in the immune analysis of patient blood samples: What happens to a patient’s immune system when exposed to the virus early on as well as over time; and what protective features of an immune response allow for successful viral clearance?

Some of the patients enrolled in these studies will have been given various treatments designed to lessen the impact of their symptoms. This information will help the team get a glimpse into what regimens may be useful and at what time point in the course of the illness. Unlike a randomized controlled clinical trial, however, where all subjects start at the same time point, each arm is respectively treated uniformly, and patient responses are tracked prospectively, information from the Seattle COVID-19 patients will be retrospective, and the treatments will have been much more diverse. Nonetheless, this information could be helpful to more precisely design clinical trials downstream.

It is an understatement to say that the biology of SARS-CoV-2 has been perplexing. In some regards, viruses can be viewed as the ultimate machine learners. They readily adapt to defense mechanisms mounted by their hosts, constantly incorporating features that give them the best possible advantage for replicating themselves and surviving. Heath speculates that in the case of SARS-CoV-2, it may be that the virus has figured out how to exhaust the host’s immune system. If this is the case, there may indeed be biological mechanisms at play that are also exploited by cancer cells, which need to evade the immune system to progress to full blown tumor formation and ultimately metastasis.

Taking advantage of the same high-tech measurements used for the study of cancer biomarkers, such as in-depth protein and cellular profiling in blood and other tissues, the Seattle team will generate rich data sets that can be mined for new knowledge and insights. The data types gathered will include comprehensive gene expression in patient tissues in bulk and at the level of single cells. The team will sequence the functional receptors present on individual B cells and T cells to establish a profile of patients’ immune repertoires and focus in those receptor sequences that are most relevant to a productive response against the virus. They will also sequence whole genomes to get a better view into the role that genetics plays in the course and severity of viral infection.

Because it relies heavily on host cell machinery for its replication and life cycle, the virus itself can stay genetically streamlined. SARS-CoV-2 encodes a small number of proteins. Heath and his team took the sequences of these viral proteins and computationally predicted antigens (entities that the immune system sees as foreign) that might be recognized by T cells. With this information, they are experimentally expressing about 100 computationally-derived peptides in cells in conjunction with the major histocompatibility complexes that display foreign antigens to T cells and then testing which ones activate T cells when combined in the laboratory with patient blood. In these early analyses, Heath and colleagues are seeing variation and time dependence in the immune responses mounted in patients. Remarkably, however, the same antigens for the most part stimulate response across the majority of patient samples.

Heath speculates that the virus has evolved a very sophisticated mechanism to exhaust the immune system that spares the virus from attack. One of the predominant antigens recognized by patient T cells maps to a viral peptide that gets cleaved upon viral entry into cells. It is possible that the virus has created a decoy that recruits, activates, and ultimately exhausts, T cells, allowing it to move past one of the body’s strongest defense mechanisms. Currently, this is just a hypothesis, but the studies that Heath and collaborators are pursuing will test this and other hypotheses.

Importantly, the ISB is known for strength in data analytics and machine learning approaches. So in addition to vetting hypotheses, the team will be able to apply their robust algorithms to all the data gathered to uncover the unknown unknowns about SARS-CoV-2 and ultimately point us down the right path to preventive measures such as vaccines and other lifesaving treatments.

As I think about what the ISB–Swedish team is setting out to achieve, I keep coming back to the benefits this endeavor will have for cancer research, particularly with respect to insights about mechanisms for immune system evasion. We have powerful immunotherapies that work for well for some cancer patients but not for others, and while many plausible leads have emerged in this space, we still really don’t know how to convert non responders to responders. I am optimistic that we may learn things from COVID-19 that shed light on the immune system/disease nexus that can be reworked into approaches that optimize cancer immunotherapy. That said, irrespective of the enormous advances this project will make in new knowledge about biology, it is clear that the computational tools that will need to be designed and refined will have enormous utility in the measurement and analysis of biomarkers for cancer and other diseases.

We at The Mark Foundation are very eager to see Jim Heath and his collaborators get to a rapid and successful conclusion of their COVID-19 patient study for the benefit of patients and for science. We are rooting for their success and eagerly await the day when this awful disease will be solved.

Since meeting with Jim Heath to learn more about this work, Merck and Co., Inc. announced a partnership with ISB that will substantially empower translation of their findings to clinical benefit. We congratulate them on this exciting development.

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