This story is part of The Cancer Letter’s ongoing coverage of COVID-19’s impact on oncology. A full list of our coverage, as well as the latest meeting cancellations, is available here.
It’s hard to fathom the number of scientific discoveries that are exploding from the COVID-19 disaster. Though there may be tumbleweeds on every street around the globe and impotent silence in the shuttered stores of every town, the scientists at the frontline of this epidemic are busier and more energized than they’ve been in a long time.
The tragedy and confusion of our current reality will linger for a very long time to come, but the history of medicine is likely to look back on these months with humbled reverence and gratitude.
The strategies anyone might use to study and combat the virus are diverse, and they depend on the context and focus of a given scientist’s work. Physicians who are supervising the care of hospitalized patients have first-hand access to the natural history of the disease.
Bench scientists with access to clinical samples are uniquely suited to dissect the biological underpinnings of the clinical picture. In collaboration with an extremely responsive and supportive global regulatory community, a broad array of clinical and bench-based scientists is generating a whirlwind of hypotheses—and potential therapies are flying off the shelf. Clinical studies are starting in record time, and great ideas are speeding from white board to publication in weeks. These are the worst of times, but they are also the best of times.
To read the pulse from the front lines, I connected with a ready-made community of world-class physicians and scientists who assembled in 2007 because of their mutual love of immunology and also because of their mutual love, of all things, music.
The group, a blues-rock band called The Checkpoints, is composed of global leaders who are leveraging their deep knowledge of the immune system to assist in the battle against COVID-19. They include multiple heads of cancer or immunotherapy departments in major American institutions, former and current presidents of the Society for Immunotherapy of Cancer (SITC), and a Nobel Prize-winning scientist (The Cancer Letter, Oct. 5, 2018).
What do we know today? What are these folks seeing in their COVID-19-infected patients and in their own personal scientific explorations? What are the ongoing hypotheses that drive the emerging clinical studies, and what can we say about the rapid evolution of medicine, in light of their ongoing work?
To get some answers, I reached out to members of the band and conducted structured interviews around these questions. While the content of their responses overlapped considerably, I was surprised to find that each of them came from meaningfully different angles and that their integrated story was richer than I’d found from any one member of the group. Relevant references for further reading are provided at the bottom.
Here’s what I learned:
By way of introduction
As we’ve been hearing routinely throughout the past weeks, up to 25% of COVID-19-infected people don’t experience symptoms at all and may never know that they’ve been infected. For everyone else, key symptoms center around the lungs, where patients’ experiences could range from a benign and short-lived dry cough to deadly diffuse lung failure requiring artificial ventilation in the ICU.
What has been emerging in the last few weeks, though, is that the constellation of meaningful symptoms isn’t confined to the lung. Some patients experience GI symptoms (e.g. severe diarrhea) and/or a loss of their sense of smell as the primary symptom.
Kidney injury, bone marrow reduction, and severe heart damage are also seen. A rare disorder previously associated with other viral infections and certain T cell-based immunotherapies, secondary hematophagocytic lympho-histiocytosis (sHLH), was identified in some COVID-19 subjects within the past few weeks, and the observations of physicians in the UK was published in the Lancet last Saturday.
Cancer doctors who have been studying the immune system for the last two decades recognize the symptoms of COVID-19 infection from their experience in oncology. To them, the constellation of toxicities in some infected patient looks like an immune response run amok.
Their thinking is that when key elements of the immune system are kick-started by the virus, an over-ambitious immune response in some patients will lead to life-threatening fulminant multi-organ failure. If this explosive blast of immunity occurs early enough in the infection, they reason, the patient may die before the virus has the chance to be fully cleared from the body.
The scientific tools we need to dissect the myriad of open questions are available in ways that the victims of the 1918 Spanish flu epidemic couldn’t leverage 100 years ago. These tools include an intimate knowledge of the immune system, derived from years of study in the context of HIV infection, autoimmune diseases and cancer.
Additionally, large networks of multinational collaborations that were initiated in recent decades increased in size and number dramatically in the last few weeks. “Basket clinical studies” that enable physicians to test lots of potential therapies in a single clinical study are now opening in record times at a scale and global reach never seen before. Bioinformatics technologies to help design vaccines has also entered the scene within the past few decades.
What we know
Let’s start with what we know today, and by “today” I mean observations made as recently as yesterday.
The short answer is that no one knows anything with certainty, and for that reason we must interpret the following with caution. We need to recognize that the definitive answers are still weeks, possibly months, away. Solid and scholarly hypotheses abound. They include the observations that symptoms in seriously ill COVID-19 patients resemble familiar symptoms in the settings of other viral infections and cancer.
“Cytokines”—helpful or hurtful? Many clinicians are observing high serum levels of key cytokines, like IL-6 and IL-1, in the sickest patients with COVID-19. Cytokine storm is a familiar event to oncologists, seen in patients with cancer who receive CAR T immunotherapy. In this setting, the powerful anti-cancer effect of CAR Ts puts the system into overdrive, increasing expression of cytokines and creating clinical symptoms that look very much like those in critically ill COVID-19 patients. The running hypothesis, then, is that cytokine release, usually a necessary element of the normal response to viral infection, becomes unacceptably high in some patients for reasons that are poorly understood. The high levels of cytokines overwhelm normal body systems, causing injury, particularly in the lung.
Open questions here include: if cytokines are a necessary feature of the anti-viral immune responses, what are the consequences of inhibiting them in some patients? How can we distinguish those patients that must have inhibition of cytokines from those that might be harmed by it, and if we end up concluding that cytokines must be blocked, is inhibiting one cytokine enough? Do we need to inhibit in a combination of more than one? If so, which ones?
In collaboration with an extremely responsive and supportive global regulatory community, a broad array of clinical and bench-based scientists is generating a whirlwind of hypotheses—and potential therapies are f lying off the shelf.
Cellular immunity—helpful or hurtful? The response of activated T cells to the virus is traditionally thought to be a key component of the immune response to the virus. However, enhancing T cell immunity with T cell checkpoint blockers (e.g. CTLA-4 of PD-1 pathway inhibitors) in cancer patients can also cause life-threatening inflammation in the lungs (pneumonitis), the same type of pneumonitis that is seen in COVID-19 patients. Could it be that the pneumonitis in the two clinical settings are related due to an over-active cellular immunity? Could it be that direct lung damage by the virus at the point of entry in the respiratory track increases the sensitivity of that tissue to the adverse effects of T cell stimulation, and are there already bacteria in the lung microbiome in some patients that predispose them to damage by an active anti-viral T cell response? These are questions that need answers.
Consequently, there’s lots of ongoing discussion about whether it’s appropriate or even safe to apply checkpoint blockade to cancer patients who are in the midst of an active, even mild, COVID-19 infection. However, there’s evidence that the types of lung damage in the cancer vs. infection setting may be different, and the caution that might lead physicians to stop checkpoint blockade in cancer patients may be misplaced. Pneumonitis from checkpoint blockers respond to anti-TNF, while the pneumonitis from COVID-19 apparently does not.
Still, caution is appropriate. The National Comprehensive Cancer Network will be releasing guidelines shortly on the treatment of cancer patients with checkpoint blockers during the period of COVID-19 infection.
Some scientists think that T cells aren’t the culprit in lung damage during COVID-19 infection. Stimulation of other cells in the lung microenvironment, like macrophages, may make the difference. If confirmed, this line of reasoning could lead to other forms of therapy during COVID-19 viral infection. Interestingly, anti-malaria drugs like chloroquine and hydroxychloroquine inhibit production of pro-inflammatory cytokines by antigen presenting cells and macrophages, and this explains in part why clinicians have tested their use in infected patients. However, anti-malarial drugs don’t have target specificity and may be inhibiting desirable biological functions that patients need to fight the virus. Antibodies, which more precisely target specific cytokines of interest may be better suited to treat patients.
Open questions here include: Is it ever appropriate to amplify the T cell response as a means of clearing COVID-19 faster, perhaps early in the infection when such a boost to the immune system may be useful? Or is such treatment always likely to exacerbate the life-threatening symptoms? In chronic viral infections, T cell stimulators can be helpful, but what about in acute infections? Will they cause harm? What are the other predominating cells that play a role in COVID-19, and what are the implications for treatment options?
The timing of the various immune responses may matter. In the normal response to an infection like COVID-19, all elements of the immune system may be important. Antibodies, a first pillar in the immune system, can directly clear virus, and/or mark virally infected cells for destruction. T cell stimulation, a second pillar, causes a direct attack on virally infected cells, as it does for cancer cells, and cytokines, the third pillar, play a role as non-specific overarching stimulators of immune function. The timing, relative importance and/or relative magnitude of these independent and interdependent elements of the immune system likely impacts the course of COVID-19 infection. Each arm of the immune system causes a different constellation of symptoms, depending on the magnitude of the response. Each arm is activated at different times in the immune response and the choreography between them is likely an important factor in patient outcome.
Open questions here include: can we use therapeutic intervention to impact the timing and magnitude of multiple arms of the immune system, and, again, can we better select patients who need one type of immune support over another?
Key differences between people may impact how they respond to the virus. The conditions within each person that govern how they might respond to the COVID-19 virus clearly differ between people. Otherwise, we wouldn’t be seeing such a diverse array of outcomes. But what are these differences? Candidates include genotypic differences (e.g. HLA type), phenotypic differences (e.g. age of condition of the immune system) or environmental elements (e.g. the patient’s lung microbiome, the size of mechanism of viral inoculum, co-morbidities like cancer or other infirmities).
An open question that covers all the hypotheses: as we drive a better understanding of which drugs to give these patients and when to give them, one big open question is at what dose and for how long.
In pursuit of the answers
In response to this massive list of incoming observations, hypotheses and uncertainties, physicians and scientists around the world are rapidly creating resources to answer these questions. Taskforces are forming. Dropboxes filled with papers are being populated and shared. Clinical protocols are being disseminated and conducted widely. Cytokine panels are being added to research—and lots of information is already out there.
At the University of Chicago, where Thomas Gajewski, AbbVie Foundation Professor of Cancer Immunotherapy, is spearheading the bedside to bench to bedside work, there is a systematic effort to understand who benefits from the candidate therapies and who doesn’t. Bio-banked serum from cancer patients who experienced pneumonitis from checkpoint blockade is being compared to newly bio-banked serum from COVID-19 patients, with some of those patients receiving anti-viral agents, cytokine blockers, or hydroxychloroquine. In this way, the two fields are learning from each other.
Resident microbes in the airways are being evaluated from the diagnostic nasal swabs. That material is being sequenced to see if specific microbiotal patterns predispose some patients to worse outcomes than others. Germline polymorphisms that are known to be linked to susceptibility to other viruses are also being evaluated in the context of the course of COVID infection.
The magnitude of the T cell and Ab response is being analyzed with respect to viral clearance as well as immune pathology. This work will be very important in defining opportunities to develop treatments in real time—building on the learnings from oncology to serve the current state of the pandemic.
At the University of Pittsburgh Medical Center, a broad catchment of patients across a community cancer network may enable bio-clinical sample collection from a wide range of patients (healthy and sick). There, Jason Luke, associate professor of medicine in the Division of Hematology/Oncology and the director of the Cancer Immunotherapeutics Center within the UPMC Hillman Cancer Immunology and Immunotherapy Program, and his colleagues plan to prospectively follow the natural history of the illness and determine which patient characteristics, from among the full spectrum of those listed above, are associated with various forms of viral response.
Routine screening of up to 1,000 patients to see who becomes sick over weeks or months will make a valuable contribution to the treatment of this virus over time. Early serological evidence of metabolites of cytokines, for example, may predict who will get sick. Following the magnitude and pattern of changes over time could help time therapeutic interventions. Hence, while others are looking to find therapies now, Dr. Luke’s teams are thinking ahead to better understand the natural history of the disease for people with all types of clinical responses.
At UCLA, John Timmerman, associate professor of medicine at the UCLA Lymphoma Program, is encouraging local efforts for transfer of convalescent serum from recovered patients into sick patients, a strategy that is underway around the world. This approach, successfully developed by the early pioneers in immunology in the 1918 Spanish flu pandemic, has also been used to treat outbreaks of polio, measles, and mumps. Hence, under Dr. Timmerman’s care the principles of sero-therapy laid out by Pasteur, Koch, and Erlich are being explored in collaboration with doctors at The Johns Hopkins hospital.
At the Parker Institute for Cancer Immunotherapy, Lisa Butterfield, vice president of research and development, and the teams in clinical development and informatics are working to widely distribute informatics technologies and standard operating procedures for immune profiling and strengthening and unifying procedures so scientists and clinicians can work from the same toolbox.
At Washington University in St. Louis, Dirk Spitzer, assistant professor of surgery, and his team is in the process of developing a therapy that is based on blocking the virus from entering the host cells using soluble ACE2 receptors. This approach is considered relatively straight forward, is universally applicable, and does not require generation of monoclonal antibodies.
Once the biologics have been validated in tissue culture, animal work in ferrets, a species that has been recently reported to support replication of SARS-CoV-2 leading to COVID-19 like symptoms, will be conducted. If studies in ferrets show reduction in symptom severity upon administration of soluble ACE2 biologics, an expedited transition into the clinic is envisioned.
Among the myriad of agents in testing around the world, there are many strategies. (1) anti-viral drugs as an early intervention, (2) blockers of immune overactivity to prevent cytokine storm, and (3) passive immunity (antibody transfer) for those whose own immune system is failing to clear the virus. Arguably the biggest holy grail, vaccination for prophylaxis, is a clear focus of the work of scores of teams around the world.
As of today, nothing has been definitively proven to be effective, but we’ll get there. I’ve no doubt. The sheer magnitude and speed of the effort is impressive. The remarkable collaboration between doctors, scientists, regulators and patients cannot be underestimated.
Pulling it all together
Pulling it all together, it’s easy to see that lots of organizations are racing to the cure for this unprecedented and tragic global pandemic. In their work, they are building from learnings across therapeutic areas to find and define a new “mechanism-based” backbone of medicine. On the shoulders of giants, these talented men and women use their understanding of the immune system to guide effective therapies for the deadly COVID-19 infection.
“The remarkable thing,” John Timmerman says, “is that our understanding of the immune system was relatively primitive until the early 1980’s, when monoclonal antibody technology was introduced. This allowed us for the first time to characterize immune cells based on surface markers (CD antigen system). When the HIV epidemic arrived in the early 80’s, we began to understand the immune system and the effects that this devastating HIV virus had upon it. Billions of dollars flooded into immunology research around the world and led to a deepening of our understanding of immune regulation.
“A decade later, this knowledge was ready to be applied to the field of cancer immunotherapy. Therefore, the HIV epidemic, as catastrophic as it was, helped to catalyze the modern science of immunology and, interestingly, has now led us to a high level of understanding that we need to tackle the current COVID-19 pandemic.
“Interleukin 2 (IL-2), an important cytokine, was first identified by Robert Gallo in the early 1980’s at the NIH in the context of the AIDS epidemic. The IL-2 was then used to cultivate CD4 cells and to grow HIV in the laboratory. Later, recombinant IL-2 was used by Steve Rosenberg (Chief of the NCI Surgery Branch) in high doses to treat cancer, leading to some of the earliest successes in anti-cancer use of the immunotherapy. Here we come full circle from AIDS to cancer and to COVID-19, as oncologists bring the knowledge we have in cancer immunotherapy back to our colleagues studying severe viral infections.”
We can’t forget, though, that this long list of anecdotes and great ideas is swirling in a sea of a global pandemic—with thousands of patients sick or dying, health care workers risking their lives in the service of the greater good, lab workers redeployed to support patient care, and a world full of people holding their breath in the hope that their loved ones stay well. To those who are truly at the front line of care we offer sincerest thanks.
Together we’ll get through it—with all hands on deck.
For further reading:
Yufant Shi et al. COVID-19 infection: the perspectives on immune responses. Cell Death & Differentiation. 10 March 2020 (https://doi.org/10.1038/s41418-020-0530-3)
Mehta P et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 28 March 2020. (https://doi.org/10.1016/S140-6736(2)30628-0)
Mukherjee S. How Does the Coronavirus Behave Inside a Patient? (https://www.newyorker.com/magazine/2020/04/06/how-does-the-coronavirus-behave-inside-a-patient)
SITC Statement on anti-IL-6/IL-6R for COVID-19 (https://www.sitcancer.org/research/covid-19-resources/il-6-editorial)
Conti P et al. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVID-19 or SARS-CoV-2): anti-inflammatory strategies. J Biol Regul Homeost Agents. 2020 Mar 14;34(2). pii: 1. doi: 10.23812/CONTI-E. [Epub ahead of print]
https://jamanetwork.com/journals/jamaoncology/fullarticle/2763673
Li W, et al. Cancer Patients in SARS-CoV-2 infection: a nationwide analysis in China. Lancet 21 March 2020. (https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(20)30096-6.pdf)
The following individuals contributed to this story:
- Brad Reinfeld, MD, PhD student at Vanderbilt University
- Thomas Gajewski, AbbVie Foundation Professor of Cancer Immunotherapy, University of Chicago
- Jason Luke, director of the Cancer Immunotherapeutics Center within the UPMC Hillman Cancer Immunology and Immunotherapy Program,
- John Timmerman, associate professor of medicine at the UCLA Lymphoma Program,
- Lisa Butterfield, vice president of research and development, Parker Institute for Cancer Immunotherapy,
- Dirk Spitzer, assistant professor of surgery, Washington University in St. Louis.
