Deploying Dana-Farber expertise against a global pandemic

  • April 06, 2021
  • By Richard Saltus

    In early 2020, as the pandemic erupted, Dana-Farber physician-scientist Paul Richardson, MD, read reports of COVID-19 patients developing life-threatening blood clots in their lungs and other organs — and he quickly became intrigued.

    It reminded Richardson of another disease he knew extremely well: veno-occlusive disease (VOD), a serious thrombotic complication of bone marrow transplants that blocks circulation in the liver and is underpinned by endothelial damage triggered by the effects of both chemotherapy and inflammation of the transplant itself.

    Richardson, director of Clinical Research for the Jerome Lipper Multiple Myeloma Center at Dana-Farber, has pioneered the treatment of VOD with defibrotide, a naturally derived first-in-class compound which has proved anti-inflammatory, anti-thrombotic, and pro-fibrinolytic, which reverses endothelial injury. Driven by the similarity to the blood vessel complications in COVID-19 patients, he and other experts formed an international study group to test defibrotide as a treatment option for patients infected with the virus. Preclinical studies by the group in allogenic transplant mouse models performed at Johns Hopkins and in Spain showed 80% survivorship for animals with severe lung injury treated with defibrotide, compared to zero in the control group, and these results further strengthened the rationale for clinical trials in COVID-19.

    Early reports from clinical trials showed "some remarkable results," says Richardson, even when patients receiving defibrotide had been devastatingly ill on ventilators and were worsening despite receiving other treatments. In February 2020, a trial of defibrotide led by Richardson and colleagues opened at Brigham and Women's Hospital, with other centers in Boston and New England. This was in addition to an ongoing study in Michigan. Initial results have been especially encouraging, also with complete responses and recovery in 80% of critically ill patients treated so far, with excellent safety to date.

  • "Much of what we know about cancer can also help in the fight against COVID-19," says Laurie H. Glimcher, MD, president and CEO of Dana-Farber. "Dana-Farber scientists are using their cancer knowledge to develop potential treatments for the novel coronavirus."
  • While most Dana-Farber laboratories were shut down early in the second quarter of 2020, "labs working on COVID, or wanting to work on COVID, could request permission to stay operational, though with a skeleton crew," says Kevin Haigis, PhD, Dana-Farber's chief scientific officer.

    "Many investigators, both lab and clinical, followed their own interests on aspects of COVID-19," adds William Hahn, MD, PhD, chief operating officer at Dana-Farber. "We wanted to help those who had meritorious projects to be able work during the early phases of the pandemic when the labs were mostly closed."

    In addition, the Center for Cancer Genomics helped develop different COVID-19 tests for the Center for Advanced Molecular Diagnostics at Brigham and Women's, says Bruce Johnson, MD, chief clinical research officer at Dana-Farber.

    A Race for COVID-19 Drugs and Antibodies

    While clinical investigators like Richardson followed leads on how the COVID-19 virus affected patients, Dana-Farber laboratory scientists focused on clues in the basic genetic information that enables the coronavirus to replicate and infect human cells. In early 2020, scientists in China decoded and shared the genetic sequence — the instruction manual — of SARS-CoV-2, the COVID-19 virus, touching off a race in labs around the world to develop potential treatments.

    Thanks to the genetic sequence and the subsequent high-resolution structures that were published, coupled with the similarity of SARS-CoV-2 to other coronaviruses, "we know exactly what the components of this virus looks like and we know how its proteins operate, so we know where to target" parts of the virus with compounds that could lead to drug treatments, says Haribabu Arthanari, PhD, a cancer biologist at Dana-Farber. However, finding chemical compounds that closely and exclusively match and bind to key parts of the virus — which is essential to creating a drug — is a massive and time-consuming process.

  • Arthanari is working with postdoctoral fellow Christoph Gorgulla, PhD, who developed a super-fast computational drug-screening platform. Using this platform, Arthanari and Gorgulla screened more than one billion compounds each against 40 different sites on 17 different proteins — 15 of which belong to the SARS-CoV-2 virus and two of which belong to human proteins — which enable the virus to bind to (and infect) human cells. The screening process generated more than 1,000 "hits" — matches, for each of the 40 sites that were targeted, that potentially could enable compounds to dock or bind to sites on the protein molecules. This extremely high-throughput screening was accomplished in 4 weeks using computer resources from Google Cloud, resulting in more than 50 billion docking instances.

    Some of the compounds that matched sites on the COVID virus proteins are existing drugs, including 161 that have been approved for human use. Arthanari says that 16 of these drugs are being considered for clinical trials in COVID-19 patients. This work was recently published in the journal Science and all the data is made freely available to the research community.

    "Many of the sites we screened were not yet targeted by other groups, but the initial results are very promising," says Arthanari. "Thus, we explore new avenues on how to tackle the virus."

  • Carl Novina, MD, PhD, studies the biology of RNA, the information molecule in the COVID virus. He and his colleagues developed a system to rapidly screen for drugs that disrupt the interactions between RNAs and the proteins that bind to them. The goal of this work is to screen for drugs that disrupt RNA-protein interactions crucial for SARS-CoV-2 to replicate itself and thereby foil virus infection. The work is funded through a Dana-Farber collaboration with Takeda Pharmaceutical Co.

    Patients infected with coronavirus attempt to fight it off with antibodies generated by the immune system. These natural antibodies — proteins with a highly specific affinity for parts of the virus — can be isolated from people who have recovered from COVID-19 and their plasma antibodies can be used to treat patients with severe COVID-19. These antibodies can also be isolated from immune cells from recovered individuals or from large human antibody libraries and then used to manufacture huge quantities of monoclonal (identical) antibodies in the laboratory. Monoclonal antibodies can then become the basis of vaccines and drug treatments.

    Wayne Marasco, MD, PhD, an expert in creating monoclonal antibodies, is leading a COVID-19 Protective Immunity Study. The study has enrolled 150 volunteers, including health care workers, cancer patients, and others, who recovered from COVID-19 infection. Their blood will be analyzed to look for antibodies that have been generated against the virus, and which could be used in developing vaccines and treatments.

    Antibodies produced by the immune system that block the activity of an infectious agent are called neutralizing antibodies. However, they are not always totally effective in preventing disease. Joseph Sodroski, MD, a Dana-Farber researcher who has studied the AIDS virus for many years, participated in a published study that found a diverse set of potent neutralizing antibodies in the blood of severely ill COVID-19 patients. Tests showed that these neutralizing antibodies could very effectively block virus particles from infecting cells. Such antibodies "could be used to lessen the severity of COVID-19 disease and could cooperate with vaccines to prevent coronavirus infections," says Sodroski.

  • COVID-19 Research in the Cancer Clinic

    In addition to lab-based research, scientists have explored repurposing drugs used in cancer treatment as potential therapies for COVID-19 patients. Richardson's work with defibrotide is one example. Another trial, headed by Steven Treon, MD, PhD, is examining the use of ibrutinib, a drug used in treating blood cancers, to prevent lung injury in patients infected with the coronavirus.

    Francisco Marty, MD, an infectious disease specialist at Dana-Farber, led trials at Brigham and Women's Hospital of the antiviral drug remdesivir, which is the only approved drug to treat COVID-19. He is currently involved in a clinical trial of a "cocktail" of different monoclonal antibodies made by Regeneron to treat hospitalized patients with COVID-19.

    Another clinical trial, known as PRE-VENT, is trying to determine if a drug, pacritinib, a JAK inhibitor used in treating myelofibrosis — a rare form of cancer — can prevent acute respiratory distress syndrome in patients with severe COVID-19 disease. JAK inhibitors block a cell process known as JAK-STAT signaling, which produces cytokines — small proteins that activate immune and inflammation responses. JAK inhibitors can help reduce excess cytokine release, which can occur in patients with COVID-19 infections, causing damage to the lungs and other tissues. Richard Stone, MD, chief of staff and director of Translational Research in the Adult Leukemia Program, is leading the PRE-VENT trial.

    Cancer Patients and Coronavirus Vaccines

    Dana-Farber scientists are also focusing on a major concern at the Institute: the increased vulnerability of cancer patients to the coronavirus. Studies have shown cancer patients to be at significantly higher risk of infection and of developing severe disease. One reason is that their immune systems are frequently weakened by the disease or the therapies used to treat it, leaving them more susceptible to infection.

    However, there is still a lot to be learned about the interaction of COVID and cancer, and many questions are unanswered. Among them: which cancer patients are at highest risk of severe COVID-19 infection? How does immunotherapy or treatment that suppresses the immune system influence susceptibility to the coronavirus? How do chemotherapies and targeted drug therapies influence vulnerability? Could cancer immunotherapies such as checkpoint inhibitor drugs help? When is it safe to resume cancer therapy after infection? And how will cancer patients respond to the new coronavirus vaccines?

    These are some of the issues being investigated in a study called RECOVOR led by Deborah Schrag, MD, MPH, chief of Population Sciences at Dana-Farber. A large team of investigators from multiple disciplines are collaborating on the study, which will compare matched pairs of patients with and without COVID. The goal is to understand what factors predispose some cancer patients to COVID infection, particularly in its severe form, as well as which patients recover more easily from the disease. Schrag says there is some evidence for increased risk in patients with leukemia and lung cancer and for patients who are obese, but the investigators hope to gather more information on risk factors among patients who have and haven't had the vaccine.

    The RECOVOR study is being conducted in both children and adults Institute-wide and will serve as a shared resource that can be used by investigators. RECOVOR includes detailed interviews of patients who have had COVID and investigates the extent to which COVID has affected cancer treatment and recovery.

    Researchers will collect blood and saliva specimens at intervals six months apart. The samples will be analyzed for biochemical markers associated with better or worse responses to the virus. They will also search for antibodies that may have developed in patients who recover from COVID-19 and look at how long the antibodies last.

    A separate study, called IMPACT, is examining what effect COVID infections and vaccinations have on people with blood cancer precursor conditions. These precursor conditions, MGUS (monoclonal gammopathy of undetermined significance) and smoldering myeloma, are estimated to affect about 12 million people, and usually don't cause symptoms, despite the presence of abnormal proteins in the blood. However, they have the potential to progress to multiple myeloma, a blood cancer.

    The study is led by Dana-Farber's Irene Ghobrial, MD, who founded the Center for Prevention of Progression of Blood Cancers, where people with precursor conditions are monitored. Recent research has shown that the immune system is abnormal in people with MGUS and smoldering myeloma. The IMPACT study aims to determine how the immune system responds to COVID-19 infection and the long-term impact of the virus in patients with these precursor conditions.

  • Among the questions the IMPACT investigators are asking are:

    • Do people who have precursor conditions also have greater risks for COVID-19?
    • Who is most at risk for long-term symptoms and immune complications after infection with COVID-19?

    "We are doing the IMPACT study to truly understand what the response of the immune system to COVID is — not only to the infection, but also to the vaccine," Ghobrial says. "Instead of giving you a hypothesis — maybe they will respond well or not — I can actually give you data in a few months from now."

    "Research into why patients with cancer are at heightened risk of developing severe forms of the illness is moving very quickly," says Ziad Bakouny, MD, MSc, co-lead author of a report published in December 2020 on the intersection between COVID and cancer. The report "gives us an opportunity to take a step back and take stock of what we've learned — to get a sense of the most promising directions for patients, as well as where more study is needed, what we need to dig deeper into."


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  • New Strategies Keep Research on Track

    The COVID pandemic forced sweeping changes to Dana-Farber laboratory and clinical research routines in early 2020 to protect the safety of scientists and patients. Some experiments were halted or put on hold; most laboratory investigators vacated their workspaces and group meetings were curtailed; telemedicine interactions replaced in-person visits for many patients; and experimental drugs were shipped to patients rather than being dispensed at the Institute.

    In the clinical trials arena, restrictions limited enrollment of some patients and slowed the launching of new trials. One significant limitation was that researchers accustomed to analyzing fresh biopsy tissues from the operating room had to make do with frozen specimens. However, a study published in 2020 led by Sara Tolaney, MD, MPH, found that in large part workarounds enabled most participants to stay on clinical trials, even if it meant getting medications at home by mail or having laboratory tests done at outside facilities, and patient safety wasn't compromised.

    By early 2021, said Tolaney, clinical research in most ways returned to normal, with some exceptions.

    "All our therapeutic trials have reopened so we can do all our normal research activities," said Tolaney, who is the director of the breast oncology clinical trials program and associate director of the Susan F. Smith Center for Women's Cancers. "Some things have continued, such as telehealth visits and shipment of oral investigational therapies, which I think has been wonderful for patients."

    Social distancing requirements still in effect have meant many research coordinators work from home or rotate through the main campus. In fact, says Tolaney, the experience has been beneficial in some ways: "We've learned a lot of lessons about things that can be done remotely."

    Research laboratories re-opened gradually in the first half of 2020, with strict limits on how many people could occupy a laboratory workspace, meaning that some groups worked in shifts, and group meetings were prohibited. But since last June, "my lab has been back to work full-time," says James DeCaprio, MD, chief of the Division of Molecular and Cellular Oncology at Dana-Farber. "My lab has enough bays to accommodate everyone, but a few labs still have to do shift work because they have more people than bays."

    Principal investigators can spend up to two days a week in their labs, but since in-person meetings are strictly limited, "there is little reason for me or any other PI to go to the lab," DeCaprio says. "Zoom has replaced these meetings and works pretty well for the most part," he adds. "Certainly, Zoom has enabled a lot of collaborations with other institutions across Boston, the United States, and the rest of the world."