With huge portions of the global population on lockdown, researchers worldwide are racing to find treatments and a vaccine for COVID-19. The effort represents a massive collaboration of countries, research institutions and industries. It also showcases the value of interdisciplinary collaboration, as experts pool their resources to find new approaches to dealing with the disease.
That’s the case with two significant clinical trials for COVID-19 treatment using convalescent plasma and cytokine-mediated interferon therapy. The work is led by India-based Dr. Vishal Rao, Regional Director of Head Neck Surgical Oncology & Robotic Surgery and Associate Dean of the Centre of Academics & Research of the HCG Hospital Network in Bangalore, India. HCG has a separate immunology wing called iCrest, whose work on cancer immunology is being extended to find treatment options for the current pandemic.
Although it may not be immediately obvious, cancer research runs very close to immunology. Some cancers can be caused by viruses and other antigens, and therefore a significant portion of cancer therapy is centered around immunology. Those treatments can also be applied to other infectious diseases, and as such have formed the basis of Vishal’s work.
Applying cancer immunology research to coronavirus
Before the COVID-19 pandemic broke out, Vishal had been working on a dendritic cell vaccine with experts from iCrest: Dr. Jyothsana Rao, Immunologist and former research associate in Nobel Laureate Dr. Ralph Steinman’s lab at Rockefeller University in New York, and Dr. Gururaj Rao, Molecular and Cell Biologist at the University of North Carolina at Chapel Hil. “We were in the process of creating an immunological antigen bank and potential T-cell and interferon therapies for cancer,” he explained.
The team immediately realized the importance of that cancer immunology research and its implications for SARS-CoV-2, especially in terms of extending their theories with cytokine-mediated interferon priming of blood donors, allogenic mesenchymal stem cells and convalescent plasma as potential treatment options for COVID-19 where none existed.
Convalescent plasma therapy is an adaptive immunotherapy used in the prevention and treatment of many infectious diseases. It involves using blood from someone in recovery from the illness, separating out the blood cells, and then using what’s left – plasma with antibodies – to help another sufferer fight the virus. Unlike immunoglobulin (IgG)-derived antibodies such as plasma-derived monoclonal antibodies, convalescent plasma is a passive antibody therapy that showed some success as a neutralizing antibody against other coronavirus epidemics: SARS-1 and Middle East Respiratory Syndrome (MERS). Convalescent plasma-derived antibodies can neutralize a virus by preventing replication (e.g., by complement activation or phagocytosis) or by binding without interfering with replication.
The cytokine-mediated therapy involves activation of T cells from healthy donors using buffy coat, which can be used to develop an enriched cocktail of cytokines, predominantly TH1 type and rich in Interferons. Such a cocktail, when administered to a patient infected with SARS-CoV-2, can result in a surge of cytokines in the body of the infected person and will boost his ability to fight the virus. Revamping the altered immune mechanisms due to the viral infection could offer a successful cure with decreased mortality.
Mesenchymal stem cells (MSCs) are multipotent cells isolated from diverse mesenchymal tissues (e.g., bone marrow, umbilical cord, adipose tissue). A large body of preclinical data has demonstrated the efficacy of MSCs in treating Acute Respiratory Distress Syndrome (ARDS), manifested in reduced pulmonary edema, decreased plasma concentrations of pro-inflammatory cytokines, and reduced mortality rates. Although not fully understood, the mechanisms by which MSCs exert protective effects include their direct regenerative ability and secretion of multiple paracrine factors, including antibacterial peptides and anti-inflammatory cytokines and immune response modulation. Treatment with allogenic MSC transplantation has showed significantly improved functional outcomes without obvious adverse effects in recent studies. Adoptive MSC transfer is therefore be a valuable treatment option for COVID-19.
“I felt like an unofficial member of the research team.”
While Vishal and his team were working on these treatments, Dr. Ujjwal Rao, MBBS, PhD, Senior Clinical Specialist at Elsevier, contacted him to share some information from Elsevier’s own Novel Coronavirus Information Center. Ujjwal had worked with Vishal before and was aware that his work on cancer therapy may be being refocused on COVID-19. As Ujjwal recalled:
He replied to me immediately, saying that he’d been looking for articles on some of those specific topics, and so this was very timely. We started exchanging notes on an hourly basis, sharing published articles and evidence that would be relevant to this trial. I kind of felt like an unofficial member of the research team.
Together, Ujjwal, Vishal and the research team conducted literature reviews and prepared the submission of the trial proposals, with Ujjwal providing critical insights into the trial protocols. Vishal explained:
Starting with the Elsevier Novel Coronavirus Information Center, we were able to find excellent articles from high impact journals and similar clinical trials conducted globally, which we cited in our extensive submissions. We have also extensively used the Elsevier Covid-19 Healthcare Hub, which has curated clinical content for the community, clinicians and patients. I’ve personally used these resources to advise the Ministry of Health and High-Level Committee of the Principal Scientific Advisor to the Government of India.
To ensure that clinical trials moved forward quickly and thoroughly, Vishal wanted to approach those trials at a multi-country level. Ujjwal introduced Vishal to Elsevier’s Pure Research Collaboration Tool as a way of finding experts in other countries who could collaborate on clinical trials. Vishal said:
Using Elsevier’s Pure Research Collaboration tool, we saw that Dr. Rafi Ahmed, an eminent Virologist from Emory University in Atlanta, was listed among thousands of researchers and research units working on COVID-19. We saw how the Fingerprint Engine was incredible in being able to link key research terms to relevant research work, like Dr. Ahmed’s study on CD8 T-cell memory differentiation during acute and chronic viral infections. We have also explored similar research collaborations and have been able to short-list researchers conducting studies on COVID-19 immunotherapies globally, who we have now reached out to.
As the trials begin to ramp up and enroll participants, Vishal is also looking for partners for trials that have yet to receive approval. After all, he is keenly aware of the challenge that awaits:
Our challenge in India is to ensure that no-one who tests positive for COVID-19 dies of the disease.
Dr. Vishal Rao talks about India’s first clinical trials for a COVID-19 treatment
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