By and large, the patients treated at Mount Sinai Health System during the early days of the coronavirus disease 2019 (COVID-19) pandemic were not dying of the virus, according to Miriam Merad, MD, PhD. In fact, autopsies showed that patients were dying despite clearing the virus.
Investigators did not see a correlation between death and viral load or disease severity. Rather, data from these patients showed that as patients got sicker, they developed a severe inflammatory response.
“The virus was triggering the disease, but it was not really responsible for the organ damage…that we were seeing,” Merad said.
An immunologist and oncologist, Merad has spent her career studying inflammation in patients with cancer and was at the right place at the right time to translate her expertise to examine inflammation in patients with COVID-19. She is the Mount Sinai Endowed Professor in Cancer Immunology and director of the Precision Immunology Institute at Ichan School of Medicine at Mount Sinai in New York, New York. She is also the coleader of the Cancer Immunology Program at The Tisch Cancer Institute and director of the Human Immune Monitoring Center (HIMC) at Ichan School of Medicine.
“What we realized was that in those [patients with COVID-19] who were getting worse, they had a very severe inflammatory response,” she said. “I discovered the subset of macrophages that is now helping us understand their contribution to disease better.”
Merad has spent decades investigating macrophages and dendritic cells, which play a critical role in both T-cell activation and T-cell suppression in the context of cancer. Her laboratory has made key discoveries elucidating the mechanisms that control the development and functional identity of dendritic cells and macrophages during homeostasis and understanding how cancer and inflammatory diseases can affect those regulations.
Translating Cancer Research to Critical Practice
Merad and her team, in collaboration with myeloma experts, developed the Ella platform, a rapid cytokine detection system, to measure inflammatory cytokine response to therapy in patients with myeloma.1
When the time came for an all-hands-on-deck approach to address the pandemic, Merad halted her cancer research and dedicated this platform, along with her laboratory, the HIMC, and the Cancer Immunology Program, to assist in treating patients with COVID-19.
Her laboratory adapted that assay to create a test that detects the inflammatory response to COVID-19 and produces a result within 3 hours. The hypothesis is that with these data it will be easier anticipate and block inflammatory surge before the patient sustains organ damage.
“We had all these people trained to study the immune system. I told them that we were going to collect [samples from] all the patients [admitted to] the hospital,” she said. “Because of my understanding of macrophages in the context of different diseases, I was able to potentially help understand why these macrophage cells were being so activated. There are some similarities between cancer and [the virus], so there is definitely knowledge that we have acquired by studying patients with cancer that has been very useful.”
Although the exact drivers of pathologic inflammation are unknown, Merad and colleagues are interested in identifying the pathways involved in the immune response in order to optimize intervention to control the virus and prevent progressive tissue damage that can lead to deleterious hyperinflammation.2
The rapid multiplex cytokine assay was used in patients with COVID-19 admitted to the Mount Sinai Health System between March 21 and April 28, 2020, and measured serum interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α, and IL-1β.1 The test was authorized under an emergency use approval from the New York State Department of Health. In an initial cohort of 1484 patients followed up to 41 days post admission, high serum IL-6 and TNF-α levels at the time of hospitalization were strong and independent predictors of patient survival (P < .0001 and P = .0140, respectively).1
Further, sequential organ failure assessment severity scale scores were available for a subset of 663 patients. Poor survival was associated with IL-6 (HR, 2.9; P < .0001), IL-8 (HR, 1.6; P = .04) and TNF-α (HR, 1.6; P = .03) in these patients.1
“Some of these cells are really the biggest producers of inflammatory cytokine,” Merad said. Her hypothesis is that controlling inflammation could help patients survive COVID-19. “The cells are also involved in other types of diseases, especially inflammatory disease, where they are also activated. Therefore, they’re going to activate T cells and contribute to inflammation-driven injury.”
What Lies Ahead for Translational Research
COVID-19 often induces a “cytokine storm,” a severe immune reaction in which the body releases too many cytokines into the blood too quickly. Patients receiving chimeric antigen receptor (CAR) T-cell treatment for leukemia often experience cytokine storm.1
Siltuximab (Sylvant) has been used to treat cytokine storm in patients who received CAR T-cell therapy for cancer. Investigators theorize that suppressing IL-6 might be a treatment option for severe COVID-19. In July, the FDA approved a randomized, double-blind, placebo-controlled phase 3 clinical trial comparing intravenous (IV) siltuximab, an anti–IL-6 monoclonal antibody, versus corticosteroids for patients hospitalized with COVID-19–associated acute respiratory distress syndrome.2
Investigators are also conducting a clinical trial evaluating sarilumab (Kevzara), a human monoclonal antibody against the IL-6 receptor that is indicated for rheumatoid arthritis, as a potential therapy for COVID-19. The agent is concurrently being investigated in combination with capecitabine for HER2-negative metastatic breast cancer in the phase 1/2 EMPOWER trial (NCT04333706).
Results for sarilumab in COVID-19 have been mixed. In July, drug manufacturers Regeneron Pharmaceuticals and Sanofi stopped a phase 3 US trial evaluating the drug in patients requiring mechanical ventilation after the drug failed to meet primary and secondary end points.3 However, Italian investigators in October concluded that IV sarilumab is an option worth pursuing. In an article published in EClinical Medicine, investigators concluded that sarilumab appeared to be a promising short-term approach for patients with COVID-19–related severe pneumonia.4
Merad is less concerned about the clinical results with sarilumab than the biological ones. She is hoping to have that data before the United States faces a second wave of infections.
“I want to see the biological result, what happened to the inflammation, to see whether we are on the right track or not,” she said. “If we are on the right track, this means maybe you have to combine [sarilumab] with other cytokines. So I’m still waiting for Regeneron to release at least some of their biological data.”
Merad said investigators are close to understanding which inflammatory pathways they need to block. The problem now is that trials are moving forward with small patient populations. To her knowledge, investigators were not recruiting any patients in New York.
Science and Community Step Up
In a larger sense, New York City pulled together. Merad said local restaurants provided “fantastic food” to her team on a regular basis. High school students sent cards thanking them for their efforts and local schools sent N95 masks. Even her children got involved, baking cakes for investigators.
Some of her team members refused to leave the hospital and Merad had to force them to go home to rest. Others broke down crying from exhaustion. The experience was so intense and the sense of camaraderie so strong that some of her volunteers cried when she released them back to their normal jobs.
At the height of the pandemic in late February and early March, Merad had an “army” of 60 to 80 investigators collecting DNA samples from patients. She and her team worked 12-hour days for weeks on end.
“There was a sense of...facing a war and that we were here together and were fighting together. There was a sense of fighting a war with all members of this community,” she said. “I’ve been here 15 years—I’ve met so many new people, colleagues that I never had the time to meet before.”
Mount Sinai, with locations in Manhattan and Brooklyn, was at the epicenter of the pandemic. At one point, Merad said that the hospital system was seeing 100 new cases of COVID-19 each day, and patients with COVID-19 occupied 6000 beds across the Mount Sinai Health System. Every resource was devoted to battling the pandemic.
“All the scientists were here to help the clinicians come up with clinical strategies because they were overwhelmed. They didn’t know how to treat patients initially—you can’t treat what you don’t understand. So, it was difficult, and the scientists decided that we were going to go full force.
“Science stepped up to the front line. Scientists did it,” she said. “It was an extraordinary time. There was a lot of bleakness and anxiety and sadness and fear. But there was also an extraordinary sense of collaboration and humanity that came out of the bleakness.”
1. Del Valle DM, Kim-Schulze S, Huang HH, et al. An inflammatory cytokine signature predicts COVID-19 severity and survival. Nat Med. 2020;26(10):1636-1643. doi:10.1038/s41591-020-1051-9
2. EUSA Pharma announces FDA approval of phase 3 clinical trial for siltuximab in hospitalized patients with COVID-19 associated acute respiratory distress syndrome. News release. BioSpace July 2, 2020. Accessed October 26, 2020. https://www.biospace.com/article/releases/eusa-pharma-announces-fda-approval-of-phase-3-clinical-trial-for-siltuximab-in-hospitalized-patients-with-covid-19-associated-acute-respiratory-distress-syndrome/
3. Regeneron and Sanofi provide update on Kevzara (sarilumab) phase 3 U.S. trial in COVID-19 patients. News release. Regeneron Pharmaceuticals. July 2, 2020. Accessed October 20, 2020. https://investor.regeneron.com/news-releases/news-release-details/regeneron-and-sanofi-provide-update-kevzarar-sarilumab-phase-3
4. Gremese E, Cingolani A, Bosello SL, et al; GEMELLI AGAINST COVID-19 Group. Sarilumab use in severe SARS-CoV-2 pneumonia. EClinicalMedicine. Published online October 2, 2020. doi:10.1016/j.eclinm.2020.100553
This article was originally published on OncLive as, "Cancer Research May Pave the Way for Treating Severe COVID-19."