This story is part of The Cancer Letter’s ongoing coverage of COVID-19’s impact on oncology. A full list of our stories, as well as the latest meeting cancellations, are available here.
A class of drugs that has been used to treat adverse events associated with CAR T-cell therapy is emerging as a potential treatment for COVID-19.
The available drugs, both interleukin-6 receptor antagonists, have the capacity to treat the cytokine release syndrome, sometimes also known as the cytokine storm syndrome, a large, rapid release of cytokines into the blood as a result of viral infections or immunotherapy.
The drugs—two of which are now being rushed into late-stage clinical trials—are approved by FDA for rheumatology indications:
Actemra (tocilizumab), sponsored by Genentech, was approved in 2011.
Kevzara (sarilumab), sponsored Regeneron Pharmaceuticals and Sanofi, was approved in 2017.
Sylvant (siltuximab), sponsored by EUSA Pharma, was approved in 2014.
Tocilizumab was used in mitigation of CRS for both approved CAR T-cell therapies on the market: the Novartis agent Kymriah (tisagenlecleucel) and the Gilead Sciences agent Yescarta (axicabtagene ciloleucel). Sarilumab isn’t mentioned specifically on either of the CAR T labels, though the tisagenlecleucel label states that alternative methods of controlling CRS are acceptable after repeated failures of tocilizumab.
The sponsors of both tocilizumab and sarilumab said they are initiating clinical trials of the agents. The studies involve the Biomedical Advanced Research and Development Authority, an HHS agency focused on chemical, biological, radiological, and nuclear threats, pandemic influenza, and emerging infectious diseases.
The federal government has also obtained 10,000 vials of tocilizumab to the U.S. Strategic National Stockpile “for potential future use at the direction of the HHS,” Genentech announced.
The studies that are being launched will test whether blocking IL-6 would stop the overactive inflammatory response in the lungs of patients who are severely or critically ill with COVID-19. The hypothesis regarding the role of IL-6 is based on preliminary data from a 20-patient single-arm study in China using tocilizumab.
An abstract from the study follows:
Background: In December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified in Wuhan, China, which spread rapidly and has become a world-wide public health challenge. We aimed to assess the efficacy of tocilizumab in severe patients with Corona Virus Disease19 (COVID-19) and seek a new therapeutic strategy.
Methods: The patients diagnosed as severe or critical COVID-19 in The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital) and Anhui Fuyang Second People’s Hospital were given tocilizumab in addition to routine therapy between February 5 and February 14, 2020. The changes of clinical manifestations, CT scan image, and laboratory examinations were retrospectively analyzed.
Findings: Within a few days, the fever returned to normal and all other symptoms improved remarkably. Fifteen of the 20 patients (75.0%) had lowered their oxygen intake and one patient need no oxygen therapy. CT scans manifested that the lung lesion opacity absorbed in 19 patients (90.5%). The percentage of lymphocytes in peripheral blood, which decreased in 85.0% patients (17/20) before treatment (mean, 15.52 ± 8.89%), returned to normal in 52.6% patients (10/19) on the fifth day after treatment. Abnormally elevated C-reactive protein decreased significantly in 84.2% patients (16/19). No obvious adverse reactions were observed. Nineteen patients (90.5%) have been discharged on average 13.5 days after the treatment with tocilizumab and the rest are recovering well.
Interpretation: Tocilizumab is an effective treatment in severe patients of COVID-19, which provided a new therapeutic strategy for this fatal infectious disease.
The entire paper is posted here.
Earlier this month, China’s National Health Commission published a treatment guideline that allows the tociluzumab to be used to treat coronavirus patients who have high IL-6 levels and who show serious lung damage.
The data on tocilizumab and sarilumab fall short of a demonstration of safety and efficacy in COVID-19-related indications, and the tidbits of information from China—as well as the news of 10,000 vials of tocilizumab going to the U.S. Strategic National Stockpile—constitute a threat to equipoise in ongoing studies, drug developers warn. It’s self-evident that equipoise here is all the more important, because fundamental questions about appropriateness of these drugs for COVID-19 remain unanswered while the drugs are available for off-label use.
The Society for Immunotherapy of Cancer has published an editorial, “Insights from immuno-oncology: The Society for Immunotherapy of Cancer statement on access to IL-6-targeting therapies for COVID-19” that calls for creating a compassionate use protocol based on existing templates as well as making effort for emergency approval of using of IL-6 receptor blocking antibodies by local institutional review boards within 24 hours of the request being made.
The editorial was submitted to JITC for publication and was posted on the society’s website without peer review “to allow the rapid dissemination of this information.”
The editorial reads:
“Although randomized data definitively showing that IL-6 receptor blockade benefits patients with COVID-19 induced pneumonitis are currently lacking, we propose that an effort should be made to maximize the availability of anti-IL-6 agents, including tocilizumab and sarilumab for use on a compassionate basis to hospitalized critically ill COVID-19 infected patients during this extraordinary situation.
“In addition, consideration should be given to focus efforts on rapidly expanding the ability of clinicians and clinical investigators to access investigational anti-IL-6 agents, in particular for those agents where Phase 1 and/or Phase 2 studies have been completed, and acceptable safety has been demonstrated. Even if the primary impact of a single dose of these drugs is to accelerate recovery and get patients off ventilator support and out of the ICU more rapidly, this could significantly decompress our severely over-burdened healthcare systems.
“We suggest that straightforward parameters including complete blood counts and differentials, serum LDH, ferritin, CRP and IL-6 be recorded in treated patients, that serum be retained for future analyses, and simple clinical parameters be assessed including time in ICU, days of hospitalization, and pulmonary parameters including FEV1, Fi02, PaO2/FiO2 ratio and oxygen need be recorded. A simple compassionate use protocol could be assembled from existing templates, and all efforts should be made for emergency approval of the use of IL-6 receptor blocking antibodies by local institutional review boards within 24 hours of the request being made.
“Additionally, consideration should be given by pharma and biotech to redirect the use of facilities and increase personnel involved in drug manufacturing and those serving as liaisons to the frontlines to facilitate drug availability. Extraordinary times call for extraordinary measures, and SITC calls on all involved, including pharmaceutical sponsors, health authorities and IRBs, to continue to move swiftly and creatively to respond and unite in removing barriers to provide our patients with care.”
SITC’s resources for immuno-oncology are also found on the new SITC COVID-19 Resources page, which includes:
Online discussion forums for patient management as well as basic and translational
SITC statement urging scientific journals to grant open access to COVID-19
FDA clinical trials guidance.
CDC COVID-19 resources.
On March 23, Genentech, a member of the Roche Group, said FDA has cleared the way a randomized, double-blind, placebo-controlled phase III clinical trial, COVACTA, which would be conducted with in collaboration with BARDA, Genentech said.
The trial will seek to evaluate the safety and efficacy of intravenous tocilizumab plus standard of care in hospitalized adult patients with severe COVID-19 pneumonia.
The primary and secondary endpoints include clinical status, mortality, mechanical ventilation and intensive care unit variables. Patients will be followed for 60 days post-randomization, and an interim analysis will be conducted to look for early evidence of efficacy, the company said.
Genentech has also been working with distributors to manage product supply to enable both Genentech and its distributors to meet patient needs.
“We thank the FDA for rapidly expediting the approval of this clinical trial to evaluate Actemra in critically ill patients suffering from pneumonia following coronavirus infection and we’re moving forward to enroll as quickly as possible,” Alexander Hardy, Genentech CEO said in a statement. “Conducting this clinical trial in partnership with BARDA and providing Actemra to support the national stockpile, through the efforts of Secretary Azar and HHS, are important examples of how the U.S. government the biotechnology industry and healthcare communities are working together in response to this public health crisis.”
The company said that several independent clinical trials have begun globally to explore the efficacy and safety of Actemra for the treatment of patients with COVID-19 pneumonia. “However, this new trial is vital, because there are no well-controlled studies and limited published evidence on the safety or efficacy of Actemra in the treatment of patients suffering from COVID-19,” the company said.
On March 16, Regeneron and Sanofi said they have started a clinical program evaluating sarilumab.
This phase II/III, randomized, multi-center, double-blind, phase II/III trial has an adaptive design with two parts and is anticipated to enroll up to 400 patients, the companies said. The trial will begin in New York and will recruit patients at approximately 16 U.S. sites.
The trial uses an adaptive design. To be eligible, patients must be hospitalized with laboratory-confirmed COVID-19 that is classified as severe or critical, or who are suffering from multi-organ dysfunction. All patients must have pneumonia and fever. After receiving the study dose, patients will be assessed for 60 days, or until hospital discharge or death.
In the phase II component of the trial, patients will be randomized 2:2:1 into three groups: sarilumab high dose, sarilumab low dose, and placebo. The primary endpoint is reduction of fever and the secondary endpoint is decreased need for supplemental oxygen.
The phase II findings will be utilized in an adaptive manner to determine transition into phase III, helping to determine the endpoints, patient numbers and doses. The second, larger part of the trial will evaluate the improvement in longer-term outcomes including preventing death and reducing the need for mechanical ventilation, supplemental oxygen and/or hospitalization.
If the trial continues with all three treatment arms to the end, it is expected to enroll approximately 400 patients, depending on the status of the COVID-19 outbreak and the proportion of patients with severe COVID-19 and high levels of IL-6.
“To initiate this trial quickly, so that the results may inform evidence-based treatment of this ongoing pandemic, Regeneron and Sanofi have worked closely with FDA and the Biomedical Advanced Research and Development Authority,” George D. Yancopoulos, co-founder, president and chief scientific officer of Regeneron, said in a statement. “Data from China suggest that the IL-6 pathway may play an important role in the overactive inflammatory response in the lungs of patients with COVID-19. Despite this encouraging finding, it’s imperative to conduct a properly designed, randomized trial to understand the true impact.
“Our trial is the first controlled trial in the U.S. to evaluate the effect of IL-6 inhibition prospectively in COVID-19 patients. In addition to our Kevzara program, Regeneron is also rapidly advancing a novel antibody cocktail for the prevention and treatment of COVID-19, which we hope to have available for human testing this summer. Both of these programs are made possible by our unprecedented end-to-end antibody discovery, development and manufacturing technologies, starting with our proprietary VelocImmune human antibody mouse, and incorporating our associated rapid manufacturing technologies designed to select and produce the best neutralizing antibodies. Collectively, these technologies expedite a typically years-long process into a matter of months. This same technology was applied to the Ebola virus, where our therapy, REGN-EB3, was shown to dramatically improve survival in infected patients last year.”
To delve deeper into the fundamental questions that surround the role treatments for the cytokine release syndrome—especially IL-6 receptor antagonists—may play in COVID-19 indications, The Cancer Letter administered a questionnaire to the following experts:
Carl H. June, MD
Richard W. Vague Professor in Immunotherapy
Department of Pathology and Laboratory Medicine
Perelman School of Medicine of the University of Pennsylvania.
John DiPersio, MD, PhD
Chief, Division of Oncology, and Virginia E. and Samuel J. Golman Endowed Professor of Oncology, Washington University School of Medicine in St. Louis
Deputy Director, Siteman Cancer Center, and
Armin Ghobadi, MD
Associate Professor of Medicine, Washington University School of Medicine in St. Louis.
Paolo A. Ascierto, MD
Melanoma. Cancer Immunotherapy and Development Therapeutics Unit
Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale.”
Randy Q. Cron, MD, PhD
Professor of pediatrics and medicine,
Director of the Division of Pediatric Rheumatology at the University of Alabama at Birmingham,
Author of “Cytokine Storm Syndrome,” a textbook on cytokine storms, and
Winn Chatham, MD
Professor of medicine, clinical immunology, and rheumatology
Senior scientist at the Comprehensive Arthritis, Musculoskeletal, Bone and Autoimmunity Center (CAMBAC)
Director of Rheumatology Clinical Services
University of Alabama at Birmingham.
Carl H. June: First of all, as far as the terminology goes, I prefer to distinguish cytokine release syndrome from cytokine storm.
Cytokine release syndrome is due to a targeted immune response and can be delayed in onset. With CAR T-cell therapy we have seen cytokine release syndrome delayed for as long as 50 days after the infusion of CAR T in patients with leukemia; this is an on-target response that almost always correlates with beneficial anticancer effects.
In contrast, cytokine storm is a nonspecific release of cytokines and chemokines by many cells in the immune system and can occur immediately. The scientific community became commonly aware of cytokine storms about a decade ago, after the administration of super agonistic administration CD28 antibodies to healthy volunteers.
However, during the Cold War, both the United States government and the Soviet Union studied the use of bacterial superantigens, such as staphylococcus enterotoxin B as biologic warfare agents. These bacterial superantigens can kill mice and larger animals within hours after administration.
John DiPersio and Armin Ghobadi: CRS is an inflammatory syndrome, which is due to the excessive activation of human monocytes/macrophages by multiple etiologic agents, which either directly activate monocytes or activate macrophages via the activation of T cells.
In the case of CRS associated with CAR T therapy, it is the interaction of activated and rapidly expanding CAR T with their target cells and the release and/or direct interaction with neighboring monocytes to release specific inflammatory cytokines, such as IL-6 and IL-1, as well as other cytokines and chemokines that result in CRS (fever, edema, capillary leak, new oxygen requirement).
The release of IL-6 by monocytes is largely responsible for the fevers associated with CRS; however, the neurotoxicity may or may not be related to IL-6 and may be mediated by other cytokines and chemokines, such as IL-1, TNF, GM-CSF, and even other vascular trophic cytokines such as VEGF, Angiopoietin-1 etc.
The entire syndrome mimics other macrophage activation syndromes, such as HLH (primary or secondary), and is manifested by elevation of temperature, vascular leak, hypoxia and then even altered mental status.
All can be mild, moderate or life-threatening/ending. Serum markers can be used to follow the disease, such as IL-6 levels, ferritin and C-reactive protein (CRP).
There is some increasing evidence (although still controversial) that COVID-19 is associated with a component of CRS, and that CRS may accompany terminal event of respiratory failure and death, which is not necessarily due to progression of pneumonia, but to excessive macrophage activation syndrome (MAS), which is driving terminal events such as hypotension, vascular leak and increasing O2 requirements from the both the inflammation induced by the pneumonia, but also to the body’s immune response (excessive immune response resulting in CRS and MAS) to the viral infection and to the pneumonia caused by COVID-19.
Paolo A. Ascierto: Cytokine release or cytokine storm is a severe systemic inflammatory response to an injury.
Randy Q. Cron and W. Winn Chatham: An illness complication whereby there is unchecked immune activation leading to ongoing accentuated release of pro-inflammatory cytokines that cause injury to multiple organs, frequently resulting in death if not treated.
June: I have no first-hand knowledge of the immunopathology in COVID`-19. However, a preprint from China has some intriguing data in about 20 COVID-19 patients who had progressed on supportive care for about five days and were then given an infusion of tocilizumab. The temporal relationship of the fall in C-reactive protein and the resolution of fever are compelling in the data that is shown.
DiPersio and Ghobadi: See above. Still controversial, but yes, we believe that there is increasing evidence that CRS is occurring co-incident with the progressive pneumonia and in severe cases may be driving the pathology and increasing the risk of death above and beyond what would be expected by the viral infection by itself.
Ascierto: Xu et al. (chinaXiv:202003.00026) reported data from biopsy samples coming from autopsy in a patient who died for COVID-19, suggested that an inflammatory factor or a cytokine storm have occurred. They also found that aberrant pathogenic T cells and inflammatory monocytes are rapidly activated and are responsible of an inflammatory storm.
Cron and Chatham: There are increasing reports of series of patients critically ill with Covid-19 that have clinical features and blood abnormalities that are hallmarks of CSS (sepsis syndrome, ARDS, coagulopathy, hepatobiliary dysfunction, cytopenias). There are no formal studies we have seen yet that would answer the question of what percentage of deaths from Covid-19 are attributable to CSS as this is not routinely being assessed (it needs to be!).
June: Cytokine release syndrome is best thought of as a subset of secondary haemophagocytic lymphohistiocytosis (HLH), which also goes by an alternative name of macrophage activation syndrome.
Related to secondary HLH are cases of primary HLH generally seen by pediatricians that are caused by certain genetic lesions. It is possible that some of the COVID-19 patients that have hyper-inflammation have some of the predisposing genetic abnormalities that are found in other people with secondary HLH.
It is good to remember that a subset of patients with systemic viral infections are diagnosed with secondary HLH. In many of these patients, interleukin-6 is at the center of the immunopathology, along with high levels of interferon-gamma and serum ferritin levels.
DiPersio and Ghobadi: See above, again. We have not seen the inflammatory state of COVID-19 as well characterized as it has been with CAR T-associated CRS.
This needs to be done. This includes cytokine assays, fibrinogen, ferritin, CRP, IL-6, etc., as well as neurocognitive testing. It would appear different than CAR T in one important feature, and that is CRS and fever is an acute and dramatic early feature of CAR T CRS, while the CRS associated with feature of CAR T in an acute and early and fulminant (in first 1-4 days), while the CRS associated with COVID-19 is slow to develop and appears late with fevers and progressive pulmonary insufficiency.
Also, the fatal events in CAR T CRS (neurotoxicity) occurs late with progressive neurotoxicity—still, we have no idea what is causing this, although IL-1 has been implicated in some preclinical studies which may not have any relevance to what we see in patients receiving CAR T—when the “CRS” and CRS markers have often returned to normal, while the COVID-19 CRS are more associated with the terminal events high fever and worsening pneumonia and excessive tissue damage and death.
Ascierto: In CAR T-cell therapy the cytokine release syndrome is due to the activation of T cells armed with CAR, while in the COVID-19 such aberrant response seems to be mainly due to monocytes/macrophages.
According to Xu et al., and previous studies in SARS and MERS, it seems that IL-6 is still the most important cytokine involved in the cytokine storm by COVID-19.
Cron and Chatham: The clinical phenotype is the same and IL-6 levels have been noted to be elevated in Covid-19 critical illness, but the principal inflammatory mediators in Covid-19 CSS have not been well characterized as of yet.
June: Exactly, it is likely that COVID-19 cases of hyper-inflammation are the same syndrome as seen in other systemic viral infection, such as with some strains of influenza (1918 pandemic) and beta coxsackie viruses such as MERS and SARS.
DiPersio and Ghobadi: No, not really.
Ascierto: Even if some other viral infection could hypothetically trigger a cytokine storm, coronavirus infections seems to be those with a higher incidence of such condition.
Cron and Chatham: Other viruses (particularly influenza and herpes viruses such as EBV, CMV, HSV) are well known triggers of CSS in genetically susceptible individuals.
June: Extreme elevations of serum ferritin requiring dilutions by the laboratory technicians as well as high levels of C-Reactive Protein are characteristic if not pathognomonic of cytokine release syndrome and secondary HLH.
Our group, in conjunction with the scientists at Children’s Hospital in Philadelphia, have studied the cytokines and other biomarkers in serum that are found elevated in cytokine release syndrome after CAR T and have compared this to markers that are found elevated in sepsis (PMID: 27632680 and 27076371).
DiPersio and Ghobadi: See above. Fibrinogen, ferritin, CRP, cytokine levels (especially IL-6).
Ascierto: From my point of view the evaluation of serum IL-6, C-reactive protein (which is strongly related to IL-6 level) and ferritin are the most relevant
Cron and Chatham: An elevated serum ferritin should be a danger signal that should prompt immediate assessment for CSS. The higher the ferritin level, the greater the likelihood of CSS.
June: It is really interesting that the first use of tocilizumab for hyper-inflammation and secondary HLH was in the case of Emily Whitehead, our first pediatric patient given the experimental form of Kymriah (PMID 23527958).
It clearly saved her life, and later became co-labeled by the FDA for therapy of CRS after CAR T for both Kymriah and axicab [Yescarta]. I think it is highly likely that interruption of interleukin-6 signaling (and probably IL-1) will be beneficial in the subset of patients with COVID-19 that have hyper-inflammation and immunopathology.
There are many questions in this area, such as when to initiate such therapy, how long should it be given, and should it be given preemptively rather only in reaction to progressive ventilatory failure.
Fortunately, many trials are being started in China and here in the United States that will provide answers to these questions.
One major issue that needs to be answered is whether or not this therapy will lead to delayed clearance of the virus and therefore potentially more patients who could be asymptomatic vectors of the virus?
DiPersio and Ghobadi: Yes. Both toci FDA approved IL-6R and sarilumab (IL-6R blocking agent from Regeneron/Sanofi and approved in Canada but not in the U.S.). Remember, it is not a treatment for COVID-19 but a treatment of the life-threatening and terminal CRS events associated with COVID-19 (high fever, progressive O2 demands or post-intubation).
I know that Regeneron has sent out some feelers to intensivists around the country for a clinical trial that they are considering. Also, other agents could be considered including the IL-6 antibody (siltuximab) and the IL-1 receptor antagonist, anikinra (Kineret).
All should be considered especially in the context of clinical trials if possible. Finally, we are proposing a similar intervention with JAK1/2 inhibitors in these terminally ill patients that are intubated and febrile to reduce death associated with CRS from COVID-19. We are considering several JAK inhibitors produced by several companies (Incyte and Lilly) in the context of a clinical trial here at Washington University and at other centers for the treatment of COVID-19 associated CRS.
The major advantage is that this would be easy to administer and relatively cheap and could be targeted to those patients who have either increasing cardiac symptoms (seems to be associated with the terminal event) or progressive pulmonary decline or findings. One caveat regarding this approach is that JAK1/2 inhibitors will potently block interferon-gamma signaling (and IL-6 signaling).
T cell production of Interferon-gamma has been associated with enhanced clearance of viral infections in mouse models. So, this may best be used for the treatment of the end stage CRS phase of COVID-19 as opposed to early use in asymptomatic or minimally symptomatic COVID-19 patients where there is a possibility of limiting innate antiviral responses that may aid in clearing the virus.
This approach could be considered in moderately symptomatic patients in conjunction with some effective antiviral therapy which does not currently exist. If better preclinical mouse models or viral induced ARDS/CRS existed and especially if quantitative RT-PCR for COVID-19 was available then early interventions with inhibitors of interferon-gamma signaling could more safely be tested.
We and a group from Ohio State (Goldsmith et al. Blood Adv, 2020 and Ahmed et al. Lancet Oncol, 2019) have shown that one JAK1/2 inhibitor, ruxolitinib, is extremely effective in blocking life-threatening CRS in patients with severe secondary HLH, and it is likely it would also be very effective in COVID-19 associated CRS and potentially reduce deaths, especially if viral replication and viral clearance is not impaired.
Ascierto: Preliminary experience from Xu et al clearly indicate that tocilizumab is an important tools against COVID-19 respiratory distress
Cron and Chatham: There are reports of favorable responses to tocilizumab when used as part of the treatment of critically ill Covid-19 patients in China. There are numerous case reports/series of patients with CSS associated systemic JIA or adults Stills disease responding favorably to tocilizumab (probably more experience with IL-1b inhibitors such as anakinra/rhIL-1ra in this setting)
DiPersio and Ghobadi: Vaccines should be used as preventive strategies.
Infusion of anti-COVID-19 serum of antibodies against COVID-19 could be used early in the infection of anti-viral agents should be tested early after documented infection. A validated quantitative test such as qRT-PCR (does not exist to my knowledge) measuring viral loads would be key to evaluating the benefit of these.
Agents like IL-R, IL-6, IL-RA and JAK inhibitors could best be used late during the severe CRS phase.
Finally, those older patients with progressive disease and or new cardiac symptoms would be the best candidates for these interventions to reduce death.
Ascierto: In Italy at the moment is ongoing a large multicenter, open-label, phase II study with tocilizumab in COVID-19 pneumonia.
Cron and Chatham: The critical questions are:
How are patients who are developing CSS best identified?
Studies to assess markers of CSS sequentially in patients admitted with Covid-19 infection are needed to determine how to best identify early patients infected with Covid-19 who will develop CSS
Can early intervention in such patients forestall development of severe respiratory dysfunction in COVID-19?
Early intervention trials are needed, not just trials of patients who are critically ill—our experience in CSS occurring in other settings is that the earlier we intervene, the better the outcome.
What interventions are most effective?
Randomized controlled trials are necessary to confirm the effective interventions.
These are planned/underway with inhibitors of IL-1b (anakinra), IL-6 (tocilizumab), and anti-IFNg (emapalumab).
Ascierto: The ongoing phase II trial, and data coming from the observational study in Italy (hundreds of patients were treated in a real world experience) will give us a lot of information
Cron and Chatham: Funding of the needed clinical studies/trials. Rapid dissemination of interim results.
Ascierto: All anti-IL-6 could potentially get the same results of tocilizumab … sarilumab and others.
This story was updated March 25 at 10:14 AM