Editor’s Note: Find the latest and MOST COVID-19 news in the Medscape Coronavirus Resource Center.
When the first reports of a “cytokine storm” in patients with severe COVID-19, all eyes turned to cancer research. Oncologists have years of delight in the cytokine release syndrome (CRS) table in patients treated with chime antigen receptor (CAR) treatments for complex blood cancers.
Drugs used to suppress CKD in cancer patients were expected to be effective in patients with severe COVID, but the promise of a rapid solution with cancer drugs has not yet been fully fulfilled.
Part of the challenge is that the two similar conditions “are not the same,” said Nirali Shah, MD, head of the haematological cancer segment in the pediatric oncology branch of the National Cancer Institute.
“It has to do with the underlying physiopathology, which triggers inflammation,” Shah said.
CAR T-linked CRS is caused by activated T cells in cancer patients who do not have an infection, he said. In contrast, cytokine typhoon in COVID-19 is triggered by a viral pathogen that can lead to “uncontrollable” inflammation. These differences would possibly explain why drugs paint in the first case, but not in the second case, he added.
Drugs that inhibit interleucine-6 (such as tocilizumab, sarilumab and siltuximab) are used effectively to decrease CRS in patients receiving the CAR remedy for blood cancers and although trials of these agents in COVID patients are still ongoing, the initial effects are disappointing.
The first phase 3 global randomized controlled trial of tocilizumab in severe COVID-19 did not meet its number one clinical condition improvement criterion and did not meet its secondary mortality improvement criterion at week 4.
In their recent recommendations, NIH noticed a lack of knowledge about the efficacy of IL-6 inhibitors in COVID-19, and advised not to use them unless in a clinical trial.
When researchers began decoding the immune procedure underlying severe COVID-19, they turned to other cancer drugs to control the cytokine storm.
Louis Staudt, MD, PhD and Wyndham Wilson, MD, PhD, either in the NCI, that the cytokine typhoon in COVID-19 is caused by macrophages, which cause the release of several cytokines.
For years, the couple have been reading lymphoid tumors. Staudt is the chief of the Lymphoid Malignant Tumors branch at NCI and Wilson is the chief of the Lymphoma Healing section. In previous work, Staudt found that inhibiting an enzyme called bruton tyrosine kinase (BTK) reduces the function of macrophages.
When the pandemic began, Staudt and Wilson learned that opting for a single cytokine like IL-6 was not enough. They think that a more effective technique is to target macrophages with a BTK inhibitor called acalabrutinib (Calquence), which would inhibit several cytokines at the same time.
Staudt compares the immune reaction to a tree, with the macrophages that form the trunk of the tree and the branches composed of cytokines.
“Targeting macrophages is at the center of the problem,” he said. “They cut their limbs with tocilizumab. “
In just three days, Staudt and Wilson went from design to approval to launch a prospective and observational exam. The test was conducted at five centers in the United States and included 19 patients hospitalized by COVID-19; The effects were published in Science Immunology. During a 14-day treatment period, most patients treated with outdoor MMA with acalabrutinib improved, some within 24 hours. Eight of the 11 patients receiving the most oxygen were evacuated into the ambient air. Four of the 8 fan patients were extubated, two of whom were discharged into ambient air and two fan patients died. No appreciable toxicity was observed.
Tests also showed increased BTK activity and higher il-6 grades in monocytes, macrophage precursors, in patients with severe COVID-19, in healthy volunteers.
“We have shown that the target of acalabrutinib is active in the immune cells of patients with severe COVID-19,” Staudt said. “So we have the goal. We have the drug to reach the target. And we have an obvious benefit. “
These 3 elements were convincing enough to launch CALAVI’s Phase 2 trial, an open randomized controlled trial sponsored by AstraZeneca and the NCI, which takes place in the United States and around the world. compared to BSCs in other people hospitalized by COVID-19. The trial is expected to be completed on 26 November.
Previews of this test are expected shortly. “These are not data that we will probably publish, but it is data that will lead to the launch of a definitive phase 3 double-blind random test, which we hope to publish next month. Wilson said.
Other scientists are reading janus kinase inhibitors (JAK), a circle of enzyme relatives who play a key role in orchestrating immune responses, especially cytokines. Interest in inhibition of JAK to control hyperinflmation in cancer dates back at least 15 years, and drugs that act as JAK inhibitors are already approved for use in the treatment of myelofibrosis (ruxolitinib [Jakafi], fedratinib [Inrebic]) and also for rheumatoid arthritis (upadacitinib [Rinvoq], baricitinib [Olumiant].
“It’s not a big step for those of us with a deep knowledge of JAK inhibitors recommending taking them to the clinic to treat COVID-19 patients,” said John Mascarenhas, MD, head of clinical studies on the myelophollative health program. Icahn School of Medicine in Mount Sinai, New York.
Mascarenhas is also the lead researcher in the PRE-VENT trial, which compares the experimental inhibitor of JAK2 pacritinib plus the popular of care with the popular of care in patients hospitalized with severe COVID-19, with and without cancer. BioPharma (manufacturer of pacritinib) and takes position at 10 sites in the United States.
In a movement that can lift the eyebrows, PRE-VENT skipped stages 1 and 2 and went straight to phase 3. Pacritinib has still been approved by the FDA and has been studied primarily in myelofibrosis, an intensely inflammatory disease.
The resolution was discovered in trials on pacritinib in malignant hemorrhoids and also in the effects of a Phase 2 study in China that discovered clinical advantages imaginable for ruxolitinib JAK 1/2 inhibitor in 43 patients hospitalized for severe COVID-19, although the effects were not significant, Mascarenhas explained.
Recent effects of Lilly’s ACTT-2 test provided more help for the role of JAK inhibitors in the cytokine storm remedy. ACTT-2 is a placebo-controlled double-blind Phase 3 ECR, sponsored through NIH and NIAID, which compares JAK 1/2 baricitinib inhibitor plus antiviral remedivir for single remdesivir in patients hospitalized by COVID-19. In September, Lilly announced that the trial had achieved its number one goal of reducing recovery time in patients who gained baricitinib in mixture with remdesivir.
But the mechanism of action of pacritinib can make all the difference. The drug selectively inhibits JAK2 and saves JAK1, which is vital for the antiviral activity of the immune system. In addition, in vitro knowledge recommends that pacritinib can reduce inflammation and fight the virus through selectively inhibiting two more enzymes and two other receptors.
“The justification for me is very strong for the use of pacritinib,” Mascarenhas said. “I think this technique is ambitious but appropriate. “
The main challenge of protecting pacritinib may simply be bleeding, especially in patients taking blood thinners, Mascarenhas said. Because some patients with severe COVID-19 have a tendency to expand blood clots, anticoagulation has popular attention in many institutions.
As the trial has just begun, a minority of the expected general population of 358 patients have been recruited, no intermediate effects are available.
Inhibition of IL-6 still has a role to play in COVID-19, but the trick may also be in the moment. Most trials to date have studied tocilizumab in patients with severe COVID-19, many of whom were already on respirators. At this point, it may be too old to fix the damage that has already occurred.
One of the main reasons tocilizumab works so well in CRS after the CAR T remedy is that oncologists have learned to use it early, within 24 hours of the onset of fever. Oncologists use the consensus of the American Society of Transplants and Cell Therapy (ASTCT). scoring system, which helps them identify CRS when it is less difficult to control.
But applying the ASTCT classification formula to COVID-19 is problematic. “Almost by definition, patients hospitalized with COVID-19 have low oxygen levels, which throws the ladder,” said Joshua Hill, MD, an infectious disease specialist at Fred Hutchinson Cancer Research Center in Seattle, Washington, who has complications in investigating infectious diseases after treatment with CAR T.
“The key is to interfere before damaging the lungs and other terminal organs. We have nothing magical that can oppose that damage,” Hill said.
The effects of the EMPACTA Phase 3 trial (sponsored through Genentech) seem to see this, which evaluates the use of tocilizumab in less severe COVID-19 hospitalized patients who do not yet require mechanical ventilation. The trial stands out as the first global phase 3 trial to demonstrate the efficacy of tocilizumab compared to placebo in hospitalized patients with COVID-19 pneumonia, and to reach a higher percentage of racial/ethnic minorities (85% of 389 participants), who were severely affected by the pandemic and were still underrepresented in drug trials.
Last month, Roche announced that EMPACTA had achieved its main objective. The effects showed that patients hospitalized for COVID-19 pneumonia who gained tocilizumab plus popular care were 44% less likely to go through mechanical ventilation or die, compared to those who gained placebo plus popular attention (P -0. 0348), there was no statistically significant difference in deaths on day 28 between tocilizumab and placebo (10. 4% vs. 8. 6% Array p – 0. 5146).
However, early management of tocilizumab poses some other problem. IL-6 and its pathway are vital for eliminating viral infections. The use of tocilizumab in the context of an ongoing infection may pose protective problems.
In addition, tocilizumab remains in the frame for a relatively long period of time. In rheumatoid arthritis remedy, it is given once a month and has a black box warning for the reactivation of tuberculosis.
While empacta’s effects showed similar infection rates related to tocilizumab and placebo (10% vs. 11%), at least one other test found higher rates of overinfection in patients with severe COVID-19 who gained tocilizumab. a lower death threat in this most recent study.
A Phase 2 trial called COVIDOSE addresses the problem of protection. COVIDOSE evaluates whether low-dose tocilizumab is effective in non-critical COVID-19 patients, with the concept that decreasing doses would possibly be safer. The review indicated that the low dose of tocilizumab (ranging from 40 mg to 200 mg) is related to clinical improvement in 32 non-critical patients hospitalized by COVID-19.
Five patients (15. 6%) developed bacterial superinfections and five (15. 6%) died after 28 days of follow-up, there was no better “folding” among those patient teams. Bacterial superinfection was not the cause of death in the five deceased patients, and not all deceased patients developed bacterial superinfections, according to lead writer Pankti Reid, MD, MPH, who commented via email. Reid is an assistant professor of medicine at the University of Chicago.
The effects of COVIDOSE also showed that the tocilizumab remedy did not appear to have the ability of patients to expand antibodies opposed to COVID-19. The effects set the level for a larger (still ongoing) randomized controlled trial to determine the optimal dose of tocilizumab.
Still, the hill at Hutchinson Cancer Center requires caution.
Many of these immunomodulators have been used only in one clinical trial, or only for patients with terminal cancer and without other remedy options. In cancer patients, these drugs were studied and showed an “acceptable protection profile,” according to NCI Shah.
But it’s another situation, and when it comes to reassigning them to healthy patients with COVID-19, Hill puts pressure on the desire for in-depth research.
“We are still heavily involved in the administration of drugs that suppress the immune reaction if other people have active infections,” Hill said.
“We often think it makes things worse, and that’s the case,” he warned.
Mascarenhas investment for the institutional research of CTI Biopharma.
Hill, Staudt, Wilson and Shah disclosed any applicable monetary relationships.
For more information about Medscape Oncology, sign up for Twitter and Facebook
Medscape Medical News © 2020
You’ve already made up your mind about My Alerts
Click the subject below to receive emails when new items are available.