Cytokine Release Syndrome (CRS) is a potentially life-threatening condition where the immune system becomes over-stimulated by certain triggers, such as immunotherapies and infections.
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The TGN 1412 trial: learning from failure
The dangers of CRS came to the attention of the general public and medical community in 2006, during the infamous clinical trial at Northwick Park Hospital in London, when a first-in-human trial produced an unexpected and dangerous result.
The drug being tested – Tegenero Immuno Therapeutics’ TGN 1412 – unexpectedly triggered CRS, leading to all six patients in the trial being hospitalized, with at least four having multiple organ dysfunction.
While the patients eventually recovered, albeit with the loss of toes and fingers in one case, the trial became an important milestone in the history of immunotherapy, when the potential dangers of these powerful drugs became apparent.
While the TGN 1412 trial led to several technical changes in the way drugs are manufactured to reduce the risk of CRS, immunotherapy use has rapidly developed and it’s still difficult to avoid onset while also stimulating the immune system to fight cancer.
Managing CRS means that cancer immunotherapies such as bispecific antibodies are limited to specialist cancer centers, which have the capacity to provide intensive care to manage the life-threatening symptoms of the disease.
This has created a need for drugs that manage CRS, and potentially allow patients to return to their homes once they have received their immunotherapy, improving their quality of life while also reducing healthcare costs associated with long stays in hospitals.
Are currently available drugs doing enough to address cytokine release syndrome?
Several drugs that are already on the market or in trials have shown promise in managing cytokine release syndrome, which also turned out to be one of the potential symptoms that made COVID-19 such a dangerous virus.
After the extreme responses to immunotherapies, such as CAR-T cell therapies, the COVID pandemic underlined the danger posed by CRS, and several drug classes were trialed to improve the immune response to infection by the SARS-CoV2 virus.
Roche’s Actemra (tocilizumab) has been used to inhibit the progression of CRS after patients have been treated with CAR-T therapies, as well as in COVID patients with severe symptoms.
JAK inhibitors such as Jakafi/Jakavi (ruxolitinib) – marketed by Incyte in the U.S., and Novartis elsewhere in the world as a treatment for myelofibrosis – have been shown in the clinic to inhibit CRS.
However, ruxolitinib achieves this by dampening the anti-tumor activity of CAR-T therapies too. So, by putting the brakes on CRS with this drug, the efficacy of the therapy may also be compromised.
CRS is particularly dangerous in immunotherapy because it causes similar symptoms experienced with infections, but the ‘stopping’ mechanisms that the body usually has in place when it senses an infection are not present.
Dexamethasone, a commonly used steroid, is also used against CRS, along with SOBI’s Kineret (anakinra) but these have drawbacks as well.
High levels of CRS are still in place with these treatment options, and there are other limitations; even with prophylactic tocilizumab, 40% of patients still go on to develop the condition after immunotherapy, according to the latest clinical research.
To add to that, most of the treatment options are given intravenously, meaning patients have to stay in the hospital for lengthy periods, placing a burden on both the patient and the hospital.
New clinical trials tackling cytokine release syndrome
U.K.-based Poolbeg Pharma is taking a different approach with its POLB 001, a small molecule immunomodulator that has already shown promise in a lipopolysaccharide (LPS) human challenge trial. A human challenge trial is a type of clinical study typically in vaccine development, when participants are intentionally given an infection in a controlled environment to understand the onset and development of a disease.
The inflammatory symptoms associated with LPS are also caused by the overproduction of cytokines, and the trial results showed a highly significant reduction in p38 mitogen-activated protein (MAP) kinase driven cytokines, back in March, 2023. p38 MAP kinase is largely expressed in white blood cells, and can unleash inflammation. So, inhibiting p38 MAP kinase could essentially steer the cytokine storm.
Poolbeg followed this in January, with in vivo results that show its potential as a therapy for cancer immunotherapy-induced CRS. Unlike JAK inhibitors, data so far suggest POLB 001 can act against the cytokine storm while maintaining the effectiveness of the immunotherapy.
As POLB 001 is administered orally, Poolbeg hopes it will be convenient for patients, and could allow them to return to their homes soon after treatment with an immunotherapy, minimizing the risks of a dangerous bout of CRS.
Preparation for clinical trial is underway and the company is preparing for talks with regulators for a phase 2 trial.
Dr. Martin Kaiser, associate professor in molecular hematology at The Institute of Cancer Research, said: “Three drugs are currently available, but they all come with their downsides of either being intravenous drugs or not being completely efficacious in terms of mitigating side effects or even causing other side effects.”
“That does open up an unmet need in this field to facilitate the delivery of these immunotherapies that are coming our way both in hematology and solid oncology.”
Other developers have seen the opportunity too. U.S.-based CytoAgents received clearance from the U.S. Food and Drug Administration (FDA) to begin a phase 1b/2a clinical trial of its drug candidate CTO1681.
This works by targeting the NF-kB signaling pathway to modulate the production of cytokines, thus reducing inflammation while still allowing for a functioning immune system.
Another drug that has been tested in the clinic for CRS is American biotech Humanigen’s lenzilumab, which is a monoclonal antibody targeting colony stimulating factor 2 (CSF2)/granulocyte-macrophage colony stimulating factor (GM-CSF). GM-CSFs are proteins secreted by immune cells that can aggravate CRS.
Lenzilumab is being developed as a therapy for CRS associated with COVID-19 and CD-19 targeted CAR-T cell therapies.
In a phase 1b trial of lenzilumab given in combination with Gilead’s CAR-T therapy Yescarta (axicabtagene ciloleucel), it gave an 83% overall response rate in six patients with advanced diffuse large B-cell lymphoma, with no incidence of severe CRS or neurotoxicity at the recommended phase 2 dose.
According to Poolbeg, the data so far point to a market with considerable commercial potential. In CRS alone, Poolbeg states that due to the increased use of immunotherapy, the market could exceed $10 billion annually, and that’s just in the main blood cancer indications of multiple myeloma and acute lymphoblastic leukemia.
From the harrowing events of 2006, and the later tragedy of the Covid pandemic, medical science is beginning to get a grip on cytokine release syndrome, which has become one of the major medical challenges of the 21st century.
New technologies related to cytokine release syndrome
- Topoisomerase 1 (Top1) Inhibition as a Novel Treatment Strategy for Sepsis and Cytokine Release Syndrome – Mount Sinai Health System
- Interleukin-37 to Enhance Effectiveness of CAR T-cell Therapy – Emory University
- AAV-based Particles Mimicking CARs (CARAAVs) are able to Reduce the Killing Activity of CAR T Cell – Heidelberg University