Identifying and Treating Cytokine Release Syndrome

Victoria Miller, FNP-BC

As part of our coverage of the Oncology Nursing Society Conference that was held May 4th to May 7th in Denver, Colorado, we are speaking with Victoria Miller, FNP-BC, a nurse practitioner who specializes in oncology at the MD Anderson Cancer Center in Houston, Texas, about how to identify and treat cytokine release syndrome in cancer patients being treated with immunotherapy. Victoria and a colleague discussed the presentation of cytokine release syndrome specifically in patients who are being treated with chimeric antigen receptor (CAR)-modified T-cell or CAR T cells, and bispecific T-cell engaging antibodies as part of clinical trials.

OncoTherapy Network: First, could you describe what cytokine release syndrome is and why CAR T-cell therapy and bispecific T-cell engaging antibodies may cause this reaction?

Victoria Miller: Thank you for having me. I am excited to talk about this area in cancer research. I work with phase I trials at MD Anderson and I work primarily with solid tumors and CAR T cells and bispecific T-cell engaging antibodies are right now, being use for B-cell leukemias and lymphomas, but we are now starting to do trials in solid tumors. So this is really exciting. We have many patients that come in that know someone or have heard about a friend of a friend that had this therapy or have seen it on CNN.

CAR T-cell therapy or bispecific T-cell engaging antibodies are one way to use the body’s natural defense system to fight cancer. The CAR protein is called chimeric because it is engineered using different components. Antigens are proteins on the cancers that the T cells are engineered to target. The goal is that the immune system recognizes the immune system recognizes these abnormal antigens an attacks them. The CAR protein is added to the surface of the engineered T cell and functions as a receptor. These receptors then search for the matching antigen on a cancer cell so that the T cell can destroy it.

Bispecific T-cell engagers are a class of artificial, bispecific, monoclonal antibodies. They are fusion proteins consisting of two single-chain variable fragments, as different antibodies or amino acid sequences. The principle here is that the protein enters the tumor cells and then initiates the cell’s death. Now, cytokines are cell-signaling molecules that aid cell to cell communication and immune response. And cytokine release syndrome or CRS is an uncontrolled inflammatory response ranging from symptoms that are very mild to severe cases and the most severe can lead to death.

OncoTherapy Network: Are there factors that make certain patients more susceptible to developing cytokine release syndrome? Do we know anything about that?

Victoria Miller: I would say that the biggest factor is a high-disease burden. We also carefully monitor patients with comorbidities and patients that are older than 60 years of age. Those patients are more at risk. And we monitor them a lot closer.

OncoTherapy Network: What are the signs and symptoms and what can happen in a patient who has a severe form of the syndrome? Are there biomarkers that can predict cytokine release syndrome onset of CRS or biomarkers to help diagnose it?

Victoria Miller: Sure. So we use a grading system for CRS. Grade 1 would be very mild and grade 4 would be a patient that would be very sick and in the ICU [intensive care unit].

Mild symptoms of CRS include fever, nausea, headache, myalgia, and malaise. And with these therapies, most of the time, we do see a bit of these symptoms and we want to see a bit of these symptoms because that means that the immune system is helping and working with this therapy. Now, these mild symptoms would be considered grade 1 or 2. Severe reactions are grade 3 or 4 and include hypotension requiring vasopressors, grade 3 organ toxicity. These patients are definitely in the ICU. Examples of grade 3 organ toxicity would be an EF [ejection fraction] of 20% to 39% for heart, respiratory issues including shortness of breathe at rest, having to place a chest tube, and neurotoxicity would be mental status changes, confusion, tremors, seizures, incontinence. Grade 4 symptoms would be very, very severe. The patient would be most likely on a ventilator, dialysis, in the ICU, and this would be life-threatening for the patient.

Now, as far as biomarkers, there can be serum elevations of inflammatory cytokines such as IL [interleukin]-2 or IL-6 and it’s limited because many hospitals don’t have this testing available and it is also challenging because baseline cytokine levels can be high in patients with disease burden. Other labs that we frequently do include C-reaction protein, ESR [erythrocyte sedimentation rate], liver function test, ferratin levels, and these can also be elevated in patients experiencing CRS. And of course we also do routine labs such as CBC [complete blood count] and CMP [comprehensive metabolic panel] daily.

OncoTherapy Network: Are there ways to treat cytokine release syndrome, and are these different for mild and severe cases?

Victoria Miller: Sure. So mild treatment would be supportive measures. We would treat with IV [intravenous] fluids, Tylenol, possibly antibiotics and a lot of careful watching from the nurses and caregivers and the team. More moderate or grade 2 symptoms would be an IV fluid bolus for hypotension, supplemental oxygen. High-risk patients we would likely transfer to the ICU. And we would consider starting tocilizumab at this point, also. Tocilizumab is a drug that is approved for rheumatoid arthritis and we found that it has been helpful in CRS. It is a humanized monoclonal antibody against IL-6 receptors. It’s given every 6 hours up to 3 doses. Now, we can also consider steroids here, but we are very cautious with this because we don't want the steroids to interfere with the treatment because steroids can suppress the immune system.

For severe reactions, of course the patient would be in the ICU. This would be considered grade 3 or 4 and this would be where we have grade 3 organ involvement and that would be a patient on vasopressors, mechanical ventilation, dialysis, and usually it is multiorgan involvement. We would give the tocilizumab as needed up to 3 doses and if this is not successful we would start high-dose steroids with dexamethasone, 10 mg IV every 6 hours. These patients are highly monitored in the ICU and the team is heavily involved, the critical care, and the rounding team. There are lots of consults and we would be very closely monitoring this patient.

OncoTherapy Network: Based on the literature and also your own experience, what advice do you have for fellow nurses and other clinicians who are managing patients on these therapies and what to look out for as far as CRS?

Victoria Miller: I think MD Anderson has done such a great job in preparing our patient nurses on the floor. They receive special training and any patient that is receiving this therapy is going to have a nurse that has gone through this extra training. And I think this gives comfort to the patient, to the nurse, and all around is really a good approach. We also work as a team. We have an RN, the nurse practitioner, the PA [physican assistant], the pharmacist, and attending doctors, and we have formed algorithms that are helpful for our nurses so they know if there is a vital sign change, such as a patient having hypotension or they have a fever, they contact us immediately and say, “Hey, Tori, what is going on here? These may be mild symptoms of CRS.” And my biggest advice is to listen to the nurse and the caregiver for any mild changes, especially mental status changes.

I work a lot in the clinic, also, and this should all start with consenting the patient and education of the patient before they even go into the hospital to receive treatment. And I think, having open communication and working together as a team is extremely important in catching CRS symptoms and intervening as urgently as possible.

OncoTherapy Network: Thank you so much for speaking to us today, Tori.

Victoria Miller: Thank you, I am excited to share this and educate. I’m really excited that we are going to be doing more with these therapies in solid tumors soon.