Monitoring, Managing Immunotherapy and Immune-Related Adverse Events

The following article features coverage from the 2022 Oncology Nurse Advisor Summit. Click here to read more of Oncology Nurse Advisor‘s conference coverage.

An important place to start in the discussion of immunotherapy is terminology. Chemotherapy is the use of drugs that stop cancer cell growth by killing the cells or stopping them from dividing. It is commonly known as a cancer therapy, and often all cancer therapies are categorized with this label. Immunotherapy is the use of substances to activate or inhibit the immune response to help the body fight cancer, infection, and other diseases. Targeted therapy is the use of drugs or substances to seek out and attack specific types of cancer cells. It is less harmful to normal cells. Types of targeted therapy kill cancer cells by enhancing the immune system’s ability recognize and kill cancer cells or delivering toxic substances directly to cancer cells.

Distinguishing between the types of cancer therapies is important when explaining treatments and adverse events to patients, explained Rowena (Moe) Schwartz, PharmD, BCOP, of the University of Cincinnati, Ohio, during her presentation at the 2022 Oncology Nurse Advisor Summit.

Immunotherapy Types and Mechanisms

Early immunotherapy agents were nonspecific immunostimulants. Recombinant cytokines are interferon, colony stimulating factors. These cytokines are the proteins that stimulate the immune response.

Monoclonal antibodies (mAbs) continue to evolve. They target specific surface receptor proteins on the cancer cell to activate immune response or suppress cancer cell response. Monoclonal antibody drug conjugates (ADCs) are mAbs designed to be hooked to chemotherapeutic agents or radioisotopes to deliver the agent directly to the cancer cell, sparing normal cells. Bispecific antibodies are mAbs that target 2 types of receptors.

Vaccination strategies are infection inhibitors that many consider to be an immunotherapy. Immune checkpoint inhibitors (ICIs) are actually mAbs. These immunotherapies are very different in terms of what they target. “I think that over time you’re going to see this list develop more and more, which means more therapy options,” Dr Schwartz said.

The ICI mechanism is to activate or suppress the cell pathways thereby regulating the cancer cell life. Receptors on the mAbs (eg, PD-1, PD-L1) attach to receptors on the cancer cell to inhibit the cell pathway. Other pathways under investigation include TIGIT, BTLA, TIM-3, LAG-3 (which suppress CD155), HVEM, galectin 9, and MHC-II.

ICIs used in oncology and currently marketed in the United States, based on what they target, are ipilimumab (cytotoxic T lymphocyte antigen 4 [CTLA-4] inhibitor); nivolumab, pembrolizumab, cemiplimab-rwlc, dostarlimab-gxly (PD-1 inhibitors); and atezolizumab, avelumab, durvalumab (PD-L1 inhibitors).

Management Strategies for irAEs

Immune-related adverse events (irAEs) are common in patients undergoing treatment with ICIs. The spectrum of AEs can resemble those of autoimmune responses (eg, hyper- and hypothyroidism, myasthenia gravis), with manifestation reflecting that spectrum. Symptoms also can overlap with those of other anticancer therapies (eg, peripheral neuropathy, severe cutaneous reactions, arrhythmias).

The timing of AE onset ranges from 2 to 3 days after initiation to as long as 6 months after completion of therapy; although adverse events can occur at any point after initiation of treatment. How long an AE can be an issue depends on the adverse event. Close monitoring is worthwhile for at least a 2 to 3 months, and the patient’s history of ICI therapy should be kept in mind for at least 6 months posttreatment, advised Dr Schwartz.

Five steps to a general approach to managing irAEs are: anticipate, detect, assess, treat, monitor, then rechallenge or discontinue. Engage the patient and family in patient/caregiver education that stresses self-management with reporting of symptoms, and communication with the care team. “I tell my patients [to] call us any time a new symptom occurs,” said Dr Schwartz.

The following patient cases demonstrate the range of adverse events to be alert for in patients receiving ICIs, and potential management strategies.

• The family member of a patient with comorbidities reports the patient is increasingly tired and has lost interest in family interactions. The family member is asking if the patient should be given an iron supplement. Is this patient anemic or is something else causing the symptom? An evaluation of fatigue should include an assessment of thyroid function, as ICI therapy may cause hypothyroidism.
• A patient presents to clinic prior to his third cycle of treatment with combination ICI therapy. A new left-sided facial droop is noted on examination prior to infusion. Published guidelines address numerous neurologic irAEs; however, published case reports have associated Bell palsy with ICI therapy. Although the guidelines are phenomenal, if you do not find something, look further. “The reason I say this is that we are still learning,” advised Dr Schwartz. New information is continually being reported in the literature.
• A patient on current combination therapy has his treatment complicated by watery diarrhea that is diagnosed as colitis. The patient’s colitis is managed by discontinuing therapy and treat with corticosteroids. Corticosteroids may be needed to manage ICI irAEs, which have their own potential adverse events. Patients and their caregivers need to know what symptoms to watch for, what to do if they occur, and where to turn for support. These instructions should be discussed orally with the patient and also written down for their reference.

Adverse Events with CAR T-Cell, Bispecific T-Cell Therapies

Chimeric antigen receptor T-cell (CAR-T) therapy is a type of immunotherapy in which the patient’s T-cells are harvested and genetically modified to develop receptors that can identify cancer cells. CAR-T cells are better able to target a patient’s cancer cells.

Bispecific T-cell engager antibody (blinatumomab) binds to CD19 of B-cells and CD3 of T-cells to activate endogenous T-cells with malignant B-cells. Bispecific mAbs trigger upregulation of cell adhesion molecules, production of cytolytic proteins, release of cytokines, proliferation of T-cells, and lysis of CD19+ cells. Significant irAEs with CAR-T therapy and bispecific T-cell engager antibody are cytokine release syndrome (CRS) and neurotoxicity syndrome (ICANS).

Risk factors for CRS include disease burden, the agent used, and the CAR-T doses. CRS manifests as fever and chills, hypotension and tachycardia, and potential organ cardiac, renal, hepatic, and pulmonary dysfunction. Onset can be relatively fast, occurring 2 to 3 days following cell administration, and lasts for 1 week or longer.

Recent studies have shown an association between CRS and IL-6, making IL-6 receptor blocking antibody (tocilizumab) a viable treatment. Corticosteroids and supportive care also are components of managing CRS. Available guidelines define symptoms by grade, ranging from fever (grade 1) to fever with hypotension requiring multiple vasopressors (excluding vasopressin) and/or hypoxia requiring positive pressure (eg, CPAP, BiPAP, intubation, mechanical ventilation; grade 4).

Onset of neurotoxicity syndrome is 4 to 10 days after cell administration, and symptoms generally last for 2 weeks or longer. Neurotoxicity syndrome manifests in a wide range of symptoms, including encephalopathy, headache, tremor, dizziness, aphasia, delirium, insomnia, anxiety, and autonomic neuropathy. Less common symptoms are agitation, hyperactivity, and signs of psychosis. Seizures and cerebral edema also are potential manifestations of neurologic toxicity.

Management is based on grade of severity and clinical manifestations, including supportive care, corticosteroids, and if there is an overlap with CRS, use of tocilizumab is appropriate. “Any time you see any kind of neurologic symptom, it should be evaluated extensively,” Dr Schwartz advised.

Read more of Oncology Nurse Advisor’s coverage of 2022 Oncology Nurse Advisor Summit by visiting the conference page.

Reference

Schwartz R. Anticipate and effectively manage immune-related adverse effects. Oral presentation at: 2022 Oncology Nurse Advisor Summit.