The side effects of immunotherapy for cancer are as diverse as the type of treatments that have been devised. and many of the side effects are treatable.
Side effects of immunotherapy for cancer: cancer vaccines
Cancer vaccines usually have low toxicity, perhaps because they target antigens abundant on tumor cells but seldom found on normal cells.
For example, sipuleucel-T (Provenge, Dendreon Corporation), the only cancer vaccine currently approved by the FDA, generally has low toxicity. Its most common side effects include back pain and chills, seen in 2% of patients. Fewer than 4% of patients develop grade 3 or 4 adverse events.
Side effects of immunotherapy for cancer: cytokines
In 1992, the FDA approved recombinant human interferon alfa (IFN) for treating hairy cell leukemia and as an adjuvant in high-risk melanoma. The FDA approval of high-dose interleukin-2 (IL-2) in advanced renal cell carcinoma or melanoma followed in 1998. Use of either agent frequently results in severe adverse events, with vascular leak a particular problem.
More than 80% of patients who receive IFN develop fever and fatigue, the latter of which can be dose- or treatment-limiting. Patients also commonly report headache and myalgias, often controlled by nonsteroidal anti-inflammatories.
Patients may also develop severe, though uncommon, neuropsychiatric symptoms with IFN. Up to 45% develop depression, but suicide is rarely reported. For these reasons, IFN is contraindicated in patients with a history of severe depression.
Other common side effects with IFN include diarrhea, seen in about one third of patients, as well as nausea and anorexia, seen in two thirds. Both are treatable with over-the-counter medications and antiemetics. About 10% of patients develop thrombocytopenia and leukopenia, and 15% develop hyper- or hypothyroidism.
Patients who receive IL-2 often experience fever, chills, fatigue, and GI symptoms. IL-2 increases vascular permeability and can cause pleural effusions, pulmonary edema, kidney failure, and hypotension. The latter, though often dose-limiting, can be managed outside the ICU with pressor support and cardiac monitoring. Most Il-2 adverse events resolve by holding or discontinuing the medication.
Side effects of immunotherapy for cancer: adoptive cell therapy
Life-threatening autoimmunity can result when a receptor targeting self is engineered into a T-cell or when receptor-engineered T-cells cross-react with antigens in different organs.
Use of preparative chemotherapy can lead to immunosuppression and sepsis, which accounts for 1% to 2% of treatment-related mortality in these regimens.
Cytokine release syndrome (CRS) may also develop with adoptive cell therapies. Similar to sepsis, symptoms of CRS include fever, tachycardia, vascular leak, oliguria, hypotension, and organ failure, which is reversible with supportive care.
Life-threatening toxicities can be managed with high-dose corticosteroids and alemtuzumab.
Side effects of immunotherapy for cancer: immune checkpoint inhibitors
A "significant" number of patients who receive these therapies develop autoimmune syndromes. Dr Weber advises clinicians to be on the lookout for inflammation in various organs, such as colitis, pancreatitis, pneumonitis, hepatitis, hypophysitis, and skin reactions.
Immune-related adverse events follow a specific pattern, with most developing by week 24. Rashes and GI toxicities develop first, followed by liver and endocrine abnormalities. Other immune- related adverse events include arthralgias, enteritis, encephalitis, Guillain-Barre syndrome, myasthenia gravis–like syndrome, and autoimmune bone marrow suppression.
"Nearly all" of the adverse effects of these drugs resolve with treatment with high-dose corticosteroids, say the authors. Infliximab (Remicade, Janssen Biotech, Inc) may become necessary when colitis fails to resolve or relapses occur.
Side effects of immunotherapy for cancer: monoclonal antibodies
Monoclonal antibodies are given intravenously (injected into a vein). The antibodies themselves are proteins, so giving them can sometimes cause something like an allergic reaction. This is more common while the drug is first being given. Possible side effects can include:Fever, Chills, Weakness, Headache, Nausea, Vomiting, Diarrhea, Low blood pressure, Rashes.
Compared with chemotherapy drugs, naked mAbs tend to have fewer serious side effects. But they can still cause problems in some people. Some mAbs can have side effects that are related to the antigens they target. For example:
Bevacizumab (Avastin®) is an mAb that targets a protein called VEGF that affects tumor blood vessel growth. It can cause side effects such as high blood pressure, bleeding, poor wound healing, blood clots, and kidney damage.
Cetuximab (Erbitux®) is an antibody that targets a cell protein called EGFR, which is found on normal skin cells (as well as some types of cancer cells). This drug can cause serious rashes in some people.
Conjugated antibodies can be more powerful than naked mAbs, but they can also cause more side effects. The side effects depend on which type of substance they're attached to.
Although the side effects of cancer immunotherapy are various, they are based on similar mechanisim, and can be treatable.
Weber J S et al. Toxicities of Immunotherapy for the Practitioner[J]. Journal of Clinical Oncology, 2015, 33(18): 2092-2099.