How to Treat Side Effects of New Cancer Immunotherapies

Veronica Hackethal, MD

May 06, 2015

The major side effects of newly and soon-to-be approved immunotherapies for cancer vary widely, but many are treatable, according to a review article published online April 27 in the Journal of Clinical Oncology.

"The side effects of immuno-oncology therapies are in some cases unique, different than what many oncologists have experienced with chemotherapy or targeted drugs, are mechanism based, and have   some common themes," commented lead author Jeffrey Weber, MD, PhD, of the Moffitt Cancer Center, in Tampa, Florida, to Medscape Medical News.

These side effects can be understood on the basis of immune mechanisms that lead to hyperactivation of T-cells. For example, cytokines cause nonspecific T-cell reactivity and diffuse effects.   Checkpoint protein inhibitors, vaccines, and adoptive cell therapies cause more specific T-cell activation and tend to cause specific organ damage, according to the authors.

"These side effects are manageable with standard treatment algorithms developed over years of experience," Dr Weber explained. "While there will be a learning curve, medical oncologists can   successfully deal with these toxicities."

Dr Weber advises having "a high degree of suspicion for the commonly seen side effects with immune-oncologic agents and cultivating a close relationship between the patients receiving these   drugs and the staff, so that early warning of symptoms occurs and early intervention ensues."

Cancer Vaccines

The authors say that 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.


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, according to the   authors.

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, according to the authors.

Adoptive Cell Therapy

Adoptive cell therapies are grown from tumor-infiltrating lymphocytes in melanoma and human papillomavirus–related cancers or are genetically engineered from the patient's own peripheral blood   lymphocytes. They may be effective treatments for metastatic melanoma, cervical cancer, synovial sarcoma, and B-cell malignancies.

Another type of adoptive cell therapy consists of chimeric antigen receptors (CARs), derived from monoclonal antibodies. These have been shown to be effective in B-cell malignancies. CARs   targeting the CD19 antigen are being studied in several clinical trials and may soon enter clinical practice.

Toxicities resulting from adoptive cell therapies may require a "high level of expertise to manage," according to the authors.

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 (Campath, Lemtrada, Genzyme Corporation).

Checkpoint Protein Inhibitors

Since 2011, the FDA has approved three checkpoint protein inhibitors: ipilimumab (Yervoy, Bristol-Myers Squibb Company), which blocks CTLA-4; pembrolizumab (Keytruda, Merck Sharp   & Dohme Corp), which blocks PD-1; and nivolumab (Opdivo, Bristol-Myers Squibb Company), which also blocks PD-1. These therapies block proteins that downregulate the immune system,   leading to immune attack of tumor cells. They can be used for treating melanoma and will likely be approved for many other tumor types.

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.

No biomarkers yet exist for identifying potential immunotherapy toxicities, though active research is ongoing.

Multiple authors report financial relationships with industry, including companies with cancer immunotherapies.

J Clin Oncol. Published online April 27, 2015. Abstract


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