NONSPECIFIC IMMUNOTHERAPIES AND ADJUVANTS


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Various immunotherapy strategies target cancer cells nonspecifically, stimulating the immune system in a more general way.8 These include immunomodulatory drugs such as thalidomide (Thalomid), lenalidomide (Revlimid), pomalidomide (Pomalyst), and imiquimod (Aldara, Zyclara, generics). Another immunotherapy strategy is the live attenuated virus Bacille Calmette-Guerin; this virus is used in the treatment of the bladder.

All immune reactions involve cytokines, and several nonspecific cancer immunotherapy strategies use cytokines.9 Cytokines interact in complex ways to provide homeostasis and immune control through positive and negative feedback mechanisms.

Interleukin-2 is a type of cytokine that leads to the growth of T lymphocytes. It was FDA-approved for the treatment of advanced renal cell carcinoma in 1992 and for metastatic melanoma in 1998; but its toxicity limits its use to patients with excellent organ function.2 It had an objective response rate of 16% in 270 melanoma patients, and the 6% of patients who achieved complete response had a durable response. Its toxicities include fever, chills, myalgias, diarrhea, nausea, anemia, thrombocytopenia, hepatic dysfunction, myocarditis, confusion, and a predisposition to infection; but these effects are dose-dependent, largely predictable, and reversible. Interleukin-2 can only be used at well-established treatment centers with clinicians experienced in administering interleukin-2 therapy. At high doses, interleukin-2 is given in the inpatient setting.

Another type of cytokine is interferons, which were discovered in the 1950s.2 Analyses of high-dose interferon-alfa use in melanoma cases found a consistent benefit for high-risk patients with melanoma, as it improved relapse-free survival by 13% to 18% and overall survival by 10% to 11%. Notably, interferon is difficult to tolerate, and its toxicity limits its use and often leads to treatment discontinuation. Predominant side effects include myelotoxicity, elevation of liver enzymes, nausea, vomiting, flulike symptoms, and neuropsychiatric symptoms. Interferon-alfa is only recommended for patients with a risk of relapse greater than 30%. It is FDA-approved for hairy cell leukemia, chronic myelogenous leukemia, follicular non-Hodgkin lymphoma, cutaneous T-cell lymphoma, kidney cancer, melanoma, and Kaposi sarcoma.

Granulocyte-macrophage colony-stimulating factor (GM-CFS) is another cytokine that stimulates the immune system. GM-CSF boosts white blood cells after chemotherapy, and is FDA-approved to help increase the number and function of white blood cells after bone marrow transplantation.10 GM-CFS is indicated for cases of bone marrow transplantation failure or engraftment delay, before and after peripheral blood stem cell transplantation, and following induction chemotherapy in older patients with acute myelogenous leukemia. Patients taking GM-CSF have commonly experienced fever, liver-associated events, skin-associated events, infection, nausea, metabolic disturbances, and diarrhea.

TABLE 1. Immunological reagents against cancer

Immunotherapy Mechanism/target Indications
Antibody-drug conjugates
Brentuximab vedotin (Adcetris) Targets CD30 with the cytotoxic agent MMAE Anaplastic large cell lymphoma, Relapsed or refractory Hodgkin lymphoma
Trastuzumab emtansine (Kadcyla) HER2 receptor HER2+ metastatic breast cancer
Antibody-radioparticle conjugate
Ibritumomab tiuxetan (Zevalin) Targets CD20 with yttrium-90 attached Refractory non-Hodgkin lymphoma
Cancer vaccine
Sipuleucel-T (Provenge) Culture dendritic cells to target the antigen prostatic acid phosphatase Metastatic prostate cancer
Cytokines
Granulocyte-macrophage colony-stimulating factor (Leukine) Stimulates immune system • Before and after peripheral blood stem cell transplantation • Bone marrow transplantation failure or engraftment delay
• Following induction chemotherapy in older patients with acute myelogenous leukemia
Interferon-alfa • Activates JAK-STAT pathway
• Modulates function of natural killer cells and T cells
• Activates distribution of cellular subsets
• Induces pro-apoptosis genes
Chronic myelogenous leukemia, Cutaneous T-cell lymphoma, Follicular non-Hodgkin lymphoma, Hairy cell leukemia, Kaposi sarcoma, Kidney cancer, Melanoma
Interleukin-2 Increased T lymphocytes Advanced renal cell carcinoma, Metastatic melanoma
Immunomodulatory drug
Thalidomide (Thalomid) Augment natural killer cell cytotoxicity Increase interleukin-2 secretions Newly diagnosed multiple myeloma
Monoclonal antibodies
Bevacizumab (Avastin) Vascular endothelial growth factor Breast cancer, Colorectal cancer, Non-small cell lung cancer
Cetuximab (Erbitux) Epidermal growth factor receptor Colorectal cancer, Head and neck cancer
Ipilimumab (Yervoy) Blockades CTLA-4 for immune checkpoint blockade Metastatic melanoma
Rituximab (Rituxan) CD20 B-cell surface antigen Chronic lymphocytic leukemia, Non-Hodgkin lymphoma
Trastuzumab (Herceptin) HER2 receptor HER2+ breast cancer, HER2+ metastatic gastric cancer