Interleukin 2 immunotherapy was applied to a 33-year-old woman with metastatic melanoma in 1984. She was the first cancer patient to respond to the administration of IL-2 and, thus, the first to demonstrate that a purely immunologic maneuver that stimulated T lymphocytes could mediate complete destruction of large, invasive, vascularized cancers in humans. This patient and thousands that subsequently received IL-2 played a major role in the introduction of immunotherapy into the mainstream of cancer treatment.
The following will briefly discuss interleukin 2 immunotherapy, interleukin 7 immunotherapy, interleukin 12 immunotherapy, interleukin 15 immunotherapy, interleukin 21 immunotherapy and interleukin 27 immunotherapy.
Interleukin 2 immunotherapy was approved for the treatment of metastatic renal cell carcinoma (1992) and later for metastatic melanoma (1998) by FDA.
High-dose interleukin 2 induces objective clinical responses in 15-20% of patients with advanced melanoma and durable complete responses in 5-7% of these patients. Interleukin 2 immunotherapy has severe side effects, such as hypotension, tachycardia, peripheral edema, fever, chill, fatigue, nausea, vomiting, anorexia, transaminase elevation, cholestasis and diarrhea.
While improved interleukin 2 formulation might be used as monotherapy, their combination with other anti-cancer immunotherapy, such as adoptive cell transfer regimens, antigen-specific vaccination, and blockade of immune checkpoint inhibitory molecules, for example cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) mono-antibodies, would held the promise of treating metastatic cancer.
Interleukin 7 immunotherapy has distinct actions on different subsets of T-cells. Two Phase I reports have identified no clinically significant toxicity, but have noted efficacy of recombinant human IL-7 (rIL-7) treatment in improving CD4+ and CD8+ counts.
In the study reported in 2006, four groups of patients with metastatic cancer received four different doses of rIL-7 (3, 10, 30, and 60 μg/kg) every 3 days, for eight doses. Absolute numbers of CD4+ and CD8+ T-cells increased in a dose-dependent manner over the 21-day period.
In the study reported in 2008, 16 patients with refractory cancer of various types were enrolled on a Phase I dose escalation trial. The CD4+ and CD8+ counts increased similarly in a dose dependent manner.
Interleukin 12 (IL-12) seemed to represent the ideal candidate for tumor immunotherapy, due to its ability to activate both innate (NK cells) and adaptive (cytotoxic T lymphocytes) immunities.
However, severe side effects associated with interleukin 12 immunotherapy in clinical investigations and the very narrow therapeutic index of this cytokine markedly tempered enthusiasm for the use of this cytokine in cancer patients.
Despite those setbacks, interleukin 12 (IL-12) continues to be the focus of interest in clinical oncology.
Interleukin 2 immunotherapy enhances the proliferation of cytotoxic T lymphocytes and natural killer (NK) cells, but it also exerts immunosuppressive activity through maintenance of regulatory T cells and activation-induced cell death. However, interleukin 15 immunotherapy displays similar immune cell stimulatory activity, but without the inhibitory effects of IL-2. Interleukin 15 has demonstrated significant therapeutic activity in several pre-clinical murine models of cancer. IL-15 has just entered Phase I trials in human subjects and is expected to have value in a variety of immunotherapeutic strategies, including both in vivo and in ex vivo strategies for adoptive cell therapies.
Interleukin 21 immunotherapy has demonstrated therapeutic activity in murine tumor models of melanoma and has recently entered Phase I clinical trials with modest preliminary results. Like the other γc cytokines (IL-2, IL-7, IL-15), interleukin 21 (IL-21) has recently started playing a role in adoptive T cell strategies based on its ability to enhance significantly the ex vivo generation and affinity of antigen-specific T cells.
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