Immunotherapy of cancer by IL-12-based cytokine combinations

Abstract

Cancer is a multi-faceted disease comprising complex interactions between neoplastic and normal cells. Over the past decade, there has been considerable progress in defining the molecular, cellular and environmental contributions to the pathophysiology of tumor development. Despite these advances, the conventional treatment of patients still generally involves surgery, radiotherapy and/ or chemotherapy and the clinical outcome for many of these efforts remains unsatisfactory. Recent studies have highlighted the feasibility of using immunotherapeutic approaches that seek to enhance host immune responses to developing tumors. These strategies include immunomodulatory cytokines, with tumor necrosis factor (TNF) alpha, type I or type II Interferons (IFNs), Interleukins (IL)-2, IL-12, IL-15 and IL-18 being among the most potent inducers of anti-tumor activity in a variety of pre-clinical studies. More recently, some exciting new cytokines have been characterized, such as IL-21, IL-23, IL-27, and their immunomodulatory and anti-tumor effects in vitro and in vivo suggest that they may have considerable promise for future immunotherapy protocols. The promise of cytokine therapy does indeed derive from the identification of these novel cytokines, but even more fundamentally, the field is greatly benefiting from the ever-expanding amount of preclinical data that convincingly demonstrate synergistic and/or novel biological effects that may be achieved through the use of several combinations of cytokines with complementary immunestimulating capabilities. One cytokine in particular, IL-12, holds considerable promise by virtue of the fact that it plays a central role in regulating both innate and adaptive immune responses, can by itself induce potent anti-cancer effects, and synergizes with several other cytokines for increased immunoregulatory and anti-tumor activities. This review will discuss the anti-tumor activity of IL-12, with a special emphasis on its ability to synergize with other cytokines for enhancement of immune effector cell populations and regulation of host-tumor cell interactions and the overall tumor microenvironment.

New insights into IL-12-mediated tumor suppression

“…In this respect, the combination of IL-12 with cytokines, chemotherapeutic agents, multipeptide vaccines and monoclonal antibodies potentiated the therapeutic activity of this cytokine in a variety of tumor models such as melanoma, bladder carcinoma and mammary carcinoma. [62][63][64][65][66][67] Even though the rationale for combining IL-12 with other cytokines was to achieve complementary and more durable immunestimulating responses, most of these treatments resulted in high levels of systemic IFNg production and therefore a potential degree of toxicity after translating them into the clinics. 65 In combination with chemotherapy, an improved antitumor activity could only be observed in immunogenic tumors when IL-12 was administered early after chemotherapy, thus highlighting the importance of the timing for immune intervention in chemotherapy-induced antitumor responses.…”

“…[62][63][64][65][66][67] Even though the rationale for combining IL-12 with other cytokines was to achieve complementary and more durable immunestimulating responses, most of these treatments resulted in high levels of systemic IFNg production and therefore a potential degree of toxicity after translating them into the clinics. 65 In combination with chemotherapy, an improved antitumor activity could only be observed in immunogenic tumors when IL-12 was administered early after chemotherapy, thus highlighting the importance of the timing for immune intervention in chemotherapy-induced antitumor responses. 68 An example of a successful combinatorial treatment with IL-12 was reported in human epidermal growth factor receptor (HER)-2/neu transgenic mice, where the treatment with IL-12 together with tamoxifen or HER-2/neu multipeptide vaccines resulted in an effective prevention of tumor growth.…”

Antitumor effects of a tumor cell vaccine expressing a membrane-bound form of the IL-12 p35 subunit

“…8 Various effecter cells, including NK, NKT, CD4 + T and CD8 + T cells, are involved in the antitumor immunity in different tumor models. 9 In addition, IL-12 confers antitumor immunity by stimulating IFNγ production, 10,11 and inhibits neo-vascular formation by IFNγ-inducible protein 10 (IP10) and monokine-induced by IFNγ (Mig). 12 The 70 kDa heterodimeric IL-12 cytokine consists of disulfide-linked p35 and p40 subunits and is produced primarily by antigen-presenting cells such as dendritic cells, macrophages, and B cells.…”

“…12 The 70 kDa heterodimeric IL-12 cytokine consists of disulfide-linked p35 and p40 subunits and is produced primarily by antigen-presenting cells such as dendritic cells, macrophages, and B cells. 8,9,13 The p35 subunit is produced constitutively in both lymphoid tissues and non-lymphoid tissues such as brain…”

Reply to Chen

“…4 In contrast, the activity of the IL-12/interferon-g (Th1) cytokine axis, which apparently was not increased in obese women, 1 has been regarded as crucial for stimulation of NO-dependent macrophage anticancer responses. 4,5 Therefore, it is conceivable to assume that a shift of balance between Th1 and Th17 responses towards the latter, as seen in obesity, 1 could contribute to cancer progression through selective low-level inducible NO synthase activation in tumour and/or surrounding stromal cells. Such an assumption is consistent with the ability of IL-17 to promote tumour growth via stimulation of endothelial cell migration and up-regulation of pro-angiogenic factors in fibroblasts and cancer cells.…”