Since the first identification of tumor associated antigens, immunotherapy evolved rapidly as a new means to treat cancer (16). Importantly, anti-tumor immune responses can be improved by immune regulatory cytokines. In fact, the systemic administrations of IL2, IL12, or granulocyte macrophage colony stimulating factor induce or boost immune responses in such a way that they are effective in eradicating the tumor. These observations resulted in FDA approval of IL2 for the treatment of stage IV melanoma and renal cell carcinoma.
Physiologically, however, cytokines exert their function as auto- or paracrine factors that reach high concentrations only in the close vicinity of the producing cells (17). As a result, systemic administrations of cytokine doses that are distinct from this physiological mode of action are often accompanied by severe side effects. Direct injection of cytokines into solid tumors has been used to achieve curative doses of cytokines at the tumor site while reducing general toxicity. Similarly, locally disseminated tumors can be targeted by loco-regional treatment. For example, patients suffering from loco-regional metastases of melanoma or soft-tissue sarcoma benefit from an isolated limb perfusion with tumor necrosis factor (TNF) α in combination with cytotoxic drugs. However, most advanced neoplasms are neither localized nor accessible, both of which are prerequisites for either of these two treatment approaches. Consequently, to overcome these obstacles, IMMOMEC will take advantage of antibody-cytokine fusion proteins to target cytokines to the tumor microenvironment through the antigen specificity of antibodies. In fact, the selective delivery of immune stimulatory cytokines at the tumor site represents one of the most promising avenues for the development of anticancer therapies with unprecedented efficacy and tolerability. This approach was pioneered in the early 1990s by Ralph Reisfeld et al. (The Scripps Research Institute, La Jolla, CA) and subsequently refined by Dario Neri’s research group (Eidgenössische Technische Hochschule – Swiss Federal Institute of Technology, Zürich) (17).
The most widely studied antibody–cytokine fusion proteins are those containing IL2. In this regard, antibody–IL2 fusion proteins led to the eradication of established tumors and suppressed experimental and spontaneous metastases in xenogeneic and syngeneic neuroblastoma, melanoma and colon carcinoma models (18, 19). Importantly, the combined treatment with the parental, un-fused antibody plus IL2 displayed only minimal therapeutic effects demonstrating that the improved efficacy depended on the fusion of antibody and cytokine. Biodistribution analysis in preclinical models established that the tumor-specific fusion proteins preferentially accumulated within the tumor-bearing organs. It should be further noted, that the specific accumulation at the tumor site improved over time translating in a very long half-life of the fusion protein within the tumor microenvironment. Interestingly, depending on the tumor model, the antibody–IL2 fusion protein mediated its therapeutic effect either by innate or adaptive immunity reflecting the well-known broad spectrum of IL2 activity.