Abstract
The remarkable clinical success of immune-checkpoint inhibitors for the treatment of a growing number of cancer types has sparked interest in the discovery of novel forms of immunotherapy, which may be used alone or in combination. In this context, cytokine-based therapeutics are well poised to play a role in modern cancer therapy. This article focuses on antibody-cytokine fusion proteins (also called "immunocytokines") as one class of biopharmaceuticals that can substantially improve the therapeutic index and, thus, the applicability of cytokine products. In many preclinical settings, antibodies can be used to preferentially deliver many (but not all) types of cytokines to primary and metastatic tumor lesions. The antibody-based delivery of certain proinflammatory payloads (such as IL2, IL12, and TNF) to the tumor microenvironment can lead to a dramatic potentiation of their anticancer activity. However, although some fusion proteins have advanced to late-stage clinical trials, much work remains to be done in order to fully characterize the mechanism of action and the pharmaceutical potential of immunocytokines in the clinical setting. Various factors contribute to in vivo performance, including the target antigen, the antibody properties, the nature of the payload, the format of the fusion protein, the dose, and schedule, as well as their use in combination with other therapeutic modalities. Protein engineering opportunities and insights in cancer immunology are contributing to the development of next-generation immunocytokine products and of novel therapeutic concepts, with the goal to increase antitumor activity and reduce systemic toxicity (a common problem for cytokine-based biopharmaceuticals).