A New Generation of Cytokine-Based Immunotherapy Takes Shape

The FDA is scheduled to decide by May 23, 2023, whether to approve a biologics license application for nogapendekin alfa inbakicept (N-803; Anktiva), an IL-15 superagonist, in combination with BCG for patients with BCG–unresponsive non–muscleinvasive bladder cancer (NMIBC).3,4 Cytokine-based immunotherapy is a promising field in cancer treatment because cytokines regulate the host immune response to cancer cells and help induce tumor cell death.5 Investigators have recognized the potential efficacy of this approach for several decades, culminating in FDA approvals for several cytokines that serve as early examples of immunotherapy. Subsequent indications have been added for patients with follicular lymphoma, adjuvant melanoma, metastatic renal cell carcinoma (RCC), and Kaposi sarcoma.1 High-dose IL-2 (HDIL-2; aldesleukin [Proleukin]) was approved for the treatment of patients with metastatic RCC and metastatic melanoma in 1992 and 1998, respectively.1,6 Other cytokines used in cancer therapy include peginterferon alfa-2b, which has been approved under several brand names, and granulocyte-macrophage colony-stimulating factor, which has several therapeutic uses, including in oncolytic virus immunotherapy.7,8 Of the initial cytokine-based agents, IFN-α and HDIL-2 are used less frequently in current clinical practice because of the development of newer therapies, such as immune checkpoint inhibitors (ICIs) and targeted therapies, that offer superior safety and efficacy profiles.5,9 Now, a new generation of cytokine-based therapies, including combinations with other immune therapies, is in the works. Conversely, cytokines that are found in the tumor microenvironment facilitate mechanisms associated with cancer onset, such as angiogenesis, epithelial-to-mesenchymal transition, invasion, and tumor progression.2 Cytokines also serve a key role in the administration of adoptive cell therapy (ACT).13 ACT includes various cellular approaches such as tumor-infiltrating lymphocyte, engineered T-cell receptor–based, chimeric antigen receptor (CAR) T-cell, and natural killer (NK) cell therapies.1,14 Clinically, IL-2, IL-7, and IL-15 enhance in vitro expansion and differentiation of adoptive cells and are used to augment therapeutic ACT when coadministered or genetically engineered into adoptive cells.13 Another evolving area of research is genetically modifying cancer cells to express specific cytokines using nonviral vectors and gene editing technology.15 Additionally,