Interleukin-12: Biological Properties and Clinical Application

Abstract

) is a heterodimeric protein, first recovered from EBV-transformed B cell lines.It is a multifunctional cytokine, the properties of which bridge innate and adaptive immunity, acting as a key regulator of cell-mediated immune responses through the induction of T helper 1 differentiation. By promoting IFN-g production, proliferation, and cytolytic activity of natural killer and T cells, IL-12 induces cellular immunity. In addition, IL-12 induces an antiangiogenic program mediated by IFN-g^inducible genes and by lymphocyte-endothelial cell cross-talk. The immunomodulating and antiangiogenic functions of IL-12 have provided the rationale for exploiting this cytokine as an anticancer agent. In contrast with the significant antitumor and antimetastatic activity of IL-12, documented in several preclinical studies, clinical trials with IL-12, used as a single agent, or as a vaccine adjuvant, have shown limited efficacy in most instances. More effective application of this cytokine, and of newly identified IL-12 family members (IL-23 and IL-27), should be evaluated as therapeutic agents with considerable potential in cancer patients.Interleukin-12 (IL-12) is recognized as a master regulator of adaptive type 1, cell-mediated immunity, the critical pathway involved in protection against neoplasia and many viruses. This is supported by the analysis of numerous animal (1, 2) and human clinical studies that attribute improved clinical outcome (3) and mechanisms of IL-12 -based therapy (4) to strong type 1 responses in situ. Since the initial preclinical and clinical studies of IL-12, done over a decade ago, basic and translational science studies have contributed to the greater understanding of IL-12 immunobiology. In addition to its noted effects in the priming of T helper 1 (TH1) cell responses and IFN-g production by T and natural killer (NK) cells, more recent studies support its critical role as a third signal for CD8 + T cell differentiation (5, 6), and its ability to serve as an important factor in the reactivation and survival of memory CD4 + T cells (7). This is particularly relevant in the repolarization of CD4 + T cells from dysfunctional antitumor TH2 into TH1 cells in the cancer setting (8). Here, we review the immunomodulatory and antiangiogenic functions of IL-12, as well as the results of preclinical and clinical studies in which IL-12 was used as an anticancer agent.

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

“…Studies with IL-12 have validated its role in the reactivation and survival of memory CD4 + T cells [82,83]. These studies have validated the multifunctional role of IL-12 and its potential utilization as an anti-cancer agent [82,84,85].…”

“…IL-12 is a cytokine that plays a critical role in both the innate and adaptive immune systems [81]. IL-12 induces NK and T cells to proliferate and produce IFN-γ [81,82]. Studies with IL-12 have validated its role in the reactivation and survival of memory CD4 + T cells [82,83].…”

Self-inactivating helper virus for the production of high-capacity adenoviral vectors

“…We used the HC-Ad/RUmIL-12 virus, which encodes the murine interleukin-12 (IL-12) under the control of a mifepristoneinducible system. 18 This is a stringent test, as IL-12 exerts potent immunostimulatory functions 19 that could reduce the persistence of the vector. HC-Ad/RUmIL-12 was administered intravenously to C57BL/6 mice, and IL-12 expression was induced by intraperitoneal injection of mifepristone at the indicated times.…”

HSV Recombinant Vectors for Gene Therapy

“…Although IL-4 was effective in different animal models , generation of a T H 1 response, including the induction of a memory response against tumour cells seems to have a more durable antitumor effect. At this regard the use of HSV vectors expressing IL-12 or GM-CSF, two indispensable cytokines for activating DCs and boosting the strong immune responses against cancer, seems promising [197, 198]. GM-CSF engenders protective immunity by stimulating the recruitment, maturation, and function of DCs, while IL-12 released from DCs directly primes effector lymphocytes at local environments.…”

“…In this regard, the gene transfer of GM-CSF into dying tumour cell may be more suitable form to elicit local antitumor responses by differentiating DC in situ and providing immunogenic tumour antigens for cross-presentation by paracrine fashion, whereas the expression of IL-12 may be an appropriate strategy to maximally boost antitumor effector functions. IL-12 also possesses antiangiogenic properties, which may represent a second potential mechanism of its antitumor activity [198]. M002 vector, derived from a replication-competent ICP34,5 - mutant which expresses mIL-12 was evaluated for its antitumor activity in a syngenic neuroblastoma murine model [189].…”