Pre-Existing Tumor-Sensitized T Cells Are Essential for Eradication of Established Tumors by IL-12 and Cyclophosphamide Plus IL-12

Abstract

The antitumor immune response activated by IL-12, especially by a combination of cyclophosphamide and IL-12 (Cy+IL-12), is clinically significant in certain experimental tumor models, in that a number of well-established (10–20 mm in diameter) s.c. tumors are completely eradicated. Furthermore, Cy+IL-12 treatment is also able to eradicate well-established grossly detectable experimental lung metastases and advanced ascites tumors. Despite the dramatic antitumor effects seen in some tumor models, Cy+IL-12 fails to induce regression of other established tumors. Characterization of tumor immunogenicity shows that all tumors responding to IL-12 and Cy+IL-12 treatments are immunogenic tumors, in that an antitumor immune response is detectable in tumor-bearing hosts upon tumor establishment. In contrast, none of the nonimmunogenic tumor responds to IL-12 and Cy+IL-12 treatments. Analysis of cellular requirements for successful tumor rejection through an adoptive cell transfer approach reveals that the presence of tumor-sensitized, but not naive, T cells is essential for tumor rejection by IL-12 and Cy+IL-12. Transfer of these tumor-sensitized T cells must be conducted before, but not after, IL-12 treatment in order for tumor rejection to occur. The requirement of sensitized T cells is also tumor specific. In mice bearing immunogenic tumors, the presence of pre-existing tumor-sensitized T cells is demonstrated by adoptive cell transfer experiments using purified spleen T cells from these mice. Results from our study show that Cy+IL-12-based immunotherapy of cancer may be highly effective and that pre-existing tumor-sensitized T cells are essential for the success of the therapy.

Human CD4+ T Cells Present Within the Microenvironment of Human Lung Tumors Are Mobilized by the Local and Sustained Release of IL-12 to Kill Tumors In Situ by Indirect Effects of IFN-γ

“…The role of these IL-12-responsive CD4 ϩ T cells in mediating the tumor growth suppression was established by cell depletion studies. Adoptive cell transfer experiments in mice have previously established that tumor-sensitized, but not naive T cells are essential for tumor rejection that is induced by IL-12 (34). The findings presented in this work are the first to show that a similar activated T cell exists within human lung tumors and that this cell can be reactivated by rhIL-12.…”

IL-12 immunotherapy of minimal residual disease in murine models of HPV16-associated tumours: induction of immune responses, cytokine production and kinetics of immune cell subsets

“…Depending upon the tumour system, differential effectors are stimulated and may be involved in the antitumour response generated either by IL-12 alone (8) or after chemotherapy (9)(10)(11)(12).…”

Novel Immunocompetent Murine Tumor Model for Evaluation of Conditionally Replication-Competent (Oncolytic) Murine Adenoviral Vectors

“…Interestingly, the antitumor activities of dlE102 and DLFM were different in the weakly immunogenic Pan02 tumor model (38), in which DLFM treatment significantly reduced tumor growth compared to the PBS control group, in contrast to dlE102, which did not. The control of tumor growth in the DFLM-injected animals correlated with a strong increase in activated CD4 ϩ and CD8 ϩ T cells in the periphery.…”

“…This model is classified as poorly immunogenic, as no spontaneous regression occurs after a challenge of mice with live tumor cells and immunostimulatory agents such as IL-12 are unable to induce a tumor-specific immune response in animals with established tumors (38). C57BL/6 mice bearing Pan02 tumors (average volume of 70 to 80 mm 3 ) were injected weekly (a total of six injections) with 50 l of either the vehicle (PBS-10% glycerol, n ϭ 10) or 1 ϫ 10 7 PFU of dlE102 (n ϭ 9) or DLFM (n ϭ 7), and tumor progression (Fig.…”