Dual Anti-OX40/IL-2 Therapy Augments Tumor Immunotherapy via IL-2R-Mediated Regulation of OX40 Expression

Abstract

The provision of T cell co-stimulation via members of the TNFR super-family, including OX40 (CD134) and 4-1BB (CD137), provides critical signals that promote T cell survival and differentiation. Recent studies have demonstrated that ligation of OX40 can augment T cell-mediated anti-tumor immunity in pre-clinical models and more importantly, OX40 agonists are under clinical development for cancer immunotherapy. OX40 is of particular interest as a therapeutic target as it is not expressed on naïve T cells but rather, is transiently up-regulated following TCR stimulation. Although TCR engagement is necessary for inducing OX40 expression, the downstream signals that regulate OX40 itself remain unclear. In this study, we demonstrate that OX40 expression is regulated through a TCR and common gamma chain cytokine-dependent signaling cascade that requires JAK3-mediated activation of the downstream transcription factors STAT3 and STAT5. Furthermore, combined treatment with an agonist anti-OX40 mAb and IL-2 augmented tumor immunotherapy against multiple tumor types. Dual therapy was also able to restore the function of anergic tumor-reactive CD8 T cells in mice with long-term well-established (>5 wks) tumors, leading to increased survival of the tumor-bearing hosts. Together, these data reveal the ability of TCR/common gamma chain cytokine signaling to regulate OX40 expression and demonstrate a novel means of augmenting cancer immunotherapy by providing dual anti-OX40/common gamma chain cytokine-directed therapy.

Interleukin-2: Biology, Design and Application

“…Given these properties, IL-2/S4B6 complexes could be used therapeutically in metastatic malignancies and chronic viral infection. In support of this notion, several groups have reported favorable results using IL-2/S4B6 complexes either as a monotherapy or in combination with another agent (such as Toll-like receptor ligand, agonist anti-OX40 mAb, or peptide vaccine) in various cancer models, including B16 melanoma, Lewis lung carcinoma, MC38 colon carcinoma, MCA-205 sarcoma, and TRAMP-C1 prostate carcinoma [31,[48][49][50][51][52][53]. Moreover, IL-2/S4B6 complexes have shown efficacy in models of acute and chronic infection [54,55].…”

Clinical Development of Immunostimulatory Monoclonal Antibodies and Opportunities for Combination

“…OX40 (CD134 or TNFRSF4) is a costimulatory molecule expressed on the surface of activated T lymphocytes (84). Agonists of OX40 have been used successfully in a variety of preclinical tumor models with promising results (85)(86)(87)(88), and a variety of combinatorial strategies to increase anti-OX40 antibody therapy with vaccines, chemotherapy, radiotherapy, and immunotherapy have been explored (79)(80)(81)(82)(83)(84)(85)(86)(87)(88)(89)(90)(91). A mouse anti-human OX40 mAb has shown activity in nonhuman primates and has been tested in phase I clinical trials in 30 patients at different dosages with minimal toxicity although patients showed elevated levels of neutralizing human anti-mouse antibodies (92).…”

Prostate Cancer Immunotherapy: Beyond Immunity to Curability

“…However, trials combining anti-PD-1 antibodies with ipilimumab and prostate cancer vaccines are planned for 2015. Most recently, research with OX40 ligation in combination with CTLA-4 blockade showed antitumor activity in a nonimmunogenic murine model of CRPCA, which has been predictive of ipilimumab clinical activity in mCRPCA (39). Anti-OX40 ligation in combination with ipilimumab for mCRPC is slated to enter the clinic soon.…”