Adjuvants targeting innate and adaptive immunity synergize to enhance tumor immunotherapy

Abstract

Because of mechanisms of self-tolerance, many tumor-specific CD8 T cells exhibit low avidity for tumor antigens and would benefit from strategies that enhance their numbers and effector function. Here we demonstrate that the combined use of two different types of immune adjuvants, one that directly targets the CD8 cell, IL-2/anti-IL-2 mAb complexes, and one that targets the innate immune system, poly(I:C), can achieve this goal. Provision of IL-2/mAb complexes was found to enhance the activation and effector function of low-avidity tumor-specific T cells, yet this was insufficient to achieve tumor eradication. The addition of poly(I:C) further increased the accumulation of granzyme B-expressing effectors within the tumor and resulted in tumor eradication. This strategy presents many of the benefits of whole-body irradiation, including the provision of high levels of homeostatic cytokines, enhanced expansion of effector cells relative to regulatory T cells, and provision of inflammatory cytokines, and is therefore likely to serve as a strategy for both tumor vaccines and adoptive immunotherapy of cancer.CD8 T cells ͉ cytokine complexes ͉ interleukin-2 ͉ TLR ͉ tumor immunity A ctivation of T cells by chronically expressed tumor antigens results in tolerance through deletion, anergy, and immunoregulation (1-3). As a result, residual tumor-specific T cells are generally of low avidity or anergic (4, 5). A goal of cancer immunotherapy is to identify immune adjuvants that can activate and amplify these residual low-avidity tumor-reactive T cells. Recent studies have revealed that cytokines of the common ␥ chain receptor family, including IL-2, IL-4, IL-7, and IL-15, promote expansion and survival of CD8 T cells (6). Their receptor is composed of the common ␥ chain (CD132), the ␤ chain (CD122) for IL-2 and IL-15, and a cytokine-specific receptor subunit, IL-2R␣ (CD25), IL-4R␣ (CD124), and IL-7R␣ (CD127). Regulated expression of the specific receptor subunits by different T cell subsets determines which cytokines are used for survival and proliferation.IL-2 is commonly used as an adjuvant in immunotherapy protocols (7). In addition to playing a critical role in survival of CD8 T cells, when presented at high levels to antigen-activated CD8 cells, IL-2 can also promote the induction of effector functions, such as granzyme B (gzmB) via STAT5 signaling, thereby functioning as a costimulatory molecule (8). However, controversy about the dual role of IL-2 in enhancing proliferation of both CD8 effector cells and CD4 regulatory T cells (Tregs), both of which express high levels of CD25, has raised some questions about the use of this cytokine in vivo (9). Recent studies have shown that the effect of the cytokine can be amplified and directed more specifically to CD8 cells rather than Tregs if IL-2 is complexed with the mAB S4B6 (10, 11). IL-15 bound to IL-15R␣, its natural ''presenting'' receptors, has been shown to have a similar effect on CD8 memory cells and tumor-infiltrated cells (12)(13)(14), and IL-7/anti-IL-7 mAb comp...

Antitumor activity of IL‐2/anti‐IL‐2 mAb immunocomplexes exerts synergism with that of N‐(2‐hydroxypropyl)methacrylamide copolymer‐bound doxorubicin conjugate due to its low immunosuppressive activity

“…Kamimura et al 26 showed that coinjection of S4B6 mAb with a plasmid carrying murine il2 cDNA is capable to reduce the number of B16 melanoma lung metastasis to half that seen with injection of the plasmid alone. Other studies have described the antitumor activity of IL-2 immunocomplexes, which was especially prominent when coadministrated with poly I:C. 33 However, the tumor elimination described in our work was achieved by adoptive transfer of tumor-specific T cells followed by treatment with IL-2 immunocomplexes and was thus a rather artificial model of tumor treatment. The potential of IL-2 immunocomplexes for rapid generation of a functional NK cell compartment after bone marrow transplantation was highlighted by Prlic et al, 34 and the implications for preventing the tumor relapse was discussed.…”

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].…”

IL-2/anti-IL-2 antibody complexes show strong biological activity by avoiding interaction with IL-2 receptor α subunit CD25

“…In contrast, JES6-1 anti-mIL-2 mAb produced IL-2/mAb complexes that interacted almost exclusively with immune cells expressing high levels of CD25 along with βγ IL-2R; these CD25-directed complexes, designated IL-2/mAb CD25 complexes, induced selective expansion of CD25 + CD4 + Tregs (8). In addition to IL-2, cytokine/mAb complexes can also be generated using IL-3, IL-4, IL-6, or IL-7, which have been successfully used in various animal models, including viral infections, antitumor responses, autoimmune disease, and graft tolerance (8,(14)(15)(16)(17)(18)(19)(20)(21)(22)(23).…”