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 f… Show more
“…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 (IL)-2 has been approved for treatment of metastatic renal cancer and malignant melanoma. However, its unfavorable pharmacologic properties, severe side effects and the negative role of IL-2 in maintaining T regulatory cells are severe drawbacks. It has been shown that immunocomplexes of IL-2 and certain anti-IL-2 mAbs possess selective and high stimulatory activity in vivo. Here, we show that IL-2/S4B6 mAb immunocomplexes expand not only CD122 high subsets and newly activated CD8 1 T cells but also natural killer T cells and cd T cells. Further, we demonstrate that natural killer (NK) cells expanded by IL-2/S4B6 mAb immunocomplexes in vivo have high cytolytic activity, which can be further increased by coadministration of IL-12. We also demonstrate that IL-2/S4B6 mAb immunocomplexes possess noticeable antitumor activity in two syngeneic mouse tumor models, namely BCL1 leukemia and B16F10 melanoma, but only if administered early in tumor progression. To effectively treat established tumors, we administered the tumor-bearing mice first with N-(2-hydroxypropyl)methacrylamide copolymer-bound doxorubicin conjugate, and subsequently with IL-2/S4B6 mAb immunocomplexes alone or with IL-12 to induce an efficient antitumor immune response. Importantly, we show that the conjugate has significantly lower immunosuppressive activity than free doxorubicin when using dosage with comparable antitumor activity, thus eliminating the majority of tumor cells while leaving the immune system mostly unimpaired for stimulation with IL-2/S4B6 mAb immunocomplexes. Indeed, we demonstrate that the conjugate and IL-2/S4B6 mAb immunocomplexes together have synergistic antitumor activity.Chemotherapy is able to markedly reduce the number of tumor cells in many cases, but often fails to completely eradicate all of them resulting in so-called ''minimal residual disease'' and consequently in relapse of the disease. 1 On the other hand, one of the crucial limitations for effective tumor immunotherapy is the size of the tumor population, as antitumor immune responses are usually relatively weak and are able to control only a limited number of tumor cells. Thus, it would be desirable to investigate the therapeutic potential of chemoimmunotherapy by using a suitable form of chemotherapy with limited immunosuppressive effect in combination with some novel and potent immunotherapy approach.In our study, we used a conjugate of a synthetic, watersoluble and biocompatible copolymer based on N-(2-hydroxypropyl)methacrylamide (HPMA) to which doxorubicin is attached by an amide bond via a Gly-Phe(D,L)-Leu-Gly spacer 2 and containing also a human polyclonal nonspecific IgG (henceforth polymeric conjugate). For schematic structure of polymeric conjugate, see Supporting Information Figure 1. It has been shown previously that such a conjugate has considerable antitumor activity in various tumor models in vivo, 3,4 and it has been also successfully used in five patients with metastatic mammary carcinoma. 5,6 It was also demonstrated that this polymer...
“…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 (IL)-2 has been approved for treatment of metastatic renal cancer and malignant melanoma. However, its unfavorable pharmacologic properties, severe side effects and the negative role of IL-2 in maintaining T regulatory cells are severe drawbacks. It has been shown that immunocomplexes of IL-2 and certain anti-IL-2 mAbs possess selective and high stimulatory activity in vivo. Here, we show that IL-2/S4B6 mAb immunocomplexes expand not only CD122 high subsets and newly activated CD8 1 T cells but also natural killer T cells and cd T cells. Further, we demonstrate that natural killer (NK) cells expanded by IL-2/S4B6 mAb immunocomplexes in vivo have high cytolytic activity, which can be further increased by coadministration of IL-12. We also demonstrate that IL-2/S4B6 mAb immunocomplexes possess noticeable antitumor activity in two syngeneic mouse tumor models, namely BCL1 leukemia and B16F10 melanoma, but only if administered early in tumor progression. To effectively treat established tumors, we administered the tumor-bearing mice first with N-(2-hydroxypropyl)methacrylamide copolymer-bound doxorubicin conjugate, and subsequently with IL-2/S4B6 mAb immunocomplexes alone or with IL-12 to induce an efficient antitumor immune response. Importantly, we show that the conjugate has significantly lower immunosuppressive activity than free doxorubicin when using dosage with comparable antitumor activity, thus eliminating the majority of tumor cells while leaving the immune system mostly unimpaired for stimulation with IL-2/S4B6 mAb immunocomplexes. Indeed, we demonstrate that the conjugate and IL-2/S4B6 mAb immunocomplexes together have synergistic antitumor activity.Chemotherapy is able to markedly reduce the number of tumor cells in many cases, but often fails to completely eradicate all of them resulting in so-called ''minimal residual disease'' and consequently in relapse of the disease. 1 On the other hand, one of the crucial limitations for effective tumor immunotherapy is the size of the tumor population, as antitumor immune responses are usually relatively weak and are able to control only a limited number of tumor cells. Thus, it would be desirable to investigate the therapeutic potential of chemoimmunotherapy by using a suitable form of chemotherapy with limited immunosuppressive effect in combination with some novel and potent immunotherapy approach.In our study, we used a conjugate of a synthetic, watersoluble and biocompatible copolymer based on N-(2-hydroxypropyl)methacrylamide (HPMA) to which doxorubicin is attached by an amide bond via a Gly-Phe(D,L)-Leu-Gly spacer 2 and containing also a human polyclonal nonspecific IgG (henceforth polymeric conjugate). For schematic structure of polymeric conjugate, see Supporting Information Figure 1. It has been shown previously that such a conjugate has considerable antitumor activity in various tumor models in vivo, 3,4 and it has been also successfully used in five patients with metastatic mammary carcinoma. 5,6 It was also demonstrated that this polymer...
“…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].…”
Interleukin-2 (IL-2) exerts crucial functions during immune homeostasis via its effects on regulatory T (Treg) cells, and the optimizing and fine-tuning of effector lymphocyte responses. Thus, somewhat paradoxically, low doses of recombinant IL-2 have been used for Treg cell-based immunosuppressive strategies against immune pathologies, while high-dose IL-2 has shown some success in stimulating antitumor immune responses. Recent studies of the functional, biophysical and structural characteristics of IL-2 have led to the generation of IL-2 formulations, including IL-2/mAb complexes and IL-2 variants (muteins) that selectively enhance IL-2's immune stimulatory versus inhibitory properties. Here, we review these findings, placing new mechanistic insights into improved next-generation IL-2 formulations within the broader context of IL-2 biology. We conclude by integrating these findings into a framework for understanding IL-2-mediated selective immune modulation.
“…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).…”
Section: Il-2 Is Crucial To T Cell Homeostasis Especially Of Cd4mentioning
IL-2 is crucial to T cell homeostasis, especially of CD4 + T regulatory cells and memory CD8 + cells, as evidenced by vigorous proliferation of these cells in vivo following injections of superagonist IL-2/anti-IL-2 antibody complexes. The mechanism of IL-2/anti-IL-2 antibody complexes is unknown owing to a lack of understanding of IL-2 homeostasis. We show that IL-2 receptor α (CD25) plays a crucial role in IL-2 homeostasis. Thus, prolongation of IL-2 half-life and blocking of CD25 using antibodies or CD25-deficient mice led in combination, but not alone, to vigorous IL-2-mediated T cell proliferation, similar to IL-2/anti-IL-2 antibody complexes. These data suggest an unpredicted role for CD25 in IL-2 homeostasis.CD25 | cytokine | cytokine/mAb complexes | T cell homeostasis | Fc receptor
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