Treatment of minimal residual disease after surgery or chemotherapy in mice carrying HPV16-associated tumours: Cytokine and gene therapy with IL-2 and GM-CSF

Mikyšková, Romana; Indrová, M; Šímová, Jana; Jandlová, T; Bieblová, Jana; Jinoch, Pavel; Bubenı́k, Jan; Vonka, V.

doi:10.3892/ijo.24.1.161

Cited by 29 publications

(32 citation statements)

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“…After ~15 days, when the tumours reached a size of 2-3 mm in diameter, the mice were randomly divided into groups (8 mice per group) and injected i.p. with 150 mg/kg of bromine-substituted derivative of ifosfamide CBM-4A (racemic chlorobromofosfamide) preparation (7,(21)(22)(23)(24). A week later, the mice were injected with a single dose of IL-12-producing, irradiated (150 Gy) TC-1 or MK16 cells (1.5x10 7 cells per mouse), in the vicinity of the s.c. tumours, or, twice a day, for two five-days cycles, with rIL-12 (R&D Systems, Minneapolis, MN, daily dose 0.5 μg/mouse).…”

Section: Methodsmentioning

confidence: 99%

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

Indrová¹,

Bieblová²,

Bubenı́k³

et al. 2008

Int J Oncol

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Abstract.We have established animal models of HPV16-associated tumours with distinct levels of MHC class I expression. This model was used for examination of immune responses, production of cytokines and kinetics of immune cell subsets after IL-12 therapy of minimal residual tumour disease induced by CBA-4A (cyclophosphamide derivative) treatment. Upregulation of cytokine production was detected, compared to control animals without tumours. No differences in Th1/Th2 polarization of the immune responses after immunotherapy in animals bearing tumours with different surface expression of MHC class I molecules were observed. In the spleens of TC-1 (MHC class I + ) but not of TC-1/A9 (MHC class I -) treated tumour-bearing animals, the cytotoxic CD8 + cells detectable in 51 Cr microcytotoxicity assay, were found. In the spleens of TC-1/A9 but not of TC-1 tumourtreated animals, the NK activity measured as the lysis of NK-sensitive YAC-1 targets was detected. Down-regulation of the CD4 + and CD8 + subpopulations in spleens of tumourbearing animals were not restored after therapy. The percentage of CD25 + /CD4 + T regulatory (T reg ) cells in lymph nodes remained unchanged. The cytoreductive chemotherapy led to strong upregulation and accumulation of immunosuppressive immature myeloid Gr-1 + /CD11b + cells (IMC) in the spleens of treated animals. The accumulation of Gr-1 + /CD11b + cells was significantly decreased after subsequent IL-12 immunotherapy. These data suggest that elimination of IMC after IL-12 immunotherapy may be responsible for the improvement of antitumour responses after adjuvant IL-12 vaccination for the treatment of CMRTD.

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Section: Methodsmentioning

confidence: 99%

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

Indrová¹,

Bieblová²,

Bubenı́k³

et al. 2008

Int J Oncol

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“…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.…”

mentioning

confidence: 99%

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

Tomala

Chmelova

Strohalm

et al. 2011

Intl Journal of Cancer

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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...

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“…Through ex vivo manipulation, tumor cells can enhance their immunogenicity by expressing immunomodulatory proteins, especially cytokines such as IL-2 [170,171], IL-12 [172], and GM-CSF [171,173]. Since tumor-cell-based vaccines do not require a clear identification of tumor antigens, they are more useful for cancers without well-defined tumorspecific antigens than cervical cancer, which has welldefined antigens.…”

Section: Tumor Cell-based Vaccinesmentioning

confidence: 98%

HPV and Therapeutic Vaccines: Where are We in 2010?

Ma¹,

Xu²,

Hung³

et al. 2010

CCTR

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The discovery of human papillomavirus (HPV) as a necessary etiological factor for cervical cancer has spurred the development of preventive and therapeutic HPV vaccines for the control of HPV-associated malignancies including cervical, vulvar, vaginal, and a subset of head and neck cancers. The commercial preventive HPV vaccines, Gardasil and Cervarix, use HPV virus-like particles to generate neutralizing antibodies against HPV major capsid protein L1. However, they do not exert therapeutic effects on existing lesions and are unlikely to have an immediate impact on the prevalence of cervical cancer due to their cost and limited availability in developing countries, which account for more than 80% of cervical cancers. Thus, there is an urgent need for therapeutic HPV vaccines. Therapeutic HPV vaccines can eliminate preexisting lesions and infections by generating cellular immunity against HPV-infected cells. HPV E6 and E7 oncoproteins represent ideal targets for therapeutic intervention because of their constitutive expression in HPV-associated tumors and their crucial role in the induction and maintenance of HPV-associated disease. This review discusses the current progress of various therapeutic HPV vaccine approaches, including live vector-based, peptide/protein-based, nucleic acid-based and cell-based vaccines targeting E6 and/or E7 antigens, and their future prospects for the control of HPV-associated malignancies.

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Treatment of minimal residual disease after surgery or chemotherapy in mice carrying HPV16-associated tumours: Cytokine and gene therapy with IL-2 and GM-CSF

Cited by 29 publications

References 0 publications

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

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

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

HPV and Therapeutic Vaccines: Where are We in 2010?

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