Antitumor effects of residual tumor after cryoablation: the combined effect of residual tumor and a protein-bound polysaccharide on multiple liver metastases in a murine model

Urano, Masato; Tanaka, Chihiro; Sugiyama, Yasuyuki; Miya, Kiichi; Saji, Shigetoyo

doi:10.1016/s0011-2240(03)00039-7

Cited by 71 publications

(39 citation statements)

References 9 publications

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“…Therefore, the evaluation of novel therapeutic options is of great interest. Since the discovery of the regression of metastases after cryotreatment, investigators have examined immune responses in animal models in hopes of showing a 'cryoimmunologic' effect (12,(23)(24)(25). Despite the lack of response to cryotreatment alone, we observed a synergistic effect when cryotreatment was combined with DCs (11).…”

Section: Discussionmentioning

confidence: 74%

Enhancement of antitumor immunity by combining anti-cytotoxic T lymphocyte antigen-4 antibodies and cryotreated tumor lysate-pulsed dendritic cells in murine osteosarcoma

et al. 2013

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Abstract.Immunotherapy with tumor lysate-loaded dendritic cells (DCs) is one of the most promising strategies to induce antitumor immune responses. However, the antitumor activity of cytotoxic T cells may be restrained by their expression of the inhibitory T-cell coreceptor cytotoxic T lymphocyte antigen-4 (CTLA-4). By relieving this restraint, CTLA-4-blocking antibodies promote tumor rejection, but the full scope of their most suitable applications has yet to be fully determined. In the present study, we offer proof of a preclinical concept in a C3H mouse osteosarcoma (LM8) model that CTLA-4 blockade cooperates with cryotreated tumor lysatepulsed DCs in a primary tumor to prevent the outgrowth of lung metastasis. To evaluate immune response activation, we established the following four groups of C3H mice (60 mice in total): i) control immunoglobulin G (IgG)-treated mice; ii) tumor lysate-pulsed DC-treated mice; iii) anti-CTLA-4 antibody-treated mice and iv) tumor lysate-pulsed DC-and anti-CTLA-4 antibody-treated mice. The mice that received the tumor lysate-pulsed DCs and anti-CTLA-4 antibody displayed reduced numbers of regulatory T lymphocytes and increased numbers of CD8 + T lymphocytes inside the metastatic tumor, inhibition of metastatic growth, a prolonged lifetime, reduced numbers of regulatory T lymphocytes in the spleen and high serum interferon-γ levels. Combining an anti-CTLA-4 antibody with tumor lysate-pulsed DCs enhanced the systemic immune response. To the best of our knowledge, these findings document for the first time an effect of the combination of tumor lysate-pulsed DCs and CTLA-4-blocking antibodies in osteosarcoma. We suggest that cryotreated tumor lysatepulsed DCs, although insufficient on their own, may mediate the rejection of metastatic lesions and prevent recurrence of the disease when combined with CTLA-4 blockade in osteosarcoma patients in the clinical setting. IntroductionOsteosarcoma is the most common primary malignant tumor of bone. Remarkable advances in the treatment of osteosarcoma have occurred, including the introduction of adjuvant chemotherapy and appropriate surgical excision (1-4). However, there have also been advances in the field of immunotherapy for the treatment of osteosarcoma that have received less attention (5,6). Following cryotreatment, the necrotic tumor lesion remains within the body, and the release of tumor antigens by dying cells has been hypothesized to activate a tumor-specific immune response via antigen presentation by antigen-presenting cells (APCs) such as dendritic cells (DCs) to T cells (7,8). A number of tumor studies combining immunomodulation methods such as the injection of Toll-like receptor agonists with cryotreatment have demonstrated a synergistic effect on tumor rejection, and this was attributed to the enhanced activation of APC function (9,10). We developed a method using cryotreated tumor tissue and DCs to enhance tumor-specific immunoreactions since DCs are the main APCs initiating cell-mediated immune responses in vivo (11,12).Mon...

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Section: Discussionmentioning

confidence: 74%

Enhancement of antitumor immunity by combining anti-cytotoxic T lymphocyte antigen-4 antibodies and cryotreated tumor lysate-pulsed dendritic cells in murine osteosarcoma

et al. 2013

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“…At present, local destruction of tumor masses by freezing and thawing provides a conventional estimate for the clinical use of cryotherapy, whereas the antimetastatic effect is considered negligible (4). Numerous studies revealed reduced immune responses and elevated metastasis following cryosurgery (4,18). There is evidence that by combining immunoadjuvants with cryosurgery, one may augment the host systemic antitumor immune response.…”

Section: Discussionmentioning

confidence: 99%

“…There is evidence that by combining immunoadjuvants with cryosurgery, one may augment the host systemic antitumor immune response. A short list of studies addressing this issue includes intralesional injections of bacille Calmette-Guérin in animal models and in clinical settings (19,20), as well as systemic administration of protein-bound polysaccharide in a murine model (18). This is the first study to address the influence of in situ administration of immature dendritic cells following cryotherapy of primary tumors on systemic antitumor immunity.…”

Section: Discussionmentioning

confidence: 99%

Combined Dendritic Cell Cryotherapy of Tumor Induces Systemic Antimetastatic Immunity

Machlenkin

Goldberger

Tirosh

et al. 2005

Clinical Cancer Research

106

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Purpose: Cryotherapy of localized prostate, renal, and hepatic primary tumors and metastases is considered a minimally invasive treatment demonstrating a low complication rate in comparison with conventional surgery. The main drawback of cryotherapy is that it has no systemic effect on distant metastases. We investigated whether intratumoral injections of dendritic cells following cryotherapy of local tumors (cryoimmunotherapy) provides an improved approach to cancer treatment, combining local tumor destruction and systemic anticancer immunity. Experimental Designs: The 3LL murine Lewis lung carcinoma clone D122 and the ovalbumintransfected B16 melanoma clone MO5 served as models for spontaneous metastasis. The antimetastatic effect of cryoimmunotherapy was assessed in the lung carcinoma model by monitoring mouse survival, lung weight, and induction of tumor-specific CTLs. The mechanism of cryoimmunotherapy was elucidated in the melanoma model using adoptive transfer of T cell receptor transgenic OT-I CTLs into the tumor-bearing mice, and analysis of Th1/Th2 responses by intracellular cytokine staining in CD4 and CD8 cells. Results: Cryoimmunotherapy caused robust and tumor-specific CTL responses, increased Th1 responses, significantly prolonged survival and dramatically reduced lung metastasis. Although intratumor administration of dendritic cells alone increased the proliferation rate of CD8 cells, only cryoimmunotherapy resulted in the generation of effector memory cells. Furthermore, cryoimmunotherapy protected mice that had survived primary MO5 tumors from rechallenge with parental tumors. Conclusions: These results present cryoimmunotherapy as a novel approach for systemic treatment of cancer. We envisage that cryotherapy of tumors combined with subsequent in situ immunotherapy by autologous unmodified immature dendritic cells can be applied in practice.Minimally invasive therapies are an alternative approach to surgical intervention in the treatment of malignant diseases. Cryoablation, i.e., tissue destruction by repeated deep freezing and thawing, is under the larger category of thermal therapy and, during the past decade, it has become an acceptable clinical tool for the management of dermatologic tumors, hepatocellular carcinoma, renal and prostate tumors, and hepatic colorectal metastases (1, 2). Compared with surgical excision, the main advantages are the potential for less invasiveness resulting in reduced mortality and morbidity, and the ability to perform ablative procedures on outpatients, which decreases the treatment cost. In the case of hepatic colorectal metastases, the use of cryosurgery improves the percentages of resectability (2). A comparative study on domestic pigs showed that the cryoablation of renal parenchyma is beneficial over other necrosis-inducing ablations such as microwave thermoablation, radiofrequency energy, and chemoablation by ethanol, hypertonic saline, and acetic acid gels, in terms of reproducibility, consistency in size and shape, and the ability to monitor b...

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“…It is a heat/cold reversal treatment and has a thorough destructive effect on tumor tissues. Its cryoimmunologic effect has been clinically confirmed in liver tumors, 1 prostate tumors, 2 and rectal cancer. 3 However, very few studies have examined the cryoimmunologic effect of this technique on intracranial glioma treatment.…”

Section: Introductionmentioning

confidence: 93%

Functional Changes of Dendritic Cells in C6 Glioma-Bearing Rats That Underwent Combined Argon-Helium Cryotherapy and IL-12 Treatment

Cui

et al. 2016

Technol Cancer Res Treat

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Objective: The aim of this study was to explore changes in tumor tissues of glioma-bearing rats that underwent argon-helium cryoablation as well as changes in antitumor immunity before and after combined interleukin 12 treatment. Methods: Two hundred sixty Wistar rats were randomly divided into a blank control group, intravenous injection interleukin-12 group, cryotherapy group, and cryotherapy þ intravenous injection group. C6 glioma cells proliferated in vitro were implanted subcutaneously on the backs of rats to establish C6 glioma-bearing animal models. Each group underwent the corresponding treatments, and morphological changes in tumor tissues were examined using hematoxylin-eosin staining. CD11c staining was examined using immunohistochemistry, and differences in dendritic cells and T-cell subsets before and after treatment were analyzed using flow cytometry. Results: The control group showed no statistical changes in terms of tumor tissue morphology and cellular immunity, cryotherapy group, and cryotherapy þ intravenous injection group, among which the count for the cryotherapy þ intravenous injection group was significantly higher than those of all other groups. In the argon-helium cryotherapy group, tumor cells were damaged and dendritic cell markers were positive. The number of CD11cþ and CD86þ cells increased significantly after the operation as did the cytokine interferon-g level (P < .01), suggesting a shift toward Th1-type immunity. Conclusion: Combined treatment of argon-helium cryoablation and interleukin 12 for gliomas not only effectively injured tumor tissues but also boosted immune function and increased antitumor ability. Therefore, this approach is a promising treatment measure for brain gliomas.

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Antitumor effects of residual tumor after cryoablation: the combined effect of residual tumor and a protein-bound polysaccharide on multiple liver metastases in a murine model

Cited by 71 publications

References 9 publications

Enhancement of antitumor immunity by combining anti-cytotoxic T lymphocyte antigen-4 antibodies and cryotreated tumor lysate-pulsed dendritic cells in murine osteosarcoma

Enhancement of antitumor immunity by combining anti-cytotoxic T lymphocyte antigen-4 antibodies and cryotreated tumor lysate-pulsed dendritic cells in murine osteosarcoma

Combined Dendritic Cell Cryotherapy of Tumor Induces Systemic Antimetastatic Immunity

Functional Changes of Dendritic Cells in C6 Glioma-Bearing Rats That Underwent Combined Argon-Helium Cryotherapy and IL-12 Treatment

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