Adoptive transfer of <i>ex vivo</i>‐activated memory T‐cell subsets with cyclophosphamide provides effective tumor‐specific chemoimmunotherapy of advanced metastatic murine melanoma and carcinoma

Gold, Jay E.; Zachary, David T.; Osband, Michael E.

doi:10.1002/ijc.2910610424

Cited by 12 publications

(7 citation statements)

References 28 publications

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“…These observations may imply activation of anti-tumor immunity since CD45RO+ represents T memory subset while CD68+ is the marker of monocyte/macrophage [23] . Anti-CD3Ab can activate CD45RO+ T subset [24] , so we deduced that the increase of CD45RO+ cells in the tumor locals may come from CIK.…”

Section: Discussionmentioning

confidence: 91%

CIK cells from patients with HCC possess strong cytotoxicity to multidrug-resistant cell line Bel-7402/R

Youshun¹

2005

WJG

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AIM:To investigate the cytotoxicity of the cytokine-induced killer (CIK) cells from the post-operation patients with primary hepatocellular carcinoma (HCC) to multidrugresistant (MDR) cell of HCC both in vitro and in vivo. METHODS:A drug-resistant cell line was established by culturing human HCC cell line Bel-7402 in complete RPMI 1640 medium with increasing concentrations of adriamycin from 10 to 2 000 nmol/L. CIK cells were obtained by inducing the peripheral blood mononuclear cells with rhIFN-, monoclonal anti-CD3 antibody, rhIL-1 as well as rhIL-2, which were added into the culture. To detect the cytotoxicity of the CIK cells from HCC patients, the Bel-7402/R was taken as target (T) cells and CIK cells as effect (E) cells. Cytotoxic test was performed and measured by MTT. As to in vivo test, CIK cells were transfused into patients with HCC. The tumor specimens of the patients were obtained and immunohistochemistry was carried out to detect CD3, CD45, CD45RO as well as CD68. RESULTS:A MDR 1 HCC cell line Bel-7402/R was established. Its MDR1 mRNA overexpressed which was shown by RT-PCR; the P-glycoprotein expression increased from 1.32% of parent cells to 54%. CIK cells expanded vigorously by more than 70-fold and the CD3+CD56+ increased by more than 600-fold after 3-wk incubation on average. The cytotoxicity of CIK from HCC patients to Bel-7402/R was about 50% and to L-02 below 10% (t = 8.87, P<0.01), the same as that of CIK from normal individuals. Each of the 17 patients receiv ed 1 -5×10 10 of CIK cell transfusion. No side effects were observed. After CIK treatment, the tumor tissue nodules formed and a large amount of lymphocytes infiltrated in the liver cancer tissue and CD3, CD45, CD45RO, and CD68 increased greatly which was shown by immunohistochemistry. CONCLUSION:A stable MDR1 HCC cell line has been established which could recover from liquid nitrogen and CIK from HCC patients has strong cytotoxicity to MDR HCC cell. CIK adoptive immunotherapy is safe and has no side effects. Receivers improved their immunity to tumor evidently. CIK treatment may be a better choice for HCC patients after operation to prevent the recurrence, especially when tumors have developed drug resistance.

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Section: Discussionmentioning

confidence: 91%

CIK cells from patients with HCC possess strong cytotoxicity to multidrug-resistant cell line Bel-7402/R

Youshun¹

2005

WJG

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“…Previous studies have shown that cyclophosphamide potentiates the antitumor activities of a number of immunotherapeutic strategies (25,39). The immunomodulatory effects of cyclophosphamide are not fully understood, but several mechanisms have been proposed, including enhanced expansion of antigenspecific T cells (40); stimulation of innate immune response, in particular the activation of dendritic cells (41); induction of type I IFN (42); Th2/Th1 shift in cytokines profile (27); and elimination/inhibition of regulatory T cells (43).…”

Section: Discussionmentioning

confidence: 99%

“…Cyclophosphamide is a widely known chemotherapeutic agent (21) that has been used by several groups, including ours, as an immunomodulatory agent against murine and human cancers (22)(23)(24)(25). We have previously shown that a single lowdose cyclophosphamide can inhibit the metastasis of a B-cell lymphoma (L-TACB) in a rat model, likely due to the induction of potent immunomodulatory mechanisms that result in a significant reduction in IL-10 levels (26).…”

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confidence: 99%

A Novel Synergistic Combination of Cyclophosphamide and Gene Transfer of Interleukin-12 Eradicates Colorectal Carcinoma in Mice

Malvicini

Rizzo²,

Alaniz³

et al. 2009

Clinical Cancer Research

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Purpose: Interleukin-12 (IL-12) is an immunostimulatory cytokine with potent antitumor effects in several animal models. However, serious toxicity has been associated with its systemic application in humans. Gene transfer has emerged as a tool to specifically express therapeutic genes into the tumor/peritumoral milieu, thus avoiding systemic toxicity. The aim of this study was to analyze whether subtherapeutic doses of an adenovirus encoding IL-12 (AdIL-12) might synergize with low immunopotentiating doses of cyclophosphamide in the treatment of colorectal carcinoma. Experimental Design: The antitumor effect of combining a single low dose of cyclophosphamide with an intratumoral injection of AdIL-12 was evaluated in an in vivo murine colorectal carcinoma model. The immune responses achieved with different treatments were monitored, comparing the effect of combining both therapies with individual treatments. Results: The combined therapy induced a complete tumor regression in >50% of mice in a synergistic fashion, and it significantly prolonged their survival. This strategy was superior to each single treatment in reducing both peripheral and splenic CD4+CD25+Foxp3+ regulatory T cells, increasing the number of activated dendritic cells, and inducing IFN-γ-secreting CD4-positive T lymphocytes. Importantly, the combined treatment generated a powerful tumor-specific CTL response. Consistently, a significant reduction in IL-10 levels was found. Our data suggest that the combination of nontoxic doses of cyclophosphamide with AdIL-12 allows the generation of good antitumoral responses, thus avoiding undesired side effects of both agents. Conclusions: Our data strongly support the use of a combination of cyclophosphamide and AdIL-12 as a novel therapeutic strategy against colorectal carcinoma. (Clin Cancer Res 2009;15(23):7256–65)

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“…Key Words: CD8 + T cells, CD11b, cyclophosphamide, dsRNA, dendritic cells, IFN, Ly6G, myeloid cells, OVA, OT-1 T cells, poly (I:C), TLR3, vaccine (J Immunother 2007;30: [40][41][42][43][44][45][46][47][48][49][50][51][52][53] A critical component of antitumor immunity is the development of effector T cells that can survive longterm as functional memory T cells. It is currently believed that naive T cells are programmed to expand dramatically after antigen encounter.…”

mentioning

confidence: 99%

Defining the Ability of Cyclophosphamide Preconditioning to Enhance the Antigen-specific CD8+ T-cell Response to Peptide Vaccination: Creation of a Beneficial Host Microenvironment Involving Type I IFNs and Myeloid Cells

Salem

Kadima

El‐Naggar

et al. 2007

Journal of Immunotherapy

104

123

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Although cyclophosphamide (CTX) has been clearly shown to enhance active specific and adoptive immunotherapies, the mechanism(s) underlying these beneficial effects have not been clearly defined. To define the impact of CTX preconditioning on the antigen-specific CD8 T-cell response to peptide vaccination, we used an adoptive transfer model based on the OT-1 T-cell receptor transgenic mouse. CTX preconditioning dramatically enhanced the antigen-specific CD8 T-cell response to peptide vaccination. Specifically, CTX significantly enhanced the expansion and function of responding CD8 T cells as demonstrated by flow cytometry and cytokine production. In parallel experiments, we attempted to define the mechanism(s) underlying these beneficial effects of CTX therapy. CTX therapy increased the relative number and activation status of myeloid dendritic cells, and was associated with the induction of significant levels of the inflammatory cytokines interferon-a, monocyte chemoattractant protein-1, and IL-6. Adoptive transfer experiments into type I IFNR À / À and CR3 À / À mice confirmed that the beneficial effects of CTX were at least partially dependent on type I interferons and myeloid cells. Adoptive transfer of up to 150 Â 10 6 naive spleen cells at the time of antigen-specific CD8 T-cell transfer did not abrogate the effects of CTX therapy, suggesting that the creation of a niche in the immune system may not be required. CTX decreased the absolute, but not relative number of CD4 + CD25 + T reg cells, consistent with the possibility that regulatory T cells may be targeted by CTX therapy. Of note, combination therapy with CTX and a synthetic TLR3 agonist further enhanced the antigen-specific CD8 + T-cell response. Taken together, our data suggest that CTX modulates specific components of the innate immune system resulting in a beneficial host microenvironment. Specific targeting of these components may enhance the effectiveness of CTX preconditioning for adoptive immunotherapy.A critical component of antitumor immunity is the development of effector T cells that can survive longterm as functional memory T cells. It is currently believed that naive T cells are programmed to expand dramatically after antigen encounter. This expansion phase is followed by a significant contraction phase in which the majority of antigen-specific T cells undergo apoptosis, leaving behind only a small population of memory T cells. 1 It is becoming increasing clear, however, that the state of the host environment at the time of antigen encounter can substantially impact on this CD8 program, affecting the number and quality of effector and memory T cells. [2][3][4][5][6] In this context, it has been reported that conditioning of the recipient host with chemotherapeutic agents before adoptive T-cell transfer can potentiate the efficacy of active specific and adoptive immunotherapies. 7 Cyclophosphamide (CTX) is a chemotherapeutic agent used for the treatment of several human malignancies, often in combination with adoptive immunotherapy. 7-9 A...

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Adoptive transfer of ex vivo‐activated memory T‐cell subsets with cyclophosphamide provides effective tumor‐specific chemoimmunotherapy of advanced metastatic murine melanoma and carcinoma

Cited by 12 publications

References 28 publications

CIK cells from patients with HCC possess strong cytotoxicity to multidrug-resistant cell line Bel-7402/R

CIK cells from patients with HCC possess strong cytotoxicity to multidrug-resistant cell line Bel-7402/R

A Novel Synergistic Combination of Cyclophosphamide and Gene Transfer of Interleukin-12 Eradicates Colorectal Carcinoma in Mice

Defining the Ability of Cyclophosphamide Preconditioning to Enhance the Antigen-specific CD8+ T-cell Response to Peptide Vaccination: Creation of a Beneficial Host Microenvironment Involving Type I IFNs and Myeloid Cells

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