Enhanced Efficacy of Melanoma Vaccines in the Absence of B Lymphocytes

Perricone, Michael A.; Smith, Karen; Claussen, Kirsten A; Plog, Malinda S.; Hempel, D; Roberts, Bruce; George, Judith A. St.; Kaplan, Johanne

doi:10.1097/00002371-200407000-00003

Cited by 74 publications

(49 citation statements)

References 30 publications

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“…Interestingly, treatment with a negative control (non-replicative) Ad-CXCR4-GL3 virus resulted in a partial therapeutic effect. The effect of transient tumor inhibition by a non-therapeutic adenovirus has previously been observed [28][29][30][31], and has been attributed to the recruitment and activation of the innate immune system (e.g., natural killer cells and macrophages) [32][33][34][35]. These findings may explain the nonspecific tumor inhibition we observed.…”

Section: Dual-level Targeted Crad Is Oncolytic In Vivo In a Murine Mosupporting

confidence: 70%

Cancer-specific targeting of a conditionally replicative adenovirus using mRNA translational control

Stoff-Khalili

Rivera

Nedeljkovic-Kurepa

et al. 2007

Breast Cancer Res Treat

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Background-In view of the limited success of available treatment modalities for a wide array of cancer, alternative and complementary therapeutic strategies need to be developed. Virotherapy employing conditionally replicative adenoviruses (CRAds) represents a promising targeted intervention relevant to a wide array of neoplastic diseases. Critical to the realization of an acceptable therapeutic index using virotherapy in clinical trials is the achievement of oncolytic replication in tumor cells, while avoiding non-specific replication in normal tissues. In this report, we exploited cancer-specific control of mRNA translation initiation in order to achieve enhanced replicative specificity of CRAd virotherapy agents. Heretofore, the achievement of replicative specificity of CRAd agents has been accomplished either by viral genome deletions or incorporation of tumor selective promoters. In contrast, control of mRNA translation has not been exploited for the design of tumor specific replicating viruses to date. We show herein, the utility of a novel approach that combines both transcriptional and translational regulation strategies for the key goal of replicative specificity.

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Section: Dual-level Targeted Crad Is Oncolytic In Vivo In a Murine Mosupporting

confidence: 70%

Cancer-specific targeting of a conditionally replicative adenovirus using mRNA translational control

Stoff-Khalili

Rivera

Nedeljkovic-Kurepa

et al. 2007

Breast Cancer Res Treat

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“…4B). A role for B cells in B16 melanoma model is further supported by the studies of Perricone et al [40] where they show enhanced efficacy of melanoma vaccines in the mMT mice lacking B cells. Similarly, B cells may also play a role in human breast cancer progression, where the presence of infiltrating plasma cells was linked to poor prognosis [41].…”

Section: Discussionmentioning

confidence: 77%

“…If proven, this could lead to the targeting of B cells as a means for therapeutic intervention in such disease conditions. In support, Perricone et al [40] suggest a therapeutic regimen with depletion of B-lymphocytes that may be beneficial to cancer vaccine therapy, in their preclinical B16 melanoma study. …”

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confidence: 98%

Macrophage polarization to a unique phenotype driven by B cells

et al. 2010

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Regulation of adaptive immunity by innate immune cells is widely accepted. Conversely, adaptive immune cells can also regulate cells of the innate immune system. Here, we report for the first time the essential role of B cells in regulating macrophage (M/) phenotype. In vitro B cell/M/ co-culture experiments together with experiments in transgenic mice models for B-cell deficiency or overexpression showed B1 cells to polarize M/ to a distinct phenotype. This was characterized by downregulated TNF-a, IL-1b and CCL3, but upregulated IL-10 upon LPS stimulation; constitutive expression of M2 M/ markers (e.g. Ym1, Fizz1) and overexpression of TRIF-dependent cytokines (IFN-b, CCL5). Mechanistically, this phenotype was linked to a defective NF-jB activation, but a functional TRIF/STAT1 pathway. B1-cell-derived IL-10 was found to be instrumental in the polarization of these M/. Finally, in vivo relevance of B1-cell-induced M/ polarization was confirmed using the B16 melanoma tumor model where adoptive transfer of B1 cells induced an M2 polarization of tumor-associated M/. Collectively, our results define a new mechanism of M/ polarization wherein B1 cells play a key role in driving M/ to a unique, but M2-biased phenotype. Future studies along these lines may lead to targeting of B1 cells to regulate M/ response in inflammation and cancer. Supporting Information available online IntroductionMacrophages (Mf) are a heterogeneous cell population involved in diverse physiological processes including anti-microbial defence, wound resolution, inflammation, tissue remodeling, plaque formation in atherosclerosis and promotion of tumor growth [1][2][3][4][5][6][7]. Despite their heterogeneity, Mf can be broadly divided into M1 (classically activated) or M2 (alternatively activated) phenotypes [1,[8][9][10][11][12]. The M1 phenotype is induced in response to microbial products such as LPS or proinflammatory cytokines including IFN-g, IL-1b or TNF-a. M1 Mf produce further proinflammatory cytokines (TNF-a, IL-12 and CCL3) with reactive oxygen and nitrogen intermediates, which combine to give M1 Mf potent antimicrobial, tumoricidal and inflammatory properties [12]. In contrast, the M2 phenotype results from exposure to antiinflammatory molecules such as glucocorticoid hormones, IL-4, Ã These authors contributed equally to this work. 2296IL-13, IL-10 or immune complexes [10][11][12]. M2 Mf are antiinflammatory and immunosuppressive in nature. They are highly phagocytic, preferentially activate the arginase pathway, promote angiogenesis, tissue remodeling and have pro-tumoral activity [8,12]. However, in vivo, the division between M1 and M2 cells may be blurred, with the above phenotypes likely representing two extremes in a continuum of Mf functional states [9,[13][14][15].Transcriptome data demonstrate the existence of distinct polarization phenotypes for Mf associated with specific pathological conditions [4,7,[16][17][18]. Based on this, it is believed that the phenotype of an Mf is a reflection of its immediate microenvironment....

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“…The mMT mouse harbors a disruption of the mM locus resulting in an arrest during B cell maturation (Kitamura et al, 1991). These mice can mount normal T cell responses but do not have the ability to generate antibodies (Perricone et al, 2004). The mMT mouse allows for assessment of the impact of preexisting CTLs on AAV transduction and subsequent transgene expression separate from any contribution from neutralizing antibodies.…”

Section: Neutralizing Antibodies But Not Preexisting Ctls Against Aamentioning

confidence: 99%

Cytotoxic T Lymphocyte Responses to Transgene Product, Not Adeno-Associated Viral Capsid Protein, Limit Transgene Expression in Mice

Siders¹,

Shields²,

Kaplan³

et al. 2009

Human Gene Therapy

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The use of adeno-associated viral (AAV) vectors for gene replacement therapy is currently being explored in several clinical indications. However, reports have suggested that input capsid proteins from AAV-2 vector particles may result in the stimulation of cytotoxic T lymphocyte (CTL) responses that can result in a loss of transduced cells. To explore the impact of anti-AAV CTLs on AAV-mediated transgene expression, both immunocompetent C57BL=6 mice and B cell-deficient mMT mice were immunized against the AAV2 capsid protein (Cap) and were injected intravenously with an AAV-2 vector encoding a-galactosidase (a-Gal). C57BL=6 mice, which developed both CTL and neutralizing antibody responses against Cap, failed to show any detectable a-Gal expression. In contrast, serum a-Gal levels comparable to those of naive mice were observed in mMT mice despite the presence of robust CTL activity against Cap, indicating that preexisting Cap-specific CTLs did not have any effect on the magnitude and duration of transgene expression. The same strategy was used to assess the impact of CTLs against the a-Gal transgene product on AAV-mediated gene delivery and persistence of transgene expression. Preimmunization of mMT mice with an Ad=a-Gal vector induced a robust CTL response to a-Gal. When these mice were injected with AAV2=a-Gal vector, initial levels of a-Gal expression were reduced by more than 1 log and became undetectable by 2 weeks postinjection. Overall, our results indicate that CTLs against the transgene product as opposed to AAV capsid protein are more likely to interfere with AAV transgene expression.

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Enhanced Efficacy of Melanoma Vaccines in the Absence of B Lymphocytes

Cited by 74 publications

References 30 publications

Cancer-specific targeting of a conditionally replicative adenovirus using mRNA translational control

Cancer-specific targeting of a conditionally replicative adenovirus using mRNA translational control

Macrophage polarization to a unique phenotype driven by B cells

Cytotoxic T Lymphocyte Responses to Transgene Product, Not Adeno-Associated Viral Capsid Protein, Limit Transgene Expression in Mice

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