Vascular targeting, chemotherapy and active immunotherapy: teaming up to attack cancer

Bellone, Matteo; Mondino, Anna; Corti, Angelo

doi:10.1016/j.it.2008.02.003

Cited by 32 publications

(27 citation statements)

References 71 publications

(91 reference statements)

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“…The in vivo production of LTF may then reduce the amount of biofilm colonization of the lung or other tissue resulting in a decreased disease burden for the patient. This approach has been suggested to improve chemotherapy for cancer in humans (4). Irrespective of the approach, our studies clearly indicate the importance of the human immune response to biofilm infections and suggest that in addition to the massive effort to discover novel antibiofilm antibiotics, understanding the role of the immune system in biofilm infections is vital to reducing the burden of these infections.…”

Section: Discussionmentioning

confidence: 87%

Flagellum-Mediated Biofilm Defense Mechanisms of Pseudomonas aeruginosa against Host-Derived Lactoferrin

et al. 2009

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Chronic infection with the gram-negative organism Pseudomonas aeruginosa is a leading cause of morbidity and mortality in human patients, despite high doses of antibiotics used to treat the various diseases this organism causes. These infections are chronic because P. aeruginosa readily forms biofilms, which are inherently resistant to antibiotics as well as the host's immune system. Our laboratory has been investigating specific mutations in P. aeruginosa that regulate biofilm bacterial susceptibility to the host. To continue our investigation of the role of genetics in bacterial biofilm host resistance, we examined P. aeruginosa biofilms that lack the flgK gene. This mutant lacks flagella, which results in defects in early biofilm development (up to 36 h). For these experiments, the flgK-disrupted strain and the parental strain (PA14) were used in a modified version of the 96-well plate microtiter assay. Biofilms were challenged with freshly isolated human leukocytes for 4 to 6 h and viable bacteria enumerated by CFU. Subsequent to the challenge, both mononuclear cells (monocytes and lymphocytes) and neutrophils, along with tumor necrosis factor alpha (TNF-␣), were required for optimal killing of the flgK biofilm bacteria. We identified a cytokine cross talk network between mononuclear cells and neutrophils that was essential to the production of lactoferrin and bacterial killing. Our data suggest that TNF-␣ is secreted from mononuclear cells, causing neutrophil activation, resulting in the secretion of bactericidal concentrations of lactoferrin. These results extend previous studies of the importance of lactoferrin in the innate immune defense against bacterial biofilms.

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Section: Discussionmentioning

confidence: 87%

Flagellum-Mediated Biofilm Defense Mechanisms of Pseudomonas aeruginosa against Host-Derived Lactoferrin

et al. 2009

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“…This may be even more challenging in the TRAMP model, wherein prostate epithelial cells are continuously exposed to products of the oncogene and a profound state of tumor-specific immunosuppression associates with PC development. An additional explanation for the lack of efficacy of the Arg and iNOS inhibitors in the TRAMP model, and perhaps in human PC, might be a limited penetration of the drugs into the tumor mass, due to altered vascularization, a characteristic common to tumors of different histotype (47). This would also explain why N(G)-monomethyl-Larginine is so effective in restoring the function of PCinfiltrating lymphocytes in vitro (12), wherein the drug is freely available.…”

Section: Gr1mentioning

confidence: 99%

“…This would also explain why N(G)-monomethyl-Larginine is so effective in restoring the function of PCinfiltrating lymphocytes in vitro (12), wherein the drug is freely available. One possibility to overcome this limitation is to combine drugs that normalize tumor vessels with chemotherapy and/or immunotherapy (47). Alternatively, this treatment might be suggested as adjuvant therapy after debulking surgery.…”

Section: Gr1mentioning

confidence: 99%

Modulators of Arginine Metabolism Do Not Impact on Peripheral T-Cell Tolerance and Disease Progression in a Model of Spontaneous Prostate Cancer

Rigamonti

Capuano

Ricupito

et al. 2011

Clinical Cancer Research

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Purpose: Chronic inflammation, recruitment of myeloid-derived cells, and perturbation of the arginine metabolism have been all proposed as mechanisms favoring prostate carcinogenesis and tumor immunoescape. Objective of this study was to evaluate whether accumulation of CD11b þ Gr1þ cells, also defined myeloid-derived suppressor cells, occur in mice affected by transplantable or spontaneous prostate cancer (PC). We also investigated whether N(G) nitro-L-arginine methyl ester (L-NAME) and sildenafil, both modulators of the arginine metabolism, restrain tumor growth and restore tumor-specific immunity.Experimental Design: Wild-type C57BL/6 mice bearing TRAMP-C1 PC and transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were treated with vehicle, L-NAME or sildenafil, and evaluated for CD11b þ cells accumulation in the blood, several organs, and the tumor mass and for disease progression.organs and especially in the tumor of the two mouse models. L-NAME and sildenafil impaired the immunosuppressive function of CD11b þ cells in both models and restrained TRAMP-C1 growth, but they neither break tumor-specific immune tolerance nor limit tumor progression in TRAMP mice. Conclusions: Collectively, our results emphasize substantial differences in tumor-induced alteration of myelopoiesis and sensitivity to modulators of the arginine metabolism between a transplantable and a spontaneous model of PC. They also suggest that perturbation of the arginine metabolism is dispensable for PC progression and the associated T-cell tolerance.

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“…30,31,49 In addition, TBI and chemotherapy can promote the generation of a proinflammatory environment that supports lymphocyte activation and function. 32,50 It might be possible to take advantage of the myelotoxic/immunosuppressive properties of many chemotherapeutic agents by administering antitumor allogeneic cells as an adjunct to already existing regimens. Antimetabolite drugs such as fludarabine, which have already been used as preparatory regimen for adoptive cell transfer therapy, 15 profoundly deplete host lymphocyte populations.…”

Section: Discussionmentioning

confidence: 99%

Adoptive transfer of allogeneic tumor-specific T cells mediates effective regression of large tumors across major histocompatibility barriers

Boni

Muranski

Cassard

et al. 2008

Blood

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Graft-versus-tumor effects can be achieved after allogeneic bone marrow transplantation in patients with malignancies of the kidney or hematopoietic system but are often accompanied by severe graft-versus-host-disease (GVHD). We sought to maximize graft-versus-tumor while minimizing GVHD using tumorspecific allogeneic effector T cells rather than open-repertoire T cells. We transferred allogeneic CD8 ؉ pmel-1 or CD4 ؉ TRP-1 T cells specific for the melanomaassociated antigens, glycoprotein 100 (gp100) and tyrosinase-related protein-1 (TRP-1), respectively, into B16-melanomabearing mice. Mice receiving a preparative regimen of nonmyeloablating (5 Gy) total body irradiation experienced the rapid rejection of tumor-specific allogeneic lymphocytes with no impact on tumor growth. However, when mice were given more intense total body irradiation conditioning regimens combined with autologous bone marrow transplantation, adoptively transferred allogeneic tumorspecific T lymphocytes persisted at detectable levels for several weeks and mediated significant regression of large, vascularized tumors. We found that the risk of GVHD was low when tumorspecific T cells were transferred and significant toxicity was observed only when substantial numbers of open repertoire allogeneic naive T cells were mixed with the tumor-specific lymphocytes. Taken together, these data indicate that the use of tumor-specific allogeneic CD8 ؉ T cells or CD4 IntroductionThe ability of T lymphocytes to recognize antigens with a high degree of discrimination and mediate tissue destruction makes them excellent candidates for treating malignancies. After successes obtained in treating hematologic malignancies with allogeneic bone marrow (BM) transplantation (BMT), many investigators have tried to use the same approach for solid tumors, relying on the capacity of allogeneic lymphocytes to mediate a graft-versustumor (GVT) effect. Unfortunately, most solid tumors have proven to be resistant to this therapy, and beneficial clinical responses were observed only for renal cell carcinoma 1,2 with anecdotal successes for other cancer types. [3][4][5][6][7][8] Nevertheless, reports of regressions after the development of graft-versus-host disease (GVHD) in allogeneic BMT recipients constitute a proof-of-principle that solid tumors are susceptible to immune rejection.A factor that might be important in limiting the successes of allogeneic BMT is the lack of tumor specificity. Antigenic differences between tumor cells and their nontransformed counterparts are poorly defined. 9,10 Those differences might not be sufficient to reproducibly create a therapeutic window between GVT and GVHD. The toxicity of this therapy remains high, although it is diminished with reduced intensity conditioning regimens. 1,[11][12][13][14] Adoptive cell transfer (ACT) of autologous tumor-specific T cells represents a promising alternative to GVT using openrepertoire cells. ACT of tumor-specific cells derived from tumor infiltrating lymphocytes can lead to objective tumor regression...

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Vascular targeting, chemotherapy and active immunotherapy: teaming up to attack cancer

Cited by 32 publications

References 71 publications

Flagellum-Mediated Biofilm Defense Mechanisms of Pseudomonas aeruginosa against Host-Derived Lactoferrin

Flagellum-Mediated Biofilm Defense Mechanisms of Pseudomonas aeruginosa against Host-Derived Lactoferrin

Modulators of Arginine Metabolism Do Not Impact on Peripheral T-Cell Tolerance and Disease Progression in a Model of Spontaneous Prostate Cancer

Adoptive transfer of allogeneic tumor-specific T cells mediates effective regression of large tumors across major histocompatibility barriers

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