Cytokine immunotherapy of cancer with controlled release biodegradable microspheres in a human tumor xenograft/SCID mouse model

Egilmez, Nejat K.; Jong, Yong S.; Iwanuma, Yoshimi; Jacob, Jules S.; Santos, Camilla A.; Chen, Fang-An; Mathiowitz, Edith; Bankert, Richard B.

doi:10.1007/s002620050455

Cited by 58 publications

(37 citation statements)

References 17 publications

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“…The biodegradable and biocompatible polyester polymers, such as PLA-co-glycolides, poly-D,L-lactide-co-glycolic acid, and PLA, although used for many years as suture material and as controlled-release drug delivery systems (49,53), had their adjuvant effects achieved through the encapsulation of antigens (46,48). Applications from cancer therapy (21,22) to infectious diseases (57,59) have been demonstrated. The enhanced adjuvant effect of microparticles appears to be effective as a consequence of efficient delivery of the adsorbed proteins into dendritic cells and macrophages at the injection site and local lymph nodes (61).…”

Section: Discussionmentioning

confidence: 99%

Cross-Reactivity ofSchistosoma mansoniCytosolic Superoxide Dismutase, a Protective Vaccine Candidate, with Host Superoxide Dismutase and Identification of Parasite-Specific B Epitopes

Carvalho-Queiroz¹,

Cook²,

Wang

et al. 2004

Infect Immun

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Schistosoma mansoni, an intravascular parasite, has evolved a number of immune evasion mechanisms to establish itself in the host, such as antioxidant enzymes. Our laboratory has demonstrated that the highest levels of certain antioxidant enzymes are found in adult worms, which are the least susceptible to immune killing. Vaccination of mice with naked DNA constructs containing the gene encoding Cu/Zn cytosolic superoxide dismutase (SmCT-SOD) showed significant levels of protection compared to a control group, and our data demonstrate that the adult worms are a target of the immune response that confers resistance in SmCT-SOD DNA-vaccinated mice. Because SmCT-SOD shows significant identity with the human homologue, we evaluated the reactivity of anti-SmCT-SOD antibodies derived from SmCT-SOD-immunized mice and rabbits and from S. mansoni-infected individuals to human superoxide dismutase (hSOD) and SmCT-SOD parasite-specific peptides to assess the potential for autoimmune responses from immunization with the recombinant molecule. In addition, we evaluated the ability of various SmCT-SOD adjuvant-delivered immunizations to induce cross-reactive antibodies. Both mouse and rabbit antibodies generated against SmCT-SOD recognized the denatured form of hSOD. The same antibodies did not recognize nondenatured hSOD. Sera from infected individuals with different clinical forms of schistosomiasis recognized SmCT-SOD but not hSOD. Antibodies from mice immunized with different SmCT-SOD-containing formulations of both DNA and protein were able to recognize SmCT-SOD-derived peptides but not soluble hSOD. All together, these findings serve as a basis for developing a subunit vaccine against schistosomiasis.Schistosomiasis remains an endemic problem in over 76 countries, although approaches to reduce transmission and morbidity as well as to improve sanitation, mollusciciding and mass chemotherapy, have been attempted (3, 13). Vaccine development to control schistosomiasis is a high priority, as it would offer the potential of cost-efficient, long-lasting prophylaxis (2, 65). Schistosoma mansoni, an intravascular parasite, lives in a hostile environment in close contact with host humoral and cellular cytotoxic factors. Larval parasite killing mechanisms include the release of oxidants by eosinophils, neutrophils, and macrophages potentiated by antibodies and/or cytokines (8,12,16,31,32). However, to establish itself in the host, the parasite has evolved a number of immune evasion mechanisms (17,39,51,60), such as antioxidant enzymes (7,11,30,37). These are essential enzymes involved in the prevention of reactive oxygen species-derived damage. Evidence for the involvement of schistosome antioxidant enzymes, such as cytosolic superoxide dismutase (SmCT-SOD) and glutathione peroxidase (SmGPX), in immune evasion has been presented elsewhere (39). SmCT-SOD and GPX localize to the host-parasite interface (worm tegument and gut epithelium of the adult but not the larval schistosome) (41) and show developmental regulation (29,41,42) wit...

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Section: Discussionmentioning

confidence: 99%

Cross-Reactivity ofSchistosoma mansoniCytosolic Superoxide Dismutase, a Protective Vaccine Candidate, with Host Superoxide Dismutase and Identification of Parasite-Specific B Epitopes

Carvalho-Queiroz¹,

Cook²,

Wang

et al. 2004

Infect Immun

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“…21 Briefly, the lyophilized product of polyclonal antiasialo GM1 antibody (Wako Pure Chemicals) was reconstituted in 1 ml double-deionized water and used as the stock solution; 20 ll of this stock solution was diluted 10 times with PBS and injected intraperitoneally into Balb/c mice to induce removal of NK cells.…”

Section: Antiasialo Gm1 Antibody Treatmentmentioning

confidence: 99%

Folate receptor-targeted immunotherapy: Induction of humoral and cellular immunity against hapten-decorated cancer cells

Sega

Low

2005

Int. J. Cancer

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We previously exploited the frequent overexpression of folate receptors on cancer cells to decorate malignant cell surfaces selectively with folate-hapten conjugates. In antihapten-immunized hosts, this targeted localization of foreign haptens to tumor cells led to rapid accumulation of autologous antihapten IgG, which in turn yielded potent antitumor activity upon stimulation with cytokines (IL-2, IFN-a). In an effort to understand the effector mechanisms responsible for tumor regression, we have now investigated the involvement of both humoral and cellular immune components in the tumor destruction process. We report that the dependence of therapeutic efficacy on folate-hapten concentration is bimodal, suggesting that the conjugate must bridge between a cell surface FR and an antihapten IgG in order to mediate killing. Studies with cancer cells in vitro further demonstrate that folatefluorescein-marked tumor cells are killed primarily by antibodydependent cellular cytotoxicity and phagocytosis, with no contribution from complement-dependent mechanisms. Investigations of specific immune cell involvement also reveal that asialo-GM1 1 -natural killer cells, macrophages, CD41 T cells and CD8 1 T cells contribute significantly to recognition/removal of the cancer mass, and that elimination of these cell types markedly compromises the therapy. Because the initial antibody-dependent stage of tumor cell killing is shown to lead to a long-term antibody-independent cellular immunity that involves both CD4 1 and CD8 1 T cells, we propose that F c receptor-expressing immune cells not only initiate destruction of the IgG-marked tumor cells, but also participate in presentation of endogenous tumor antigens in a manner that leads to long-term cellular immunity. ' 2005 Wiley-Liss, Inc.

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“…Lode et al [17] showed that the eradication of neuroblastoma bone metastases by an IL-2/antitumor fusion protein was exclusively NK-celldependent. In a nude mouse model, Egilmez et al [5] demonstrated that IL-2 loaded on biodegradable microspheres induced signi®cant antitumor eects mediated by mouse NK cells. Other experiments, however, demonstrated that IL-2 may be eective against tumors in the absence of NK cells; when NK cells were eliminated by an anti-NK1.1 antibody, the ecacy of IL-2 was maintained and toxic side-eects were considerably lower [24].…”

Section: Discussionmentioning

confidence: 99%

Endogenous natural killer cells do not play a role in antitumor effects induced by interleukin-2 in a syngeneic rat colon tumor model

Hagenaars

Ensink

Eggermont

et al. 2000

Cancer Immunol Immunother

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Previous experiments in a syngeneic rat liver tumor model using the colon adenocarcinoma CC531 demonstrated that injection of interleukin-2 (IL-2) induced significant antitumor responses. Furthermore, it was found that this treatment strategy was accompanied by an increase in the number of natural killer (NK) cells in and around the tumor. In the present study, the role of endogenous NK cells in IL-2-mediated antitumor responses was further elucidated by depleting tumor-bearing rats of NK cells, using the anti-CD161A mouse IgG1 antibody 3.2.3. Rats were depleted either after or prior to tumor induction and subsequently treated with IL-2. The results demonstrated that depletion of NK cells in tumor-bearing rats did not influence IL-2-induced antitumor effects. In addition, injection of IL-2 in NK-cell-depleted rats induced repopulation of NK cells in the peripheral blood from 3 days on and further after the last injection with IL-2. Therefore, the possibility cannot be excluded that de novo recruited NK cells play a role in attaining IL-2 mediated antitumor effects, but NK cells, which were present before or during the start of IL-2 therapy, were not relevant.

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Cytokine immunotherapy of cancer with controlled release biodegradable microspheres in a human tumor xenograft/SCID mouse model

Cited by 58 publications

References 17 publications

Cross-Reactivity ofSchistosoma mansoniCytosolic Superoxide Dismutase, a Protective Vaccine Candidate, with Host Superoxide Dismutase and Identification of Parasite-Specific B Epitopes

Cross-Reactivity ofSchistosoma mansoniCytosolic Superoxide Dismutase, a Protective Vaccine Candidate, with Host Superoxide Dismutase and Identification of Parasite-Specific B Epitopes

Folate receptor-targeted immunotherapy: Induction of humoral and cellular immunity against hapten-decorated cancer cells

Endogenous natural killer cells do not play a role in antitumor effects induced by interleukin-2 in a syngeneic rat colon tumor model

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