Dendritic cells engineered to secrete anti-GITR antibodies are effective adjuvants to dendritic cell-based immunotherapy

Boczkowski, David; Lee, J; Pruitt, Scott K.; Nair, Smita K.

doi:10.1038/cgt.2009.39

Cited by 47 publications

(45 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our laboratory has chosen RNA transfection for loading DCs with TAAs because of the many advantages of this approach over other methods of antigen loading that have routinely been used both experimentally and in DC-based clinic immunotherapy trials in subjects with cancer (12)(13)(14)(15)(16)(17)(18). This method relies on the DC translating the transfected RNAs into the TAA proteins, which are then degraded into peptides in the cytoplasm by the proteasome.…”

Section: Discussionmentioning

confidence: 99%

Melanoma immunotherapy using mature DCs expressing the constitutive proteasome

et al. 2013

View full text Add to dashboard Cite

Background. Many cancers, including melanoma, exclusively express constitutive proteasomes (cPs) and are unable to express immunoproteasomes (iPs). In contrast, mature DCs used for immunotherapy exclusively express iPs. Since proteasomes generate peptides presented by HLA class I molecules, we hypothesized that mature melanoma antigen-loaded DCs engineered to process antigens through cPs would be superior inducers of antimelanoma immunity in vivo.Methods. Subjects with metastatic melanoma were vaccinated with mature DCs transfected with RNAs encoding melanoma antigens MART1, MAGE-3, gp100, and tyrosinase. These DCs were derived from monocytes that were untransfected (Arm A; n = 4), transfected with control siRNA (Arm B; n = 3), or transfected with siRNAs targeting the 3 inducible iP subunits (Arm C; n = 5).Results. Vaccination stimulated antigen-specific T cell responses in all subjects, which peaked after 3-4 vaccinations, but remained elevated in Arm C subjects. Also in Arm C, circulating melanoma cell levels (as detected by quantitative PCR) fell, and T cell lytic activity against autologous melanoma was induced. In HLA-A2 + subjects, CD8 + T cells that bound tetramers loaded with cP-derived melanoma antigenic peptides were found in the peripheral blood only in Arm C subjects. Of 2 subjects with active disease (both in Arm C), one had a partial clinical response, while the other, who exhibited diffuse dermal and soft tissue metastases, had a complete response. Conclusion.These results suggest that the efficacy of melanoma DC-based immunotherapy is enhanced when tumor antigen-loaded DCs used for vaccination express cPs.Trial registration. Clinicaltrials.gov NCT00672542.Funding.

show abstract

Section: Discussionmentioning

confidence: 99%

Melanoma immunotherapy using mature DCs expressing the constitutive proteasome

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Treatment of mice with an agonistic anti-GITR mAb alone enhances anti-viral and anti-tumor immune responses [10,11,[20][21][22][23][24]. When combined with immunization against melanoma-related antigens, we and others have found that agonistic anti-GITR mAb-treated mice demonstrated increased tumor antigen-specific T cell responses and protective tumor immunity [10,17,25]. These data indicate that systemic treatment with agonistic anti-GITR mAb, alone or as an adjunct to active immunization, increases the ability to overcome immune tolerance.…”

Section: Discussionmentioning

confidence: 99%

“…Generation and electroporation of murine DCs-DCs were generated from bone marrow precursors as described previously [17] in RPMI-5% FCS with GM-CSF (15 ng/ml) and IL-4 (10 ng/ml). GITR expression on bone marrow-derived DCs was low to negative (mature DCs ≤ 15-18% and immature DCs ≤ 10-12%, data not shown).…”

Section: Murine In Vivo Experimentsmentioning

confidence: 99%

“…In preparation for translating this experimental approach to the clinic to enhance the response to DC-based cancer immunotherapy, we generated mRNAs encoding humanized H and L chains of an anti-human CTLA-4 mAb as well as a human soluble GITR-L fusion protein and demonstrated that DCs transfected with these mRNAs secrete functional immune modulating proteins that bind CTLA-4 and GITR, respectively. We then demonstrated the immune-enhancing effect of DCs transfected with these mRNAs in two in vitro human with systemic administration of anti-GITR mAb [17]. Using the same model, in the current study we evaluated the effect of co-administration of DCs transfected with mRNA encoding an anti-CTLA-4 mAb alone and of co-administration of DCs transfected with mRNA encoding both anti-GITR and anti-CTLA-4 mAbs on the induction of anti-tumor immunity in response to vaccination with DCs transfected with mRNA encoding the TAA TRP-2.…”

Section: Introductionmentioning

confidence: 99%

“…We have previously reported that coadministration of DCs transfected with mRNA encoding the H and L chains of an agonistic anti-GITR mAb or soluble GITR-L enhances the induction of anti-tumor immunity in response to vaccination with tumor associated Ag (TAA) mRNA-transfected DCs in a murine melanoma model and improves survival in tumor-bearing mice, while avoiding the induction of autoimmunity observed with systemic administration of anti-GITR mAb. [17 In our present study, we first evaluated the effect of combined immune modulation of both CTLA-4 and GITR using DCs transfected with mRNA encoding the H and L chains of anti-CTLA-4 and anti-GITR mAbs in a murine melanoma immunotherapy model. In preparation for translating this experimental approach to the clinic to enhance the response to DC-based cancer immunotherapy, we generated mRNAs encoding humanized H and L chains of an anti-human CTLA-4 mAb as well as a human soluble GITR-L fusion protein and demonstrated that DCs transfected with these mRNAs secrete functional immune modulating proteins that bind CTLA-4 and GITR, respectively.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Enhancement of Anti-Tumor Immunity Through Local Modulation of CTLA-4 and GITR by Dendritic Cells

Pruitt¹,

Boczkowski²,

Rosa³

et al. 2011

Eur. J. Immunol.

View full text Add to dashboard Cite

SummaryCancer vaccines have now demonstrated clinical efficacy, but immune modulatory mechanisms that prevent autoimmunity limit their effectiveness. Systemic administration of mAbs targeting immune modulatory receptors CTLA-4 and glucocorticoid-induced TNFR-related protein (GITR) on Treg cells and effector T cells augments anti-tumor immunity both experimentally and clinically, but can induce life-threatening autoimmunity. We hypothesized that local delivery of anti-CTLA-4 and anti-GITR mAbs to the sites where T cells and tumor antigen-loaded DC vaccines interact would enhance the induction of anti-tumor immunity while avoiding autoimmunity. To achieve this goal, DCs transfected with mRNA encoding the H and L chains of anti-mouse CTLA-4 and GITR mAbs were co-administered with tumor antigen mRNAtransfected DCs. We observed enhanced induction of anti-tumor immunity and significantly improved survival in melanoma-bearing mice, without signs of autoimmunity. In human in vitro assays, we demonstrated that DCs transfected with mRNA encoding humanized anti-CTLA-4 mAb and mRNA encoding a soluble human GITR-L fusion protein enhance the induction of antitumor CTLs in response to DCs transfected with mRNAs encoding either melanoma or breast cancer antigens. Based on these results, this approach of using local delivery of immune modulators to enhance vaccine-induced immunity is currently being evaluated in a Phase I clinical cancer immunotherapy trial.

show abstract

Enhancement of anti‐tumor immunity through local modulation of CTLA‐4 and GITR by dendritic cells

et al. 2011

View full text Add to dashboard Cite

Summary Cancer vaccines have now demonstrated clinical efficacy, but immune modulatory mechanisms that prevent autoimmunity limit their effectiveness. Systemic administration of mAbs targeting immune modulatory receptors CTLA-4 and glucocorticoid-induced TNFR-related protein (GITR) on Treg cells and effector T cells augments anti-tumor immunity both experimentally and clinically, but can induce life-threatening autoimmunity. We hypothesized that local delivery of anti-CTLA-4 and anti-GITR mAbs to the sites where T cells and tumor antigen-loaded DC vaccines interact would enhance the induction of anti-tumor immunity while avoiding autoimmunity. To achieve this goal, DCs transfected with mRNA encoding the H and L chains of anti-mouse CTLA-4 and GITR mAbs were co-administered with tumor antigen mRNA-transfected DCs. We observed enhanced induction of anti-tumor immunity and significantly improved survival in melanoma-bearing mice, without signs of autoimmunity. In human in vitro assays, we demonstrated that DCs transfected with mRNA encoding humanized anti-CTLA-4 mAb and mRNA encoding a soluble human GITR-L fusion protein enhance the induction of anti-tumor CTLs in response to DCs transfected with mRNAs encoding either melanoma or breast cancer antigens. Based on these results, this approach of using local delivery of immune modulators to enhance vaccine-induced immunity is currently being evaluated in a Phase I clinical cancer immunotherapy trial.

show abstract

Dendritic cells engineered to secrete anti-GITR antibodies are effective adjuvants to dendritic cell-based immunotherapy

Cited by 47 publications

References 48 publications

Melanoma immunotherapy using mature DCs expressing the constitutive proteasome

Melanoma immunotherapy using mature DCs expressing the constitutive proteasome

Enhancement of Anti-Tumor Immunity Through Local Modulation of CTLA-4 and GITR by Dendritic Cells

Enhancement of anti‐tumor immunity through local modulation of CTLA‐4 and GITR by dendritic cells

Contact Info

Product

Resources

About