Dendritic Cells Pulsed with an Anti-Idiotype Antibody Mimicking Carcinoembryonic Antigen (CEA) Can Reverse Immunological Tolerance to CEA and Induce Antitumor Immunity in CEA Transgenic Mice

Saha, Asim; Chatterjee, S. K.; Foon, Kenneth A.; Primus, F. James; Sreedharan, Sunil; Mohanty, Kartik; Bhattacharya‐Chatterjee, Malaya

doi:10.1158/0008-5472.can-04-0626

Cited by 38 publications

(44 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…DCs can overcome the heightened threshold of anergic T cells 41 and restore responsiveness of tolerogenic tumor-specific T cells 42 in vitro. Moreover, studies in mice demonstrate that DC-based vaccines can break tolerance against (tumor-associated) self-antigens, [43][44][45][46][47] resulting in regression of established tumors. 47 Thus, a combination of antibody-mediated strategies targeting tumor-associated antigens to DCs and strategies modulating regulatory mechanisms at the T-cell level might provide effective cancer therapies.…”

Section: Discussionmentioning

confidence: 99%

Effective induction of naive and recall T-cell responses by targeting antigen to human dendritic cells via a humanized anti–DC-SIGN antibody

Tacken

Vries

Gijzen

et al. 2005

Blood

250

230

View full text Add to dashboard Cite

Current dendritic cell (DC)-based vaccines are based on ex vivo-generated autologous DCs loaded with antigen prior to readministration into patients. A more direct and less laborious strategy is to target antigens to DCs in vivo via specific surface receptors. Therefore, we developed a humanized antibody, hD1V1G2/G4 (hD1), directed against the C-type lectin DC-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) to explore its capacity to serve as a target receptor for vaccination purposes. hD1 was cross-linked to a model antigen, keyhole limpet hemocyanin (KLH). We observed that the chimeric antibody-protein complex (hD1-KLH) bound specifically to DC-SIGN and was rapidly internalized and translocated to the lysosomal compartment. To determine the targeting efficiency of hD1-KLH, monocyte-derived DCs and peripheral blood lymphocytes (PBLs) were obtained from patients who had previously been vaccinated with KLHpulsed DCs. Autologous DCs pulsed with hD1-KLH induced proliferation of patient PBLs at a 100-fold lower concentration than KLH-pulsed DCs. In addition, hD1- KLH-targeted IntroductionDendritic cells (DCs) are professional antigen-presenting cells (APCs) that play a key role in regulating antigen-specific immunity. DCs capture antigens, process them into peptides, and present these to T cells. 1 The interaction between DC and T-cell controls the type and magnitude of the resulting immune response. Recently, preclinical and clinical studies have exploited DCs in an attempt to improve vaccine efficacy. 2 Most of these studies involve ex vivo antigen loading of autologous monocyte-derived DCs that are readministrated to the patient, a laborious and costly procedure. A more direct strategy involves targeting of antigens specifically to antigen uptake receptors on the DC in vivo. Potential candidate receptors highly expressed by DCs include Fc receptors [3][4][5] and members of the C-type lectin family. 6,7 Whereas Fc receptors are expressed by many different cell types, the expression of some members of the C-type lectin family are more DC restricted. 8 C-type lectins bind sugar residues in a calcium-dependent manner via a highly conserved carbohydrate recognition domain. C-type lectin receptors expressed by DCs are implicated in immunoregulatory processes, such as antigen capture, DC trafficking, and DC-T-cell interactions. 8 Based on the location of the amino (N) terminus, 2 types of membrane-bound C-type lectins can be distinguished on DCs. Type I C-type lectins have their N terminus located outside, while type II C-type lectins have their N terminus located inside the cell. Several studies have been conducted on antigen targeting to C-type lectin receptors for vaccination purposes, mainly focusing on the type I C-type lectins mannose receptor (MR) 9 and DEC-205. 6,10,11 Vaccines based on natural MR ligands have been shown to effectively induce humoral and cellular responses. 9 However, these ligands lack specificity for the MR, and may target multiple lectins with overlapping binding sp...

show abstract

Section: Discussionmentioning

confidence: 99%

Effective induction of naive and recall T-cell responses by targeting antigen to human dendritic cells via a humanized anti–DC-SIGN antibody

Tacken

Vries

Gijzen

et al. 2005

Blood

250

230

View full text Add to dashboard Cite

show abstract

“…Because of its unique expression pattern, CEA has been targeted as a TAA to induce CEA-specific antibodies, CD4 + T-helper cells, and CD8 + CTLs to treat CEA + tumors (19). Our previous studies suggest that murine monoclonal anti-idiotype antibody 3H1 (20) can be used as a surrogate antigen for CEA and induced anti-CEA immunity in CEA-transgenic mice (21)(22)(23) as well as in humans (reviewed in ref. 24).…”

Section: Cd8mentioning

confidence: 99%

“…3H1 showed promise as a potential vaccine candidate in the phase I/II clinical trials of colon cancer patients. Anti-idiotype 3H1 could easily break immune tolerance to CEA and induced high-titer, anti-CEA antibody as well as CD4 + T-helper (Th1) responses in mice and cancer patients (21,22,24).…”

Section: Cd8mentioning

confidence: 99%

Therapy of Established Tumors in a Novel Murine Model Transgenic for Human Carcinoembryonic Antigen and HLA-A2 with a Combination of Anti-idiotype Vaccine and CTL Peptides of Carcinoembryonic Antigen

et al. 2007

Self Cite

View full text Add to dashboard Cite

Induction of potent and sustained antitumor immunity depends on the efficient activation of CD8 + and CD4 + T cells. Immunization using dendritic cells loaded with tumor antigens constitute a powerful platform for stimulating cellular immunity. Our previous studies suggested that vaccination with an anti-idiotype antibody 3H1, which mimics a specific epitope of carcinoembryonic antigen (CEA), has the potential to break immune tolerance to CEA and induce anti-CEA antibody as well as CEA-specific CD4 + T-helper responses in colon cancer patients as well as in mice transgenic for human CEA. Here, we have combined the anti-idiotype 3H1 with the CTL peptides of CEA to augment both T-helper and CTL responses in a clinically relevant mouse model, which is transgenic for both CEA and HLA-A2. We have evaluated the potential of two different HLA-A2-restricted epitopes of CEA pulsed into dendritic cells in a therapeutic setting. The overall immune responses and survival were enhanced in groups of mice immunized with agonist peptide for CEA 691 (YMIGMLVGV)-pulsed dendritic cells or CAP1-6D (YLS-GADLNL, agonist peptide for CAP-1)-pulsed dendritic cells. Mice immunized with peptide-pulsed dendritic cells along with 3H1-pulsed dendritic cells resulted in significant increase in survival compared with mice immunized with peptidepulsed dendritic cells alone (P < 0.02). IFN-; ELISPOT and 51 Cr-release assays showed that HLA-A2-restricted, CEAspecific CTL responses were augmented by combined dendritic cell vaccinations. The combined vaccination strategy resulted in increased antigen-specific proliferation of splenocytes and secretion of Th1 cytokines by CD4 + T cells that correlated with increased survival. These results suggest the potential use of this vaccination strategy for future clinical applications. [Cancer Res 2007;67(6):2881-92]

show abstract

“…However, the immunologic tolerance to CEA is not absolute. When CEA-Tg mice were immunized with recombinant poxvirus-based vaccines (9-13), CEA-transfected syngeneic fibroblasts in combination with Corynebacterium parvum (14), dendritic cells pulsed with anti-idiotype antibody mimicking CEA (15,16), DNA vaccines encoding CEA absorbed onto cationic microparticles (17), or an oral vaccine using attenuated bacteria encoding CEA (18)(19)(20), tolerance to this self-tumor-associated antigen was overcome as evidenced by the development of CEA-specific antibody, CD4…”

Section: Introductionmentioning

confidence: 99%

Induction of Mucosal and Systemic Immune Responses against Human Carcinoembryonic Antigen by an Oral Vaccine

et al. 2005

View full text Add to dashboard Cite

Carcinoembryonic antigen (CEA) is a tumor-associated antigen targeted for the development of colorectal tumor vaccines. In this study, we developed papillomavirus pseudoviruses encoding the truncated CEA without NH 2 -terminal signal peptide (PV-CEA) as an oral vaccine to induce CEAspecific CTL responses. In CEA transgenic (CEA-Tg) mice orally immunized with PV-CEA, the immunologic tolerance to CEA as a ''self-antigen'' was overcome and both mucosal and systemic CEA-specific cytolytic activities were detected by in vitro 51 Cr release assays. In a tumor prevention model, the growth rate of CEA + tumors was significantly delayed in CEA-Tg mice orally immunized with PV-CEA when compared with the control vaccine. Further, the IFN-; enzyme-linked ImmunoSPOT and in vitro 51 Cr release assay results showed that HLA-A2-restricted, CEA-specific CTL responses were induced in both mucosal and systemic lymphoid tissues in A2 transgenic mice after oral immunization with PV-CEA. Finally, we showed that coadministration of papillomavirus pseudoviruses encoding interleukin-2 with PV-CEA enhanced the generation of A2-restricted, CEA-specific CTLs in aged CEA/A2 double transgenic mice, which were more clinically relevant. Our data suggest that PV-CEA pseudovirus vaccine is a promising oral CEA vaccine for humans to induce CEAspecific CTLs at the site of colorectal tumors (i.e., intestinal mucosa), which might efficiently eliminate CEA + colorectal tumor cells in the mucosa. (Cancer Res 2005; 65(15): 6990-9)

show abstract

Dendritic Cells Pulsed with an Anti-Idiotype Antibody Mimicking Carcinoembryonic Antigen (CEA) Can Reverse Immunological Tolerance to CEA and Induce Antitumor Immunity in CEA Transgenic Mice

Cited by 38 publications

References 22 publications

Effective induction of naive and recall T-cell responses by targeting antigen to human dendritic cells via a humanized anti–DC-SIGN antibody

Effective induction of naive and recall T-cell responses by targeting antigen to human dendritic cells via a humanized anti–DC-SIGN antibody

Therapy of Established Tumors in a Novel Murine Model Transgenic for Human Carcinoembryonic Antigen and HLA-A2 with a Combination of Anti-idiotype Vaccine and CTL Peptides of Carcinoembryonic Antigen

Induction of Mucosal and Systemic Immune Responses against Human Carcinoembryonic Antigen by an Oral Vaccine

Contact Info

Product

Resources

About