Comparison of Two Cancer Vaccines Targeting Tyrosinase: Plasmid DNA and Recombinant Alphavirus Replicon Particles

Goldberg, Stacie M.; Bartido, Shirley; Gardner, Jason P.; Guevara-Patiño, José A.; Montgomery, Stephanie C.; Perales, Miguel-Ángel; Maughan, Maureen F.; Dempsey, J. F.; Donovan, Gerald P.; Olson, William C.; Houghton, Alan N.; Wolchok, Jedd D.

doi:10.1158/1078-0432.ccr-05-1410

Cited by 53 publications

(43 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Some natural autoantibodies may have antitumor effects: tyrosinase, involved in the synthesis of melanin, is a melanoma-associated antigen (30), and carbonic anhydrase IX is a tumor-associated antigen in renal cell carcinoma (31).…”

Section: Discussionmentioning

confidence: 99%

Newborn humans manifest autoantibodies to defined self molecules detected by antigen microarray informatics

Merbl¹,

Zucker-Toledano²,

Quintana³

et al. 2007

J. Clin. Invest.

205

199

View full text Add to dashboard Cite

Autoimmune diseases are often marked by autoantibodies binding to self antigens. However, many healthy persons also manifest autoantibodies that bind to self antigens, known as natural autoantibodies. In order to characterize natural autoantibodies present at birth, we used an antigen microarray (antigen chip) to analyze informatically (with clustering algorithms and correlation mapping) the natural IgM, IgA, and IgG autoantibody repertoires present in 10 pairs of sera from healthy mothers and the cords of their newborn babies. These autoantibodies were found to bind to 305 different, mostly self, molecules. We report that in utero, humans develop IgM and IgA autoantibodies to relatively uniform sets of self molecules. The global patterns of maternal IgM autoantibodies significantly diverged from those at birth, although certain reactivities remained common to both maternal and cord samples. Because maternal IgG antibodies (unlike IgM and IgA) cross the placenta, maternal and cord IgG autoantibodies showed essentially identical reactivities. We found that some self antigens that bind cord autoantibodies were among the target self antigens associated with autoimmune diseases later in life. Thus, the obviously benign autoimmunity prevalent at birth may provide the basis for the emergence of some autoimmune diseases relatively prevalent later in life.

show abstract

Section: Discussionmentioning

confidence: 99%

Newborn humans manifest autoantibodies to defined self molecules detected by antigen microarray informatics

Merbl¹,

Zucker-Toledano²,

Quintana³

et al. 2007

J. Clin. Invest.

205

199

View full text Add to dashboard Cite

show abstract

“…We generated a replicon expression plasmid containing the CEA gene with the Cap-1(6D) mutation (15) called CEA(6D) VRP (AVX701) (Supplemental Figure 5) as previously described (9,13,27). It was formulated so that the maximum feasible dose to administer in the clinical trial was 4 × 10 8 IU.…”

Section: Methodsmentioning

confidence: 99%

“…Other advantages of VRP are their tropism for, and maturation of (5), DCs, which could result in enhanced T cell activation. A number of preclinical studies have reported that VRP induce potent immunity despite the presence of neutralizing antibodies (4)(5)(6)(7)(8)(9)(10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

An alphavirus vector overcomes the presence of neutralizing antibodies and elevated numbers of Tregs to induce immune responses in humans with advanced cancer

Morse¹,

Hobeika²,

Osada³

et al. 2010

J. Clin. Invest.

104

View full text Add to dashboard Cite

Therapeutic anticancer vaccines are designed to boost patients' immune responses to tumors. One approach is to use a viral vector to deliver antigen to in situ DCs, which then activate tumor-specific T cell and antibody responses. However, vector-specific neutralizing antibodies and suppressive cell populations such as Tregs remain great challenges to the efficacy of this approach. We report here that an alphavirus vector, packaged in virus-like replicon particles (VRP) and capable of efficiently infecting DCs, could be repeatedly administered to patients with metastatic cancer expressing the tumor antigen carcinoembryonic antigen (CEA) and that it overcame high titers of neutralizing antibodies and elevated Treg levels to induce clinically relevant CEA-specific T cell and antibody responses. The CEA-specific antibodies mediated antibody-dependent cellular cytotoxicity against tumor cells from human colorectal cancer metastases. In addition, patients with CEA-specific T cell responses exhibited longer overall survival. These data suggest that VRP-based vectors can overcome the presence of neutralizing antibodies to break tolerance to self antigen and may be clinically useful for immunotherapy in the setting of tumor-induced immunosuppression.

show abstract

“…Using tyrosinase as a prototypical melanocyte differentiation antigen, we recently showed that Venezuelan equine encephalitis virus -based VRP induced robust B-cell and T-cell responses and improved survival in mice challenged with B16 melanoma cells. In this setting, more potent and protective responses were elicited using a syngeneic (murine) rather than a xenogeneic (human) form of tyrosinase (17). Based on these findings, we prepared VRP encoding human PSMA for preclinical evaluation as a potential vaccine therapy for prostate cancer in man.…”

mentioning

confidence: 99%

A Novel Alphavirus Vaccine Encoding Prostate-Specific Membrane Antigen Elicits Potent Cellular and Humoral Immune Responses

Durso

Andjelić

Gardner

et al. 2007

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

Purpose: Prostate-specific membrane antigen (PSMA) is an attractive target for active immunotherapy. Alphavirus vaccines have shown promise in eliciting immunity to tumor antigens. This study investigated the immunogenicity of alphavirus vaccine replicon particles (VRP) that encode PSMA (PSMA-VRP). Experimental Design: Cells were infected with PSMA-VRP and evaluated for PSMA expression and folate hydrolase activity. Mice were immunized s.c. with PSMA-VRP or purified PSMA protein. Sera, splenocytes, and purified T cells were evaluated for the magnitude, durability, and epitope specificity of the anti-PSMA response. Antibodies were measured by flow cytometry, and cellular responses were measured by IFN-g enzyme-linked immunospot and chromium release assays. Cellular responses in BALB/c and C57BL/6 mice were mapped using overlapping 15-mer PSMA peptides. A Good Laboratory Practice^compliant toxicology study was conducted in rabbits. Results: PSMA-VRP directed high-level expression of active PSMA. Robust T-cell and B-cell responses were elicited by a single injection of 2 Â 10 5 infectious units, and responses were boosted following repeat immunizations. Anti-PSMA responses were detected following three immunizations with 10 2 infectious units and increased with increasing dose. PSMA-VRP was more immunogenic than adjuvanted PSMA protein. Responses to PSMA-VRP were characterized by Th-1cytokines, potent CTL activity, and IgG2a/IgG2b antibodies. T-cell responses in BALB/c and C57BL/6 mice were directed toward different PSMA peptides. Immunogenic doses of PSMA-VRP were well tolerated in mice and rabbits. Conclusions: PSMA-VRP elicited potent cellular and humoral immunity in mice, and specific anti-PSMA responses were boosted on repeat dosing. PSMA-VRP represents a promising approach for immunotherapy of prostate cancer.

show abstract

Comparison of Two Cancer Vaccines Targeting Tyrosinase: Plasmid DNA and Recombinant Alphavirus Replicon Particles

Cited by 53 publications

References 47 publications

Newborn humans manifest autoantibodies to defined self molecules detected by antigen microarray informatics

Newborn humans manifest autoantibodies to defined self molecules detected by antigen microarray informatics

An alphavirus vector overcomes the presence of neutralizing antibodies and elevated numbers of Tregs to induce immune responses in humans with advanced cancer

A Novel Alphavirus Vaccine Encoding Prostate-Specific Membrane Antigen Elicits Potent Cellular and Humoral Immune Responses

Contact Info

Product

Resources

About