Moreover, tumors may induce mutation or loss in the immunodominant epitopes capable in triggering the strongest t cell activation, which further hinders the therapeutic effects of dna vaccines. Overcoming immune tolerance of the growth factors associated with tumor growth should be a useful approach to cancer therapy by active immunity. Safety and immunogenicity of a melanoma dna vaccine. Safety of administering the canine melanoma dna vaccine.
There are promising results with a xenogeneic dna vaccination strategy in dogs with melanoma, which raise hope that this strategy will succeed in humans as well. The hypothesis of the study was that the vaccine as a supplementary therapy for cmm would increase the survival of dogs with mm. Pdf dna vaccine for cancer immunotherapy researchgate. We have chosen to investigate xenogeneic dna vaccines encoding tyrosinase as a means to induce immune responses in cmm patients. Preclinical mouse studies have shown that xenogeneic dna vaccination with genes encoding tyrosinase family members can induceantibody and cytotoxic tcell responses, resulting in tumor rejection. Immunologic responses to xenogeneic tyrosinase dna vaccine administered by electroporation in patients with malignant melanoma jianda yuan1, geoffrey y ku4, matthew adamow1, zhenyu mu1, sapna tandon1, drew hannaman3, paul chapman4, gary schwartz4, richard carvajal4, katherine s panageas2, alan n houghton1,4 and jedd d wolchok1,4 abstract. To further define the optimal vaccination strategy, we conducted a phase i study of in vivo electroporation ep of a murine tyr dna vaccine pingmutyr in malignant melanoma patients. The proposed staging system was prognostic in this study and future studies might benefit from utilizing this staging system. Each dog received either 50 mcg n 57 or 100 mcg n 1 of xenogeneic plasmid dna encoding murine tyrosinase im every 14 days for a total of 4 vaccinations in the left caudal thigh with the vitajet1 spring. These studies provided the rationale for a trial of xenogeneic dna vaccination in cmm using the human tyrosinase gene. Immunologic responses to xenogeneic tyrosinase dna vaccine. Longterm survival of dogs with advanced malignant melanoma after dna vaccination with xenogeneic human tyrosinase.
Ctla4 blockade in combination with xenogeneic dna vaccines enhances tcell responses, tumor immunity and autoimmunity to self antigens in animal and cellular model systems. Tyrosinase related proteins1 and 2 gp75trp1 and trp2 are melanosomal membrane glycoproteins recognized by antibodies and tcells from patients with melanoma. Xenogeneic dna immunization against gp75trp1 generates antibodydependent tumor immunity and autoimmune depigmentation. Pdf safety and efficacy of a xenogeneic dna vaccine encoding. In veterinary medicine, a united states department of agriculturelicensed xenogeneic dna vaccine encoding human tyrosinase hutyr is available for the treatment of canine melanoma. A dna vaccine encoding xenogeneic tyrosinase has been shown to elicit antitumor response against oral melanoma in dogs and demonstrated safety and therapeutic efficacy in a phase i trial.
This study is designed to evaluate administration of a xenogeneic dna vaccine encoding the melanosomal antigen tyrosinase by in vivo electroporation in patients with malignant melanoma. Evidence that dna vaccines are well tolerated and have an excellent safety profile proved to be of advantage as many clinical trials combines the first phase with the second, saving both time and money. Pdf to evaluate the safety and efficacy of a vaccine containing plasmid dna with an insert encoding human tyrosinase ie, hutyr vaccine as. Immunotherapy of tumors with xenogeneic endothelial cells. Due to the production and processing of immunogenic proteins within host cells, dna vaccines are likely to induce immune responses in a man. Toxicity data was also documented, and this dna vaccine appears to be safe and well tolerated in horses. Dna vaccines encoding xenogeneic differentiation antigens, such as tyrosinase tyr, mediate tumor protection and regression in implantable mouse models, and dogs with spontaneous melanoma. The purpose of this study was to evaluate the safety of the canine melanoma vaccine in cats diagnosed with melanoma.
Tyrosinase xenogeneic vaccination was able to induce a significant antigenspecific immune response, both humoral and cellular, in most of the vaccinated patients. It is a dna vaccine encoding the human enzyme tyrosinase, and has been licensed for the treatment of melanoma, in dogs. Safety and immunogenicity of tyrosinase dna vaccines in. The human tyrosinase dna vaccine was either the same or comparable to the proposed product. We used vascular endothelial growth factor vegf as a model antigen to explore the feasibility of the immunogene tumor therapy with a vaccine based on a single xenogeneic homologous gene, targeting the growth factors associated with. Xenogeneic infections belong to a larger category of bioproductacquired infections, an example of which is simian virus 40 sv40. Development of a xenogeneic dna vaccine program for canine malignant melanoma at the animal medical center. A dna vaccine expressing tyrosinaserelated protein2. Vaccination with human tyrosinase dna induces antibody. Half the patients received 3 mouse tyrosinase dna injections followed by 3 human tyrosinase dna injections, while the remaining half received the same vaccines in the opposite sequence. We conducted a trial of mouse and human tyr dna vaccines. Therapy with xenogeneic tyrosinase dna vaccines was used in phase i trials of spontaneous advanced malignant melanoma in dogs, a disease very similar to human melanoma.
Enhancement of dna vaccine efficacy by targeting the. Federal agency for sera and vaccines dna and vectored vaccines theoretical risks. Investigations into whether sv40 infection is associated with an increased risk of cancer have been inconclusive. Safety and efficacy of a xenogeneic dna vaccine encoding. Cohorts of three dogs each received increasing doses of xenogeneic plasmid dna encoding either human tyrosinase hutyr, murine gp75 mugp75, or murine tyrosinase mutyr intramuscularly 100 mcg, 500 mcg and 1500 mcg per dose for each dose level biweekly for a total of 4 vaccinations in the left caudal thigh with the biojector 2000 jet. Research article open access immunologic responses to. Xenogeneic cell therapy mps xenogeneic cells medical biotechnology paulehrlichinstitut. Tyrosinase, as well as other related glycoproteins, is a suitable target for cmm. Dose appeared, however, not to have a significant effect in this response.
Human leukocyte antigen hlaa1, a2, a24 or b35 stage iibiv melanoma patients received up to five doses of the mouse tyrosinase dna vaccine by ep every three weeks at dose levels of 0. In contrast xenogeneic trp2 dna immunization induces immunity mediated by. Safety and immunoreactivity of a xenogeneic dna plasmid. Environmental assessment for issuance of a permit fordistribution and sale of animported infectious hematopoietic necrosis virus vaccine, dna august 20 prepared by. Bergman pj, mcknight j, novosad a, charney s, farrelly j, craft d, et al. Pdf dna vaccination has emerged as an attractive immunotherapeutic. Studies show that xenogeneic tyrosinase dna vaccination yields immune. Enhancement of dna vaccine efficacy by targeting the xenogeneic human chorionic gonadotropin, survivin and vascular endothelial growth factor receptor 2 combined tumor antigen to the major histocompatibility complex class ii pathway. A plasmid dna vaccine, encoding an epitope of mouse tyrosinase, with potential antineoplastic activity. Tyrosinase, as well as other related glycoproteins, is a suitable target for cmm immunotherapy because of its restricted, tissuespecific expression. Dna vaccine for cancer immunotherapy europe pmc article.
For dna vaccines, a veterinary cancer product is oncept tm. Immunogene therapy of tumors with vaccine based on xenopus. Immunization against defined tumor antigens using a xenogeneic dna vaccine is currently being tested in early phase clinical trials for the treatment of melanoma and prostate cancers, with proposed trials for breast cancer and nonhodgkins lymphoma. These studies provided the impetus for development of a xenogeneic dna vaccine program in cmm. Xenogeneic murine tyrosinase dna vaccine for malignant. No studies have evaluated the safety or efficacy of this vaccine in cats. Use of this strategy also overcomes limitations seen in other types of cancer vaccines. Dna vaccines have elicited measurable immune responses against tyr and gp100, another melanocytic differentiation antigen, in preclinical. The breaking of immune tolerance against autologous angiogenic endothelial cells should be a useful approach for cancer theraphy. Dna vaccines are not replicating and the vaccine products are expressed within the host cells. Sv40, a polyomavirus, contaminated polio vaccine stocks in the 1950s. Due to their rapid and widespread development, dna vaccines have entered into a variety of human clinical trials for vaccines against various diseases including cancer. The human tyrosinase differs from the canine version, enabling tolerance to be broken. To further define the optimal vaccination strategy, we conducted a phase i study of in vivo electroporation ep of a murine tyr dna vaccine pingmutyr in malignant melanoma.
To evaluate the effect of xenogeneic dna vaccination with tyrosinase in vivo, mice 15 per group were immunized by gene gun weekly for 5 weeks with plasmids expressing either mouse or human tyrosinase dna followed by challenge with b16f10lm3, derived from the spontaneously arising b16 melanoma. Objectiveto evaluate the safety and efficacy of a vaccine containing plasmid dna with an insert encoding human tyrosinase ie, hutyr vaccine as adjunctive treatment for oral malignant melanoma mm in dogs animals111 dogs 58 prospectively enrolled in a multicenter clinical trial and 53 historical controls with stage ii or iii oral mm modified world health organization staging scale. Various strategies have been investigated to enhance the potency of dna vaccines. Trigrid delivery system for intramuscular electroporation. Comparison of two cancer vaccines targeting tyrosinase. Dna vaccines, which aim to exploit the hosts immune system. A dna vaccine expressing tyrosinase related protein2 induces tcellmediated protection against mouse glioblastoma. A complex dna vaccine construct that delivers several xenogeneic epitopes dramatically increased the ctl antitumor activity. Safety and immunogenicity of a melanoma dna vaccine delivered by electroporation. Immunization with xenogeneic dna encoding tyrosinase family proteins has been shown to induce antibody, t cell, and antitumor responses in mice and a small cohort of dogs. Xenogeneic immunization with human tyrosine hydroxylase dna vaccines suppresses growth of established neuroblastoma. The efficacy of dna xenovaccines was also tested in dogs, leading to the approval of the first xenogeneic dna vaccine against human tyrosinase, oncept, for the treatment of oral malignant melanoma in dogs. Request pdf xenogeneic murine tyrosinase dna vaccine for malignant melanoma of the digit of dogs malignant melanoma of dogs is a highly aggressive neoplasm and is the 2nd most common digit tumor. The xenogeneic murine tyrosinase dna vaccine was safe and appears effective when used in conjunction with local and regional disease control.
Safety and immunogenicity of a melanoma dna vaccine delivered. Immunologic responses to xenogeneic tyrosinase dna vaccine administered by electroporation in patients with malignant melanom. Dna vaccines, electroporation and their applications in. Safety and efficacy of a xenogeneic dna vaccine encoding for human tyrosinase as adjunctive treatment for oral malignant melanoma in dogs following surgical excision of the primary tumor. Xenogeneic immunization with human tyrosine hydroxylase dna. This vaccine exploits the close homology of human and canine tyrosinase 92% to generate a tyrosinase specific antitumor response. Combination of cytokineenhanced vaccine and chemogene. Here we show that immunotherapy of tumors using fixed xenogeneic whole endothelial cells as a vaccine was effective in affording protection from tumor growth, inducing regression of established tumors and prolonging survival of tumorbearing mice. Definition of xenogeneic tyrosinase dna vaccine nci drug. The tyrosinase produced from the human dna used in this vaccine is similar to canine tyrosinase and has been shown to stimulate an immune response against canine melanoma cells producing tyrosinase.
However, this vaccine is the only approved therapeutic treatment for omm. Peripheral blood mononuclear cells pbmc were collected, cultured with a peptide pool containing eight hla class. Development of immunologic assays to measure response in. Oncepttm is a bacterial plasmid dna vaccine encoding the human tyrosinase gene and is licensed for the adjuvant treatment of stage ii and iii omm after locoregional control. Xenogeneic immunization with tyrosinase dna delays tumor growth. A xenogeneic human tyrosinase dna vaccine was developed for treatment of dogs with oral malignant melanoma oncept. Pdf ctla4 blockade in combination with xenogeneic dna. Preclinical and clinical studies by our laboratory and others have shown that xenogeneic dna vaccination with tyrosinase family members can produce immune responses resulting in tumor rejection or protection and prolongation of survival. Development of a xenogeneic dna vaccine program for canine. Alternative roles for interferongamma in the immune. Tyrosinase is normally expressed in melanocytes to catalyze the ratelimiting step of melanin biosynthesis from tyrosine 32, 33.
Chimeric dna vaccines are vaccines that encode xenogeneic antigens. A murine xenogeneic dna vaccine for canine oral malignant. Dna vaccine in dogs as adjunctive treatment for oral mm. The oncepttm canine melanoma vaccine contains a gene encoding human tyrosinase, an enzyme associated with skin pigmentation.
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