Enhanced Therapeutic Effects Conferred by an Experimental DNA Vaccine Targeting Human Papillomavirus-Induced Tumors

Abstract

Human papillomavirus (HPV) infection is responsible for all cervical cancer cases, other anogenital cancers, and head and neck tumors. The epidemiological relevance of HPV-induced tumors reinforces the need for the development of therapeutic antitumor vaccines. Clinical trials with different vaccine formulations, particularly DNA vaccines, have provided promising results but have still been unable to achieve the immunogenicity required for use in infected patients. In experimental conditions, anticancer HPV-specific vaccines induced E7-specific CD8(+) T-cell responses but did not confer full therapeutic antitumor protection in mice with transplanted HPV-expressing TC-1 cells, which are the most frequently used nonclinical protection correlate for antitumor effects. Our group has developed a DNA vaccine strategy based on the fusion of HPV oncoproteins to the herpes virus gD protein. This vaccine promoted the induction of antigen-specific cytotoxic CD8(+) T-cell responses and partial antitumor therapeutic effects based on the blockade of coinhibitory signals and the enhancement of coactivation mechanisms. In the present study, we report conditions leading to full therapeutic antitumor effects using the TC-1 cell murine model after a single vaccine dose. The combination of a coadministered plasmid encoding IL-2, optimization of the coding sequence for mammalian cells, and the use of different delivery routes resulted in enhancements of the E7-specific cytotoxic CD8(+) T-cell responses and full therapeutic protection under experimental conditions. The combination of these strategies augmented the potency of the DNA vaccine formulation to levels not previously achieved by other therapeutic antitumor vaccines under similar experimental conditions, including some that have been taken to clinical trials.

Protection against HPV-16–Associated Tumors Requires the Activation of CD8+ Effector Memory T Cells and the Control of Myeloid-Derived Suppressor Cells

“…The DNA vaccine encoding the HPV-16 E7 protein genetically fused after amino acid 244 of the HSV-1 gD protein has been described previously (21,23). The gene sequence encoding the gDE7 chimeric protein was cloned into the pVAX1 vector (Invitrogen), which contains a cytomegalovirus (CMV) promoter and a kanamycin resistance gene.…”

“…We previously showed that the coadministration of a plasmid encoding IL2 with a DNA vaccine encoding the HPV-16 E7 protein genetically fused to HSV-1 gD (pgDE7) generated full therapeutic antitumor protection after a single vaccine dose (21). In contrast, under the same conditions, immunization with the vaccine vector without coadministration of the plasmid encoding IL2 resulted in the activation of similar numbers of E7-specific CD8 þ T cells but did not confer therapeutic antitumor protection.…”

“…We previously demonstrated that a DNA vaccine encoding the HPV-16 E7 protein genetically fused to the herpes simplex virus 1 (HSV-1) glycoprotein D (gD) protein, coadministered with a vector encoding IL2, induced strong activation of E7-specific CD8 þ T cells and promoted full therapeutic protection in mice grafted with tumor cells expressing HPV-16 E6 and E7 (TC-1 cells; ref. 21). In this work, we extended these studies to better define the characteristics of the CD8 þ T-cell population associated with the therapeutic eradication of HPV-related tumors.…”

Recent progress in vaccination against human papillomavirus‐mediated cervical cancer

“…Other delivery vectors for E6 and E7 peptides include Semliki Forest virus (combined with low‐dose irradiation) , Listeria , lentiviruses , fusions with heat shock proteins , ricin B chain , Shiga toxin B subunit and synthetic polymers . Several studies have examined E6 or E7 DNA vaccines combined with various adjuvants . Immunization of mice with a mixture of DNA expressing E6/E7 and IL‐33 was able to induce regression of a transplantable HPVE6/E7‐expressing tumour and generate memory CD8 T cells while an E7 DNA vaccine combined with cyclophosphamide (to reduce regulatory T cells) produced potent anti‐tumour responses .…”

Coadministration of cruzipain and GM-CSF DNAs, a new immunotherapeutic vaccine againstTrypanosoma cruziinfection

“…Among some of these properties, it is worth mentioning that: i-cruzipain is expressed in all developmental stages and strains of the parasite 10 ; ii-it is accumulated in the lysosomes, it is secreted and also present at surface level, being able to hydrolyze immunoglobulins 11 ; iii-it plays an important role in the process of internalization within mammalian cells 12 ; and iv-it is highly immunogenic in natural infection. 13 Recent improvements to DNA vaccines and the potential and flexibility of DNA as a potent immunization strategy for inducing both humoral and cell-mediated immune responses, make them an ideal therapeutic approach for treating or eliminating chronic disease, as it was shown in multiple sclerosis, 14 human papillomavirus, 15,16 hepatitis B 17 , human immunodeficiency virus, 18,19 simian immunodeficiency virus, 20 Mycobacterium tuberculosis, 21 Leishmania spp., 22,23 Schistosoma mansoni, 24 as well as against T. cruzi. 25,26 We have previously reported the efficacy of attenuated Salmonella enterica (S) carrying plasmid encoding cruzipain (SCz) to protect against T. cruzi infection.…”