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Review
. 2012 Aug;61(8):1307-17.
doi: 10.1007/s00262-012-1259-8. Epub 2012 Apr 22.

TriVax-HPV: an improved peptide-based therapeutic vaccination strategy against human papillomavirus-induced cancers

Kelly Barrios  1 , Esteban Celis
Affiliations
Review

TriVax-HPV: an improved peptide-based therapeutic vaccination strategy against human papillomavirus-induced cancers

Kelly Barrios et al. Cancer Immunol Immunother. 2012 Aug.

Abstract

Background: Therapeutic vaccines for cancer are an attractive alternative to conventional therapies, since the later result in serious adverse effects and in most cases are not effective against advanced disease. Human papillomavirus (HPV) is responsible for several malignancies such as cervical carcinoma. Vaccines targeting oncogenic viral proteins like HPV16-E6 and HPV16-E7 are ideal candidates to elicit strong immune responses without generating autoimmunity because: (1) these products are not expressed in normal cells and (2) their expression is required to maintain the malignant phenotype. Our group has developed peptide vaccination strategy called TriVax, which is effective in generating vast numbers of antigen-specific T cells in mice capable of persisting for long time periods.

Materials and methods: We have used two HPV-induced mouse cancer models (TC-1 and C3.43) to evaluate the immunogenicity and therapeutic efficacy of TriVax prepared with the immunodominant CD8 T-cell epitope HPV16-E7(49-57), mixed with poly-IC adjuvant and costimulatory anti-CD40 antibodies.

Results: TriVax using HPV16-E7(49-57) induced large and persistent T-cell responses that were therapeutically effective against established HPV16-E7 expressing tumors. In most cases, TriVax was successful in attaining complete rejections of 6-11-day established tumors. In addition, TriVax induced long-term immunological memory, which prevented tumor recurrences. The anti-tumor effects of TriVax were independent of NK and CD4 T cells and, surprisingly, did not rely to a great extent on type-I or type-II interferon.

Conclusions: These findings indicate that the TriVax strategy is an appealing immunotherapeutic approach for the treatment of established viral-induced tumors. We believe that these studies may help to launch more effective and less invasive therapeutic vaccines for HPV-mediated malignancies.

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Conflict of interest statement

Esteban Celis has filed a patent application based on the use of synthetic peptides and poly-IC combinatorial complexes for vaccination. The rights of the patent application have been transferred to the Moffitt Cancer Center. Kelly Barrios declares no conflict of interest.

Figures

Fig. 1
Fig. 1
Synergy for the potentiation of the immunogenicity of E749-57 peptide by poly-IC and αCD40 mAb. a Frequencies of antigen-specific CD8 T cells in blood measured by tetramer analysis 6 days after prime and boost induced by immunization using various vaccine formulations. Numbers below the oval gates represent the % of tetramer-positive cells of the CD8-positive population. Dot plots showing the percentage of tetramer-positive cells in blood of a mouse from each group (3 mice/group). b Average percentage of tetramer-positive cells in the blood of mice in each group measured at different time points (same experiment as in a). c Separate experiment where CD8 T cells were purified from pooled splenocytes 7 days after the boost and antigen-induced responses to various target cells was evaluated using IFNγ EliSpot assays. Stimulator cells: EL4 cells pulsed or not with E749-57 peptide and TC-1 cells (expressing HPV16-E7) were used to evaluate CD8 T-cell responses from TriVax- (top row) and BiVax (bottom row)-vaccinated mice. In this experiment, each well contained 1 × 104 CD8 T cells and 1 × 105 stimulator cells. Numbers represent the total spots present in each well. Representative results of data obtained from two different experiments
Fig. 2
Fig. 2
Therapeutic effects induced by TriVax and BiVax immunization against established TC-1 tumors. a Mice (n = 3 per group) were inoculated (s.c.) with 3 × 105 TC-1 cells and vaccinated (i.v.) 6 days later with E749-57 peptide alone, BiVax, peptide plus αCD40 mAb, or TriVax. Identical booster immunizations were given on day 13. Tumor growth was measured (two opposing diameters) and recorded twice at week. None of mice from the E749-57 and E749-57 + αCD40 mAb groups rejected their tumors. One mouse from the BiVax group and all 3 mice from the TriVax group rejected their tumors. b The percentage of antigen-specific (tetramer positive) CD8 T cells in blood of the mice from the experiment shown on a measured at different time points. Only 2 measurements were done in the mice immunized with peptide alone because these mice did not survive beyond day 24. c Mice (n = 4 per group) were inoculated (s.c.) with 3 × 105 TC-1 cells and vaccinated (i.v.) 6 days later with TriVax prepared with either E749-57 or Ova176-183 as indicated. Identical booster immunizations were given on day 13. A non-vaccinated group (No Vax) was included as control. d The therapeutic effects of E749-57 BiVax were confirmed using a larger number of mice (6/group). In this experiment, half (3/6) of the mice in the BiVax-vaccinated group rejected their tumor, while all mice in the control group did not
Fig. 3
Fig. 3
Therapeutic effects induced by TriVax against HPV16-E7 expressing tumors. a Anti-tumor effects against large TC-1 tumors. Mice (6/group) were inoculated (s.c.) with 3 × 105 TC-1 cells and 11 days later were immunized with TriVax, and a booster was given 13 days after prime. All of the mice immunized with TriVax rejected their tumors. b Anti-tumor effects against C3.43 tumors. Mice (6/group) were inoculated with 3 × 105 C3.43 cells (s.c.) and vaccinated 6 and 13 days later with TriVax. All TriVax-immunized mice rejected their tumors. c Frequency of antigen-specific CD8 T cells in the spleens of mice from the TriVax-immunized group shown in b was determined 30 days after the prime. Numbers below each oval gate represent % tetramer-positive cells of the CD8 population. d CD8 T cells were purified from pooled splenocytes of TriVax-vaccinated mice shown in c, and tumor cell recognition was evaluated using IFNγ ELiSpot assays. Stimulator cells were as follows: EL4 cells loaded or not with E749-57 peptide, TC-1, and C3.43 tumor cells previously treated or not with IFNγ (100 U/ml, 24 h, to increase MHC-I expression). Results represent the average number of spots from triplicate wells with SD (error bars) of the means. e TriVax immunization confers long-term protection against tumors. Mice (6/group) were inoculated (s.c.) with 3 × 105 TC-1 cells and 6 and 13 days later received TriVax. By day 25, all mice in the TriVax group rejected their tumors. On day 47, the mice were re-challenged with 3 × 105 TC-1 on their right flanks and 3 × 105 C3.43 on their left flanks. None of the tumors grew. As controls (CTRLs), 3 naïve mice were inoculated with the same number of tumor cells
Fig. 4
Fig. 4
Anti-tumor efficacy of intramuscularly administered TriVax. a Mice were inoculated s.c. with 3 × 105 TC-1 cells. Six days later were vaccinated i.m. with TriVax (TriVax IM) and an identical booster was given on day 13. Tumor growth was measured as described previously. By day 25, all mice (6/6) vaccinated with TriVax rejected tumor, but by day 66, one of the mice developed a tumor mass at the original site (not shown). All of the (3/3) non-vaccinated mice developed large tumors and did not survive. b Frequency of antigen-specific CD8 T cells (tetramer positive) in the blood of the mice shown in a measured 11 days after boost. Numbers below the oval gates represent the % tetramer-positive cells of the CD8 T-cell population
Fig. 5
Fig. 5
Mechanism of therapeutic anti-tumor effects of TriVax. a Tumor growth in mice depleted of NK cells, CD4 T cells, and CD8 T cells vaccinated (i.v.) with TriVax. Mice (6/group) were inoculated with 3 × 105 TC-1 cells and 6 and 13 days later received TriVax. 1 and 3 days before the TriVax prime mice received depleting antibodies via an i.p. injection as described in “Materials and methods”. b Tumor growth in IFNγ KO and IFNαβR KO mice vaccinated with TriVax in the same manner as described in a. Non-vaccinated mice and TriVax-vaccinated wild-type (WT) mice were used as controls in each experiment. All of the TriVax WT, CD4-, and NK cell-depleted mice rejected their tumors. One out of 6 mice in the IFNγ KO group and 2/4 mice from the IFNαβR KO group had complete tumor rejections. c Immune responses elicited by TriVax in naïve IFNγ KO and IFNαβR KO mice. In a separate experiment, non-tumor-bearing wild-type (WT), IFNγ KO, and IFNαβR KO mice were vaccinated with TriVax (prime/boost, 13 days apart), and the percentage of tetramer-positive cells in blood was determined 7 days after boost
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