Japanese Journal of Clinical Oncology Advance Access published online on November 16, 2008
Japanese Journal of Clinical Oncology, doi:10.1093/jjco/hyn132
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© The Author (2008). Published by Oxford University Press. All rights reserved
Recent Advances in Cancer Vaccines: An Overview
1 Department of Immunology and Immunotherapy
2 Division of Cancer Vaccine at the Research Center for Innovative Cancer Therapy
3 Multidisciplinary Treatment Center
4 Department of Urology, Kurume University School of Medicine, Fukuoka, Japan
For reprints and all correspondence: Kyogo Itoh, Department of Immunology and Immunotherapy, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan. E-mail: kyogo{at}med.kurume-u.ac.jp
Received September 30, 2008; accepted October 22, 2008
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Abstract |
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 TOP Abstract CANCER VACCINES FOR PREVENTING...THERAPUTIC CANCER VACCINESCONCLUSIONFundingConflict of interest statementReferences |
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The field of cancer vaccines is currently in an active state of clinical investigations. Human papilloma virus vaccine has been approved as a prophylactic cancer vaccine, while Oncophage (heat shock protein-peptide complex) was recently approved in Russia for a certain stage of kidney cancer, although to date none has been approved in Japan or the USA. We reviewed recent clinical trials of several different types of cancer vaccines, mainly by using PubMed from 2005 to 2008. There have been slow but substantial advances in peptide vaccines and dendritic cell-based vaccines with regard to both clinical responses and immunological markers. A personalized approach to boost immune responses, addition of chemotherapy to overcome robust cancers and changing of endpoints from tumor reduction to overall survival seem to be the three key elements for the development of therapeutic cancer vaccines.
Key Words: cancer vaccine • peptide vaccine • dendritic cell vaccine • immune responses • clinical responses
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CANCER VACCINES FOR PREVENTING ONCOGENIC INFECTIONS |
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TOPAbstractCANCER VACCINES FOR PREVENTING...THERAPUTIC CANCER VACCINESCONCLUSIONFundingConflict of interest statementReferences |
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A goal of vaccine development against oncogenic infectious agents is to provide a cost-effective vaccine that can prevent and treat premalignant disease, as well as reduce the risk of transmitting the agent to uninfected individuals. Hepatitis B virus (HBV), hepatitis C virus (HCV), human papilloma virus (HPV) and Helicobacter pylori represent the vast majority (90%) of the tumors attributable to infectious agents. We reviewed HBV, HCV and HPV vaccines, but not H. pylori vaccines, since the latter have been studied in only a limited number of clinical trials.
Prevention of Hepatocellular Carcinoma
An HBV vaccine using hepatitis B surface antigen as a subunit vaccine is the first successful prophylactic vaccine against an oncogenic infectious agent. HBV is believed to account for nearly 1 million deaths per year worldwide, and one-third of these deaths are secondary to hepatocellular carcinoma (HCC) (1–3). Indeed, the vaccination resulted in a reduction of HCC (4,5).
In contrast to HBV, there is no HCV vaccine yet available, either for prophylactic or therapeutic use. HCV is prevalent worldwide, with nearly 180 million individuals infected (6). One of the HCV genotypes, HCV1b, which is resistant to interferon therapy, is the most frequently observed in Japan (70%) and is also very highly observed in the United States (7,8). HCV-infected patients tend to develop liver cirrhosis and ultimately HCC. Thus, there have been a variety of efforts to develop an HCV vaccine. One of the approaches has been to identify immunogenic sequences capable of inducing cellular and humoral responses (9–12). There have been several clinical trials of HCV vaccine using peptides or subunits capable of inducing cellular and humoral responses (13–15). However, development of either prophylactic or therapeutic HCV vaccines is expected to be very difficult, because HCV is genetically and serologically very heterogeneous, and their antigens are highly mutable (16). Immune suppression in HCV-infected patients through regulatory T cells has also been reported (17). However, at least one-third of the subjects with HCV infection showed spontaneous clearance of HCV with acquisition of specific immunity against HCV, keeping alive our hope of developing a clinically effective HCV vaccine (18). A successful vaccine would require a combined prime-boost approach to induce both neutralizing antibodies and T helper cells, although an important first step would be to boost potent and durable cytotoxic T lymphocyte (CTL) responses against HCV. From this point of view, HCV-derived peptides capable of inducing both CTL responses and antibody production could be appropriate sources for HCV peptide vaccines (12,13,15,19).
Prevention of Cervical Carcinoma
HPV contains E6 and E7 oncogenes, and infection with HPV strains 16 and 18, which contain these gene products, confers a strong risk of cervical cancer (20). Prophylactic HPV vaccines have recently been approved for use in healthy young individuals. A monovalent HPV-16 L1 virus-like particle (VLP) vaccine (manufactured by Merck) is given intramuscularly with a standard aluminum-based adjuvant, while a bivalent HPV-16/18 VLP vaccine is given intramuscularly with a proprietary adjuvant (manufactured by GlaxoSmithKline). These vaccines are clinically effective for protection from persistent infection and cervical diseases attributed to the HPV16 or HPV16/18 types (21–26). Both the vaccines have been approved in many countries, but not yet in Japan. Protection from these vaccines seems to last 4 years or longer. However, it is unclear whether these vaccines are effective for women who have been sexually active for more than 5–10 years. In addition, these vaccines are not expected to be of benefit to women with prevalent HPV infection. Therefore, further development is needed to prevent cervical cancers in women of all ages. The other major concern is the high cost of the HPV vaccine, which would seem to rule out worldwide distribution unless financial assistance is provided for impoverished nations.
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THERAPUTIC CANCER VACCINES |
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TOPAbstractCANCER VACCINES FOR PREVENTING...THERAPUTIC CANCER VACCINESCONCLUSIONFundingConflict of interest statementReferences |
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Despite the advances in basic aspects of tumor immunology, clinical realization of effective therapeutic cancer vaccines has been poor. For example, only a 3.3% overall objective response (OR) rate was observed in 1306 vaccine treatments for metastatic cancer patients, based on a comprehensive review of cancer vaccines by Steven Rosenberg, the cancer immunotherapy pioneer (3). Nonetheless, there have been recent advances with regard to both clinical responses and immunological markers showing correlation to clinical responses, as described below. These reports are listed in Table 1.
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Peptide Vaccines
Trials for non-responders to standard cancer therapy
We reported in 2005 that a Phase I/II clinical trial of personalized peptide vaccination for advanced malignant glioma patients, in which up to four peptides were vaccinated based on screening of pre-vaccination measurements of cellular and humoral responses specific to a set of peptides (20–23 peptides), resulted in five cases with partial response (PR), eight cases of stable disease (SD) and eight cases of progressive disease (27,28). Peptide-specific immunological responses were restricted to the patients showing PR and SD. We also reported in 2006 the results of Phase I/II clinical trials in which 58 patients with advanced metastatic hormone refractory prostate cancer (HRPC) received a personalized peptide vaccination in combination with a low dose of estramustine phosphate (29). We found that 14 of the 58 patients showed a more than 50% decline in serum levels of prostate-specific antigen, and a positive immune response after the vaccination was an independent predictor of long overall survival (OS) (P = 0.0185).
Bolonaki et al. (30) reported that a Phase II trial of telomerase reverse transcriptase (TERT) peptide vaccination for human leukocyte antigen (HLA)-A2+ advanced non-small cell cancer patients resulted in a longer OS in the immunological responders (n = 16) than in the non-responders (n = 5) (P = 0.012). Domchek et al. (31) also reported the results of a Phase I/II trial of TERT peptide vaccination of HLA-A2+ metastatic breast cancer patients. The median overall survival (MST) of the nine patients showing the hTERT-specific T cell responses was 32.2 months, whereas that of the seven patients showing no/low responses was 17.5 months (P = 0.03).
At the 2008 meeting of American Society of Clinical Oncology, Becker et al. (32) reported the results of a Phase I/II trial of a survivin-based peptide vaccine for therapy-resistant advanced cancer patients (n = 79). Immune boosting was seen in 50% of the vaccinated patients. ORs were observed in six patients [7.6%, three complete response (CR) and three PR], and the patients showing CR, PR and SD were restricted to immunological responders. At the 2008 meeting of the World Cancer Congress, we reported the results of Phase I/II studies of 211 standard therapy-resistant cancer patients who received personalized peptide vaccinations (33). Increased levels of CTL precursors and IgG responses to the vaccinated peptides were observed in 131 of 199 (66%) patients and in 140 of 205 (68%) patients tested, respectively. OR was observed in 26 patients (12.3%). The MST in all patients was 12 months, including 25 months in HLA-A2+ HRPC patients. A positive immune response after the vaccination was an independent predictor of long OS (P = 0.0129). This personalized approach, although requiring screening of immune responses, could boost both potent CTL and antibody responses reactive to multi-peptides in the patients. Two representative cases (HRPC and pancreatic cancer) are shown in Fig. 1. Fifty- to 1000-fold increments of peptide-specific IgG against multiple peptides were found in the post-vaccination plasma, indicating that the vaccination boosted the multi-clonal expansion of T cells and B cells. Barve et al. (34) recently reported the promising results of a Phase II trial of a 10-epitope peptide vaccine (IDM-2101) for metastatic non-small lung cancer with 1-year survival of 60% and median survival of 17.3 months. Survival was longer in patients demonstrating an immune response to epitope peptides (P < 0.001) regardless of rare ORs (2 of 63 cases).
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These results indicate that clinical trials of peptide vaccines for cancer patients who were non-responsive to standard therapy are beginning to show improved clinical benefits, along with peptide-specific immunological markers. Randomized Phase III trials with a primary endpoint of OS would be the next and final step for approval of peptide-based cancer vaccines for advanced cancer patients.
Trials for patients after removal of cancer
Clinical studies for selected patients expressing particular antigens have had interesting clinical outcomes (Table 1). A Phase II trial of epidermal growth factor receptor variant III (EGFRvIII)-specific peptide (CDX-110) combined with temozoromide was conducted for patients (n = 21) with newly diagnosed, EGFRvIII+ glioblastoma multiforme (35). It is of note that the specific immune responses were noted in all the evaluable patients, with a median progression-free survival (PFS) of 16.6 months. Similarly, a small-scale Phase II trial of a mutant ras peptide (13-mer) corresponding to the ras mutation of pancreatic or colorectal tumors reported a marginally significant difference (P = 0.043) in the OS between the five responders and six non-responders (36). This type of peptide vaccine, however, is applicable only for selected patients whose samples can be tested for positive antigen expression, and thus might be difficult to develop at a commercial level.
In the past decade, many peptide vaccine trials have been conducted in patients with malignant melanoma, a cancer resistant to chemotherapy, in an adjuvant setting, but these trials have reported no clear clinical outcomes or immunological biomarkers. Although more recent trials have begun to identify immunological markers correlating with clinical responses, the association remains marginal (Table 1). A Phase II trial of multiple melanoma-associated peptide vaccine for Stages IIc to IV melanoma patients showed a probability of longer disease-free survival (DFS) in melanoma patients (n = 34) who developed a T cell response specific to at least one of the vaccinated peptides when compared with the DFS in patients (n = 14) who had no T cell response (P = 0.041) (37). A similar marginal correlation was reported in the Phase II trial of multiple melanoma-associated peptide vaccine for Stages IIc to IV melanoma patients with regard to relapse-free survival (RFS) between the patients (n = 33) who had a T cell response to at least one of the vaccinated peptides and the patients (n = 17) who had no T cell response (P = 0.042) (38). To our knowledge, however, there has been no report showing evidence of clinical benefit for the entire melanoma patients who received the peptide vaccination. Thus, in order to achieve clinical efficacy, it might be necessary to take several different approaches when using peptide-based vaccinations for malignant melanoma patients, such as combined use of interleukin-2 (39), pre-screening of peptides suitable for each patient or a change from the currently used melanoma or cancer-testis antigen-related peptides to other peptides.
Dendritic Cell Vaccines
Many clinical trials of dendritic cell (DC)-based vaccinations using autologous DC and tumor-associated antigens have been conducted to assess the ability of these vaccines to induce clinical responses in cancer patients. In a review by Engell-Noerregaard et al. (40), 57 of 626 malignant melanoma patients (9%) showed ORs (20 CR and 37 PR) when treated with the DC-based vaccinations, but no significant correlations were noted between those ORs and the tested parameters. de Vries et al. (41) reported a correlation between the presence of peptide-related T cells in the delayed-type hypersensitivity (DTH)-infiltrating lymphocytes (DIL) of Stage IV melanoma patients and a prolonged PFS. The median PFS of 8 patients with tumor-reactive T cells in the DIL was 17 months, whereas that of 18 patients without them was only 2 months (P = 0.0012) (41). In addition, a correlation was found between DTH-positive responses against tumor lysate and post-vaccination survival in the other trial (42). The post-vaccination survival of 11 patients with DTH-responses was 17.2 months, whereas that of 9 patients without them was 8.6 months (P = 0.026). These results suggest that T cell responses at skin sites play an important role for OS, but not for tumor reduction, although only a portion of patients showed the reactions and thus overall benefits might not be provided by the present protocols of the DC-based vaccine for melanoma patients.
The Phase III clinical trials of DC-based vaccinations for asymptomatic metastatic HRPC patients conducted by the Dendrion Corporation (Seattle, WA, USA) demonstrated a significantly longer OS in treated patients when compared with those receiving the placebo (43). MST was 25.9 months for the patients receiving a DC-like fraction enriched from autologous peripheral blood, pulsed with a prostate acid phosphatase/granulocyte macrophage-colony stimulating factor (GM-CSF) fusion protein, whereas it was 21.4 months for the patients receiving placebo (P = 0.01, log-rank test). This study also had no biomarkers for measuring the clinical benefits in the treated patients.
Collectively, these results indicate that DC-based vaccination could be a promising treatment modality for various cancers, but multiple hurdles (reliable biomarkers, vaccine standardization and complicated protocols often resulting in conflicting outcomes, labor intensity, time consumption and high cost) must be cleared before the development of an affordable DC-based vaccination that can be used worldwide.
Heat Shock Protein
The first autologous heat shock protein (HSP) vaccine introduced in clinical trials was Oncophage (HSP-peptide complex 96, HSPPC-96; Antigenics Inc., Levington, MA, USA). Since then, autologous HSP vaccines have been used for various types of cancer patients, but consistent clinical benefits have not yet been reported (44). Twenty-one of 61 metastatic kidney cancer patients who received Oncophage vaccine responded to it with a median PFS time of 18 weeks (45). A Phase III trial of Oncophage for kidney cancer showed a 45% improvement in recurrent-free survival associated with Oncophage in a well-defined subgroup of earlier-stage (better-prognosis) patients, although a significant improvement was not observed in the overall patients’ population (46). Oncophage was recently (May 2008) approved in Russia for the treatment of kidney cancer patients at intermediate risk for disease recurrence.
At the present time, there are conflicting opinions with regard to the clinical effectiveness of HSP-based vaccines (44). Therefore, more clinical trials of HSP-based cancer vaccines will be needed before such vaccination can become a clinically effective treatment modality for all kidney cancer patients or other types of cancer patients.
Whole-Cell Vaccines
Autologous tumor cells have been used as cancer vaccines for a long time, and several trials have shown clinical responses in the initial clinical studies (47–52). Accordingly, some of these vaccines have been entered into randomized Phase III trials (53–56), but none of them has shown significant efficacy in the randomized Phase III trials. The single exception was a Phase III trial of autologous renal tumor cell vaccination after radical nephrectomy with a primary endpoint of PFS (55). In this trial, the 5-year PFS rate for the vaccination group (n = 177) and the control group (n = 202) were 77.4% and 67.8%, respectively (P = 0.0204). A similar trial, however, resulted in no significant differences (57).
Because of the difficulty of producing autologous tumor cell vaccines, allogeneic tumor cell-based vaccines have been under clinical trial (43,58–60). To date, however, most of the results have been disappointing. In one randomized trial, there was no significant difference in RFS between patients treated with allogeneic melanoma cells and adjuvant DETOX and a control group (61). There was also no significant difference in OS between patients receiving allogeneic melanoma cells with BCG (called Canvaxin) and those receiving BCG alone in Phase III trials (62), although promising clinical outcomes were obtained at the Phase II trial with DTH response as a biomarker (58). Another hopeful case was the Phase II GVAX trials for prostate cancer patients, which showed promising clinical outcomes (60). Prostate GVAX consists of two prostate cancer cell lines (LNCaP and PC-3), each of which has been genetically modified to secrete GM-CSF and lethal irradiation. One of the two Phase III randomized studies, Prostate GVAX and docetaxel versus docetaxel plus prednisone for symptomatic metastatic prostate cancer patients, was recently terminated since the interim analysis revealed worse survival in the GVAX group (home page from Cell Genesys, Inc., San Francisco, CA, USA). The other Phase III randomized study, Prostate GVAX versus docetaxel plus prednisone for asymptomatic metastatic prostate cancer patients, has also been terminated on 16 October 2008 because of its expected futility with regard to the primary endpoint (OS).
One of the reasons for the disappointing outcome of whole tumor cell vaccines in the Phase III trials might be that whole tumor cells, either autologous or allogeneic tumor cells, are not a suitable source of therapeutic cancer vaccine for all cancer patients, but rather suppress anti-tumor responses in some advanced cancer patients by inducing irrelevant immunity. Indeed, we previously reported that a non-personalized peptide vaccine resulted in a shorter survival of advanced cancer patients whose pre-vaccination peripheral blood mononuclear cells had no responses to the vaccinated peptides in association with the immune suppression to the pre-existing host responses (63,64).
Collectively, these results do not suggest a very bright future for whole tumor cell vaccines at the present stage, although this type of treatment certainly has had clinical benefits for a small number of cancer patients. Finding a biomarker to predict responders might make whole tumor cell vaccines more clinically effective.
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CONCLUSION |
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TOPAbstractCANCER VACCINES FOR PREVENTING...THERAPUTIC CANCER VACCINESCONCLUSIONFundingConflict of interest statementReferences |
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We anticipate a wave of cancer vaccine approvals in the next 5–6 years, primarily due to recent advances in the clinical trials of cancer vaccines, as described above. Even so, approval of the first peptide vaccine would have been delayed 23 years since the 1990 discovery, by Boon and co-workers (65), of a complementary DNA (cDNA)-expression cloning technique to identify tumor-rejection antigens, just as approval of the first monoclonal antibody, Rituximab (66), came 23 years after the 1975 discovery of a monoclonal antibody technique by Kohler and Milstein.
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Funding |
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TOPAbstractCANCER VACCINES FOR PREVENTING...THERAPUTIC CANCER VACCINESCONCLUSIONFundingConflict of interest statementReferences |
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This study was supported in part by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (no. 12213134 to K.I.), from the Research Center for Innovative Cancer Therapy of the 21st Century COE Program for Medical Science, and by the Toshi-area program from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.
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Conflict of interest statement |
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TOPAbstractCANCER VACCINES FOR PREVENTING...THERAPUTIC CANCER VACCINESCONCLUSIONFundingConflict of interest statementReferences |
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The author, Kyogo Itoh, is a Chief Scientific Advisor for Green Peptide Company, Ltd. The author, Akira Yamada, is an Executive Officer for Green Peptide Company, Ltd.
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Acknowledgments |
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The authors thank Ms Sachika Notomi and Ms Mayumi Furumura for help in the preparation of the manuscript.
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References |
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