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Abstract

  1. Top of page
  2. Abstract
  3. Peptide vaccines
  4. Rationale for personalized peptide vaccines
  5. Rationale of combination therapy
  6. Clinical outcome of classical (non-personalized) cancer vaccines
  7. Clinical outcome of personalized peptide vaccines
  8. Personalized peptide vaccine combined with chemotherapy
  9. Conclusion
  10. References

Therapeutic cancer vaccines have enjoyed little success so far, although many clinical trials have been conducted. Therefore, the creation of new protocols capable of inducing an objective response is required. We examined two of these protocols in the present review. The first is a personalized protocol to take into account the immunological diversity of cytotoxic T lymphocyte responses among patients. The second is a combination therapy designed to adapt to the presence of major histocompatibility complex (MHC)-loss cancer cells. The objective response rates of our classical (non-personalized) peptide vaccines were 0%, whereas that of personalized vaccines was 11.1% in the total advanced cancers and ≥20% in malignant glioma and cervical cancers, respectively. A ≥50% decrease in serum prostate-specific antigen (PSA) was seen in 8.7% of advanced hormone refractory prostate cancer patients by personalized vaccination alone, whereas such a decrease was seen in 54% of patients when the personalized vaccination was combined with a low dose of estramustine. Based on these experiences, we propose a personalized peptide vaccine combined with chemotherapy as a new treatment modality for cancers. (Cancer Sci 2006; 97: 970–976)

Therapeutic cancer vaccines have become a therapeutic option because tumor-associated antigens recognized by tumor-reactive cytotoxic T lymphocytes (CTL) have been identified during the last two decades.(1–3) In fact, a large number of clinical trials for cancer vaccines have been carried out worldwide.(4) Among the vaccines tested, peptide vaccines have an advantage for the treatment of cancers, because peptides are non-biological chemicals and can be synthesized at an industrial scale under the current good manufacturing practice conditions. In contrast, cell-based vaccines, such as tumor-cell vaccines or peptide-pulsed Dendritic cells (DC) therapies, have several disadvantages, including: limited cell sources for each patient; difficulties in maintaining uniform vaccine quality; labor intensity; and high production costs. Consequently, the present review article focuses mainly on peptide-based cancer vaccines, providing both basic and clinical information in order to facilitate the development of therapeutically effective cancer vaccines.

Peptide vaccines

  1. Top of page
  2. Abstract
  3. Peptide vaccines
  4. Rationale for personalized peptide vaccines
  5. Rationale of combination therapy
  6. Clinical outcome of classical (non-personalized) cancer vaccines
  7. Clinical outcome of personalized peptide vaccines
  8. Personalized peptide vaccine combined with chemotherapy
  9. Conclusion
  10. References

Van der Bruggen et al. first reported a cDNA-expression cloning technique to identify genes and peptides of tumor-associated antigens in 1991.(1) Subsequently, a technique using autologous antibody and a reverse immunology technique was introduced for the identification of genes and peptides recognized by the host immune system.(2,3) These advanced techniques have provided a large number of antigens and peptides applicable as cancer vaccines. Peptides used as cancer vaccines usually consist of nine amino acids capable of binding to a particular major histocompatibility complex (MHC) class 1A antigen with the ability to activate CTL reactive to tumor cells in an MHC-restricted fashion (Fig. 1). Activated CTL destroy cancer cells, but not normal cells. A peptide suitable for the individual patient is generally mixed with an oil-adjuvant followed by subcutaneous administration into the upper arm, thigh or other location every 7–14 days at an outpatient clinic (Fig. 2). The injected peptide is captured by antigen presenting cells (APC), which in turn move to regional lymph nodes. Soon after (within several days) they present the loaded peptides to the circulating CTL, which possess T-cell receptors (TCR) specific to the corresponding peptide (Fig. 3). However, the chance of presentation is very small, as the frequency of peptide-specific CTL precursors is usually less than 1/10 000.(5) CTL recognizing a peptide on APC become activated within 7 days in association with clonal expansion in the nodes. These activated CTL come out through lymph nodes or blood circulation, migrate and infiltrate into tumor sites, recognize the corresponding peptide–MHC complex on cancer cells, and eliminate cancer cells, which in turn results in tumor regression if a large number of cancer cells is eliminated (Fig. 3).

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Figure 1. The general concept of peptide vaccine. Peptides consist of nine amino acids that bind to MHC-class I antigens and are recognized by cytotoxic T lymphocytes (CTL). Peptide-activated CTL destroy cancer cells, but do not destroy normal cells. Safety of peptide vaccination has been confirmed. Peptide suitable to an individual patient is mixed with oil-adjuvant and vaccinated subcutaneously into the upper arm every 7 to 14 days at outpatient clinic.

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Figure 2. A schematic image of peptide vaccination.

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Figure 3. Hurdles for tumor regression. A route from peptide vaccination to tumor regression along with the expected hurdles for tumor regression is shown. CTL, cytotoxic T lymphocyte; MHC, major histocompatibility complex.

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Rationale for personalized peptide vaccines

  1. Top of page
  2. Abstract
  3. Peptide vaccines
  4. Rationale for personalized peptide vaccines
  5. Rationale of combination therapy
  6. Clinical outcome of classical (non-personalized) cancer vaccines
  7. Clinical outcome of personalized peptide vaccines
  8. Personalized peptide vaccine combined with chemotherapy
  9. Conclusion
  10. References

There are at least four different hurdles to overcome for tumor regression by peptide vaccines (Fig. 3). The first hurdle is how to choose a suitable peptide for the individual cancer patient. A peptide selected by the in vitro techniques shown above may not necessarily be suitable for inducing tumor regression in all patients. No animal models are presently available to solve this issue, primarily because human TCR and MHC differ largely from those of animals. Translational clinical research is expected to solve this issue, but a definite answer has not yet been obtained from clinical studies conducted previously, primarily because such studies have not provided clinical benefit for patients receiving the vaccination.(4)

After a peptide has been determined to be suitable by translational clinical research, the second hurdle is how to administer the peptide capable of inducing CTL activation strong enough to eliminate cancer cells. The magnitude of activation could be in part dependent on the frequency of peptide-specific CTL precursors in the circulation. We reported previously that the frequency of peptide-specific CTL precursors in peripheral blood mononuclear cells (PBMC) was usually less than 1/100 000 when classical (non-personalized) peptide vaccination was carried out for advanced cancer patients.(6) This could be due to the fact that the number of T repertoires recognizing antigenic peptides exceeds 1017.(7) We also reported that cancer patients had at least several types of CTL precursors with a frequency of 1/3000 to 1/10 000 reacting to certain peptides in prevaccination PBMC when measured using a new and simple CTL precursor assay.(5,8–10) Vaccination of such peptides with higher levels of CTL precursors in prevaccination PBMC might induce stronger and faster activation of CTL compared to that with rare CTL precursors. Therefore, one solution to overcome this hurdle may be to take into account the immunological diversity of individual patients, and to measure CTL precursors in prevaccination PBMC followed by administration of peptides with higher CTL precursor frequency (personalized peptide vaccination). To test this hypothesis, we conducted a series of clinical trials of personalized peptide vaccinations for advanced cancer patients, and reported that personalized peptide vaccinations achieved rapid and strong activation of CTL with definite clinical benefits for certain cancer patients.(8–10)

Rationale of combination therapy

  1. Top of page
  2. Abstract
  3. Peptide vaccines
  4. Rationale for personalized peptide vaccines
  5. Rationale of combination therapy
  6. Clinical outcome of classical (non-personalized) cancer vaccines
  7. Clinical outcome of personalized peptide vaccines
  8. Personalized peptide vaccine combined with chemotherapy
  9. Conclusion
  10. References

The third hurdle to overcome for tumor regression by peptide vaccine is how to make the activated CTL infiltrate into the tumor sites (Fig. 3). Solid cancers usually form a tumor wall that inhibits infiltration of immunocompetent cells, including CTL and natural killer cells.(11) Therefore, a cancer vaccine combined with one of the other treatment modalities that facilitate infiltration of immunocompetent cells is recommended to allow easy infiltration of CTL. Alternatively, cancers having no tumor walls, such as scirrhous-type gastric cancers(12) and glioblastoma multiforme,(10) could be appropriate targets for a cancer vaccine. Administration of a peptide vaccine to cancer patients after curative surgery would also be an attractive protocol to overcome this hurdle.

The last hurdle is how to eliminate MHC class 1-loss cancer cells, because a large population (30–60%) of cancer cells do not express MHC class 1 molecules, which are crucial for CTL-mediated elimination of cancer cells.(13) This problem could be overcome by the combined use of a peptide vaccine and either chemotherapy, cytokine therapy capable of activating natural killer cells and macrophages, or one of the other treatment modalities that do not affect MHC expression on cancer cells. Cancer is an extremely complex and heterogeneous disease that exhibits a high level of robustness against a range of both host-defense systems and therapeutic efforts.(14) Loss of MHC class I expression is considered to be a major mechanism of tumor cell escape from immune surveillance,(13) whereas the appearance of multidrug resistance is the major mechanism of tumor cell resistance to chemotherapy.(15) One of the approaches to overcome cancer robustness might be the design of a new combination therapy in which each modality has the ability to impose independent selective pressures to acquired mutations of cancer. Indeed, a personalized peptide vaccine combined with a low dose (280 mg/day) of estramustine phosphate (EMP), a stable conjugate of estradiol and nitrogen mustard that possesses antimitotic properties,(16) for advanced hormone refractory prostate cancer (HRPC) resulted in favorable clinical responses.(17,18) Chemotherapeutic drugs generally suppress immune function, and each drug has a different level of immune suppression. Therefore, for combination therapy, it is pivotal to determine a maximum dose of chemotherapeutic agent that does not suppress peptide-induced immune activation (a maximum non-immunosuppressive dose). In our experience, a full dose of EMP (560 mg/day), but not a half dose, suppressed peptide-induced immune activation.(17,18) Thus, 280 mg/day of EMP was set as the maximum non-immunosuppressive dose for combination therapy with a personalized peptide vaccine for advanced HRPC.

Clinical outcome of classical (non-personalized) cancer vaccines

  1. Top of page
  2. Abstract
  3. Peptide vaccines
  4. Rationale for personalized peptide vaccines
  5. Rationale of combination therapy
  6. Clinical outcome of classical (non-personalized) cancer vaccines
  7. Clinical outcome of personalized peptide vaccines
  8. Personalized peptide vaccine combined with chemotherapy
  9. Conclusion
  10. References

Rosenberg et al. summarized the clinical responses of peptide-based vaccine therapy in 2004.(4) Objective response rates for peptide vaccines and viral vaccines administered to patients with metastatic cancers at the National Cancer Institute in the USA were 2.9% (11 of 381 cases) and 1.9% (three of 160), respectively. In a subsequent study, those trials and other trials using cell-based therapies were analyzed collectively, giving a combined objective response rate of 3.8% (29 of 765 patients, 36 protocols).(5) Similarly, no objective response was obtained as determined by the Response Evaluation Criteria in Solid Tumors in our peptide vaccine trials for advanced solid cancers at Kurume University (0 of 38; Table 1).(6,9,18,19) In addition, a large number of clinical trials of peptide-based cancer vaccines are ongoing as translational clinical research (details are available at http://www.cancer.gov/search/clinicaltrials/ and http://www.clinicaltrial.gov/). At least 12 protocols of peptide-based vaccines against various types of cancers had been carried out by industrial companies by the end of February 2006 (details available at http://www.sabin.org/cvc_news.htm). None of these trials took into account the immunological diversity of CTL responses among patients, despite the fact that the number of T-cell repertoires recognizing antigenic peptides is known to exceed 1017.(7) It is of note that no peptide-based vaccine has obtained new drug approval at the present time. Collectively, these results indicate that, at the present time, the classical types of cancer vaccines, including peptide vaccines, do not have a promising future as new treatment modalities for cancer.

Table 1. Clinical outcome of peptide vaccine for advanced solid cancer
ProtocolCancerHLA restrictionNo. vaccinated peptidesTotal no. patientsBest clinical response by RECISTReference
PRSDPD
  • Pre-vaccination peripheral blood mononuclear cells (PBMC) were provided to examine cellular immune responses to 14 or 16 peptide panels in HLA-A24+ or HLA-A2+ patients, respectively. The positively identified peptides (up to four per patient) were subsequently chosen for vaccination.

  • Pre-vaccination PBMC and plasma were provided to examine cellular and humoral immune responses to 25 or 23 peptide panels in HLA-A24+ or HLA-A2+ patients, respectively. The positively identified peptides (up to four per patient) were subsequently chosen for vaccination. HLA, Human Leukocyte antigen; PD, progressive disease; PR, partial response; RECIST, response evaluation criteria in solid tumors; SD, stable disease.

Classical (non-personalized)
 LungHLA-A242110 2 9 6
StomachHLA-A24, -A24 80 4 427
ColorectalHLA-A242120 11119
Uterine (cervix)HLA-A24, -A22–4 70 2 5 9,27
Total  380 929 
PersonalizedLungHLA-A24, -A24100 7 3 8
StomachHLA-A244110 5 612
ColorectalHLA-A24, -A24101 1 822
PancreasHLA-A24, -A24 90 3 623
Uterine (Cervix)HLA-A24, -A24 42 1 1 9
Skin (melanoma)HLA-A244 70 3 424
Brain (grade 3/4)HLA-A244215 8 810
Total  7282836 

Clinical outcome of personalized peptide vaccines

  1. Top of page
  2. Abstract
  3. Peptide vaccines
  4. Rationale for personalized peptide vaccines
  5. Rationale of combination therapy
  6. Clinical outcome of classical (non-personalized) cancer vaccines
  7. Clinical outcome of personalized peptide vaccines
  8. Personalized peptide vaccine combined with chemotherapy
  9. Conclusion
  10. References

The characteristics of cancer cells and immunological status against cancers differ widely among patients, even among those with the same histological types of cancer and identical MHC types. Subsequently, several types of personalized cancer vaccines are currently undergoing clinical trials. The first type uses autologous tumors or their components as vaccine sources, but no clear data showing clinical benefits for cancer patients have yet been reported.(20,21) In the second type of personalized vaccine, antigens or peptides are chosen by measuring their expression in autologous tumors. However, because the acquisition of appropriate cancer specimens is often very difficult, this type of protocol is not used widely.

The third type of vaccine attempts to account for the immunological diversity of individual patients. In this protocol, CTL precursors are measured in prevaccination PBMC, and then peptides for which higher CTL precursor frequencies are detected are administered (personalized peptide vaccine). As a translational clinical study, we conducted a series of clinical trials of personalized peptide vaccines for advanced cancer patients.(8–10,12,22–26) Pre-vaccination PBMC and plasma were provided to examine cellular and humoral immune responses to 14–25 or 16–23 peptide panels in HLA-A24+ or HLA-A2+ patients, respectively. The positively identified peptides (up to four per patient) were subsequently chosen for vaccination. One representative case of a patient with advanced HRPC is given in Fig. 4. Each of the 16 peptides was investigated for reactivity to prevaccination PBMC and plasma. PSA-248, PTHrP-102 and Lck-486 peptides were recognized by both the CTL (cut-off level: 50 ng/mL of peptide-specific interferon-γ production by the peptide-stimulated PBMC) and IgG (cut-off level: 5 fluorescence intensity units of peptide-specific IgG), whereas the SART3-109 peptide was recognized by IgG at the highest level. Therefore, these four peptides were administered to the patient as vaccines. The same assay was repeated using the postvaccination (6th) vaccination to evaluate immune responses to the vaccinated peptides. The scale of the horizontal line was changed due to the augmentation of peptide-specific CTL activity (two-fold) and the increased levels of antibody (IgG) reactive to the peptide (200-fold). Post-vaccination PBMC showed increased levels of CTL activity in response to SART3 and Lck peptides, whereas postvaccination plasma showed increased levels of IgG reactive to PSA-248 (750-fold increase), PTHrP-102 (730-fold) and SART3-109 (67-fold) peptides. As shown in this representative case, the personalized peptide vaccination achieved activation of both cellular and humoral responses to at least one of the four vaccinated peptides in the majority of patients, with definite clinical benefits for malignant gliomas and cervical cancers.(9,10) Kinetic studies of magnetic resonance imaging of four partial response (PR) cases with advanced malignant glioma are shown in Fig. 5.(10) An overall summary of the clinical responses of our personalized peptide vaccinations is given in Table 1. The clinical responses of advanced solid cancers (n = 72) to the personalized peptide vaccination consisted of eight PR (11.1%), 28 stable disease (SD) (38.9%) and 36 progressive diseases (PD) (50%), with an overall disease control (PR + SD) rate of 50%. There was no objective response for advanced lung, stomach or pancreatic cancer patients, or for metastatic melanoma patients, whereas the objective response was seen in advanced malignant glioma patients (two cases of grade 3 and three cases of grade 4 glioma), uterine cervical cancer and colon cancer patients. In contrast, the clinical responses of advanced solid cancers (n = 38) to our non-personalized peptide vaccination consisted of no PR, nine SD and 29 PD, with an overall disease control rate as low as 23.7% (Table 1). The overall survival of patients with advanced cervical or gastric cancer (scirrhous types) who received personalized peptide vaccination was significantly longer than that of these patients (Fig. 6).(27) In addition, measurement of cellular and humoral responses to the vaccinated peptides in the postvaccination samples was well correlated with the clinical responses if the patients received personalized peptide vaccination, but not if they received classical (non-personalized) types of peptide vaccination. For example, both CTL and IgG responses specific to the vaccinated peptides in the postvaccination samples were activated in all PR cases, a CTL response alone was activated in all SD cases, and no response was seen in all PD cases (Fig. 7).(10) Both the classical and personalized peptide vaccines were well tolerated, with the major adverse effects being a grade 1 or 2 inflammatory skin reaction at the injection site.

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Figure 4. Screening of peptides and evaluation of immune responses. Pre-vaccination peripheral blood mononuclear cells (PBMC) and plasma were provided to examine cellular and humoral immune responses to 16 peptide panels in a HLA-A24+ patient with advanced hormone refractory prostate cancer (HRPC). Namely, each of the 16 peptides was investigated for reactivity to prevaccination PBMC and plasma. PSA-248, PTHrp-102 and LCk-486 peptides were recognized by both the cytotoxic T lymphocytes (CTL) (cut-off level: 50 ng/mL of peptide-specific interferon-γ production by the peptide-stimulated PBMC) and IgG (cut-off level: 5 fluorescence intensity units of peptide-specific IgG), whereas SART3-109 peptide was recognized by IgG at the highest level. Therefore, these four peptides administered to the patient as vaccines. The same assays were conducted using the samples after the sixth vaccination to evaluate immune responses to the vaccinated peptides. The scale of the horizontal line was changed due to the augmentation of peptide-specific CTL activity (two-fold) and IgG reactive to the peptide (200-fold).

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Figure 5. Kinetic magnetic resonance imaging examinations of four partial response (PR) cases. Patients were assigned a response category according to the Response Evaluation Criteria in Solid Tumors. The details have been reported previously.(10)

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Figure 6. Overall survival of patients under the two vaccination regimens for cervical cancer and scirrhous-type gastric cancer patients. Details of the results have been reported previously.(11,12,20)

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Figure 7. Kinetic studies of immune responses. Kinetic studies of both the cellular (○) and humoral (•) responses to the vaccinated peptides were measured in advanced malignant glioma patients under the personalized peptide vaccination.(10) PD, progressive disease; PR, oartial response; SD, stable disease.

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Collectively, these results indicate that the personalized peptide vaccine is superior to the classical type of peptide vaccine for advanced solid cancers, but it is not sufficient to provide definite clinical benefits for the majority of advanced solid cancers, with the exception of malignant gliomas or uterine cervical cancers.

Personalized peptide vaccine combined with chemotherapy

  1. Top of page
  2. Abstract
  3. Peptide vaccines
  4. Rationale for personalized peptide vaccines
  5. Rationale of combination therapy
  6. Clinical outcome of classical (non-personalized) cancer vaccines
  7. Clinical outcome of personalized peptide vaccines
  8. Personalized peptide vaccine combined with chemotherapy
  9. Conclusion
  10. References

As shown above, personalized peptide vaccines provide limited clinical benefits for the major solid cancers. This failure is partly attributed to the fact that solid cancers usually form a tumor wall that inhibits the infiltration of immune-competent cells, including CTL and natural killer cells.(11) It is also partly due to the fact that a large population of cancer cells does not express MHC class 1 molecules, which are crucial for CTL-mediated recognition of cancer cells.(13) These two hurdles could be partly overcome by the combined use of a peptide vaccine and a chemotherapy that is effective against the MHC class 1-loss tumor cells located inside the tumor wall. To test this hypothesis, we conducted clinical trials in which personalized peptide vaccinations were combined with a half dose (280 mg/day) of EMP for patients with advanced HRPC. It is well known that a large population (30–60%) of prostate cancer cells does not express MHC class 1 molecules.(13) EMP is generally used as a second-line treatment for HRPC, and has a 30–40% clinical response rate as determined by measuring the serum prostate-specific antigen (PSA) level.(15) In our study, we used a half-dose of EMP because a full dose (560 mg/day) has been shown to suppress both cellular and humoral responses induced by personalized peptide vaccines.(17,18) As a result, this combination therapy achieved activation of both cellular (12 of 19 cases, 63%) and humoral (20 of 23 cases, 87%) responses to the vaccinated peptides in the majority of patients, along with definite clinical benefits for 14 of 26 cases who showed a ≥50% decline in serum PSA level (Table 2).(17,18) The quality of life (QOL) outcomes of these patients under combined therapy were evaluated using a Functional Assessment of Cancer Therapy for Prostate Cancer (FACT-P) questionnaire (Fig. 8).(18) All five QOL factors were maintained throughout the combination therapy for up to the 12th vaccination. In contrast, only two of 23 cases achieved a ≥50% decline in serum PSA level in response to the administration of a personalized vaccination alone (Table 2). The magnitude of increase in cellular (10 of 22 cases, 45%) and humoral (14 of 22, 64%) responses by personalized vaccination alone was somewhat smaller than that (63% and 87%, respectively) by combination therapy. It is worth noting that the majority of patients who were treated either with combination therapy or peptide vaccine alone had shown no improvement with prior therapy with EMP (560 mg/day) as a second-line treatment for HRPC. Both the combination protocol and personalized peptide vaccine alone were well tolerated, with the major adverse effects being a grade 1 or 2 inflammatory skin reaction at the injection site, although grade 3 arrhythmia or cerebral infarction was seen in each case of the combination.

Table 2. Peptide vaccine for advanced hormone refractory prostate cancer
ProtocolHLA restrictionTotal no. patientsIncreased immune responseDecrease in PSA levelReference
CTLIgG≥50%§<50% (none)
  • Fourteen of these patients had failed to respond to prior estramustine phosphate (EMP) therapy (560 mg/day) alone as the second line treatment for hormone refractory prostate cancer (HRPC). Pre-vaccination peripheral blood mononuclear cells (PBMC) were provided to examine cellular immune responses to 14 or 16 peptide panels in HLA-A24+ or HLA-A2+ patients, respectively. The positively identified peptides (up to four per patient) were subsequently chosen for vaccination.

  • Seventeen of these patients had failed to respond to prior EMP therapy (560 mg/day) alone as the second line treatment for HRPC. Pre-vaccination PBMC and plasma were provided to examine cellular and humoral immune responses to 16 or 16 peptide panels in HLA-A24+ or HLA-A2+ patients, respectively. The positively identified peptides (up to four per patient) were subsequently chosen for vaccination.

  • §

    Αt least two consecutive prostate-specific antigen (PSA) tests for at least 4 weeks.

Personalized peptide vaccineHLA-A24, -A22210/22 (45%)14/22 (64%) 220 (15)18,25,26
Personalized peptide vaccine + 280 mg/day EMPHLA-A24, -A22612/19 (63%)26/23 (87%)1413 (3)17,18
image

Figure 8. Evaluation of percentage quality of life (QOL) scales. The QOL outcomes of advanced hormone refractory prostate cancer (HRPC) patients under the combined therapy were evaluated using the Functional Assessment of Cancer Therapy for Prostate Cancer (FACT-P) questionnaire.(18)

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All of these results indicate that the personalized peptide vaccination combined with a half dose of EMP is superior to the personalized peptide vaccination alone for advanced HRPC, and may provide definite clinical benefits for the vast majority of advanced HRPC patients.

Conclusion

  1. Top of page
  2. Abstract
  3. Peptide vaccines
  4. Rationale for personalized peptide vaccines
  5. Rationale of combination therapy
  6. Clinical outcome of classical (non-personalized) cancer vaccines
  7. Clinical outcome of personalized peptide vaccines
  8. Personalized peptide vaccine combined with chemotherapy
  9. Conclusion
  10. References

The lack of clinical efficacy of the cancer vaccines currently available underscores the need for profound changes in the application of this approach. One useful change might be a consideration of immunological diversity among patients, as well as a consideration of the difference in robustness among cancers. We have proposed the combination of a personalized peptide vaccine and chemotherapy. The following three points must be considered in order to realize clinical benefits from the use of peptide-based cancer vaccines for advanced cancer patients.

  • 1
    Screening of suitable peptides by translational clinical studies.
  • 2
    Development of a personalized regimen to increase the magnitude of T-cell activation at regional lymph nodes.
  • 3
    Use of a personalized peptide vaccine combined with chemotherapy for MHC-loss solid tumors after setting a maximum non-immunosuppressive dose of chemotherapeutic drug.

References

  1. Top of page
  2. Abstract
  3. Peptide vaccines
  4. Rationale for personalized peptide vaccines
  5. Rationale of combination therapy
  6. Clinical outcome of classical (non-personalized) cancer vaccines
  7. Clinical outcome of personalized peptide vaccines
  8. Personalized peptide vaccine combined with chemotherapy
  9. Conclusion
  10. References
  • 1
    Van Der Bruggen P, Traversari C, Chomez P et al. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 1991; 254: 16437.
  • 2
    Chen YT, Scanlan MJ, Sahin U et al. A testicular antigen aberrantly expressed in human cancers detected by autologous antibody screening. Proc Natl Acad Sci USA 1997; 94: 191418.
  • 3
    Kobayashi K, Noguchi M, Itoh K, Harada M. Identification of a prostate-specific membrane antigen-derived peptide capable of eliciting both cellular and humoral immune responses in HLA-A24+ prostate cancer patients. Cancer Sci 2003; 94: 6227.
  • 4
    Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: moving beyond current vaccines. Nat Med 2004; 10: 90915.
  • 5
    Hida N, Maeda Y, Katagiri K, Takasu H, Harada M, Itoh K. A simple culture protocol to detect peptide-specific cytotoxic T lymphocyte precursors in the circulation. Cancer Immunol Immunother 2002; 51: 21928.
  • 6
    Gohara R, Imai N, Rikimaru T et al. Phase I clinical study of cyclophilin B peptide vaccine for lung cancer patients. J Immunother 2002; 25: 43944.
  • 7
    Janeway CA, Shlomchik MJ, Travers P, Walport M. T cell receptor gene rearrangement. In: Janeway CA, Shlomchik MJ, Travers P, Walport, eds. Immunobiology, 6th edn. New York: Garland Science, 2004; 14954.
  • 8
    Mine T, Gouhara R, Hida N et al. Immunological evaluation of CTL precursor-oriented vaccines for advanced lung cancer patients. Cancer Sci 2003; 94: 54856.
  • 9
    Tsuda N, Mochizuki K, Harada M et al. Vaccination with pre-designated or evidence-based peptides for patients with recurrent gynecologic cancers. J Immunother 2004; 27: 607.
  • 10
    Yajima N, Yamanaka R, Mine T et al. Immunologic evaluation of personalized peptide vaccination for patients with advanced malignant glioma. Clin Cancer Res 2005; 11: 590011.
  • 11
    Itoh K, Platsoucas CD, Balch CM. Autologous tumor-specific cytotoxic T lymphocytes in the infiltrate of human metastatic melanomas. Activation by interleukin 2 and autologous tumor cells, and involvement of the T cell receptor. J Exp Med 1988; 168: 141941.
  • 12
    Sato Y, Shomura H, Maeda Y et al. Immunological evaluation of peptide vaccination for patients with gastric cancer based on pre-existing cellular response to peptide. Cancer Sci 2003; 94: 8028.
  • 13
    Janeway CA, Shlomchik MJ, Travers P, Walport M. Using the immune response to attack tumors. In: Janeway CA, Shlomchik MJ, Travers P, Walport, eds. Immunobiology, 6th edn. New York: Garland Science, 2004; 63042.
  • 14
    Kitano H. Cancer robustness: tumour tactics. Nature 2003; 426: 125.
  • 15
    Ueda K, Cardarelli C, Gottesman MM, Pastan I. Expression of full-length cDNA for the human MDR1 gene confers resistance to colchicines, doxorubicin, and vinblastine. Proc Natl Acad Sci USA 1987; 84: 30048.
  • 16
    Perry CA, McTavish D. Estramustine phosphate sodium. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in prostate cancer. Drugs Aging 1995; 7: 4974.
  • 17
    Noguchi M, Itoh K, Suekane S et al. Immunological monitoring during combination of patient-oriented peptide vaccination and estramustin phosphate I patients with metastatic hormone refractory prostate cancer. Prostate 2004; 60: 3245.
  • 18
    Noguchi M, Itoh K, Yao A et al. Immunological evaluation of individualized peptide vaccination with a low dose of estramustine for HLA-A24(+) HRPC patients. Prostate 2005; 63: 112.
  • 19
    Miyagi Y, Imai N, Sasatomi T et al. Induction of cellular immune responses to tumor cells and peptides in colorectal cancer patients by vaccination of SART3 peptides. Clin Can Res 2001; 7: 395062.
  • 20
    Lewis JJ. Therapeutic cancer vaccines: using unique antigens. Proc Natl Acad Sci USA 2004; 101 (Suppl. 2): 14 653–6.
  • 21
    Yamanaka R, Homma J, Yajima N et al. Clinical evaluation of dendritic cell vaccination for patients with recurrent glioma: results of a clinical phase I/II trial. Clin Cancer Res 2005; 11: 41607.
  • 22
    Sato Y, Maeda Y, Sasatomi T et al. A phase I trial of CTL-purecursor-oriented peptide vaccine for colorectal carcinoma patients. Br J Cancer 2004; 90: 133442.
  • 23
    Yamamoto K, Mine T, Katagiri K et al. Immunological evaluation of personalized peptide vaccination for patients with pancreatic cancer. Oncol Rep 2005; 13: 87483.
  • 24
    Tanaka S, Harada M, Mine T et al. Peptide vaccination for patients with melanoma and other types of cancers based on pre-existing peptide-specific cytotoxic T lymphocyte precursors in the periphery. J Immunother 2003; 26: 35766.
  • 25
    Noguchi M, Kobayashi K, Suetsugu N et al. Induction of cellular and humoral immune responses to tumor cells and peptides in HLA-A24 positive hormone-refractory prostate cancer patients by peptide vaccination. Prostate 2003; 57: 8092.
  • 26
    Noguchi M, Itoh K, Suekane S et al. Phase I trial of patient-oriented vaccination in HLA-A2-positive patients with metastatic hormone-refractory prostate cancer. Cancer Sci 2004; 95: 7784.
  • 27
    Mochizuki K, Sato Y, Tsuda N et al. Immunological evaluation of pre-designated vaccination of the peptides frequently vaccinated to cancer patients in an individualized peptide regimen. Int J Oncol 2004; 25: 12131.