RESUMO
A novel cancer vaccine consisting of 20 mixed peptides (KRM-20) was designed to induce cytotoxic T lymphocytes (CTL) against twelve different tumor-associated antigens. The aim of this phase II trial was to examine whether KRM-20 in combination with docetaxel and dexamethasone enhances the antitumor effects in patients with castration-resistant prostate cancer (CRPC). In this double-blind, placebo-controlled, randomized phase II study, we enrolled chemotherapy-naïve patients with CRPC from ten medical centers in Japan. Eligible patients were randomly assigned 1:1 centrally to receive either KRM-20 combined with docetaxel and dexamethasone (n = 25) or placebo with docetaxel and dexamethasone (n = 26). The primary endpoint was the difference in prostate-specific antigen (PSA) decline between each treatment. The rates of > 50% PSA decline in the two arms were similar (56.5% versus 53.8%; P = 0.851). Human leukocyte antigen (HLA)-matched peptide-specific immunoglobulin G (P = 0.018) and CTL (P = 0.007) responses in the KRM-20 arm significantly increased after treatment. The addition of KRM-20 did not increase toxicity. There were no between-group differences in progression-free or overall survival (OS). The addition of KRM-20 was safe, and similar PSA decline and HLA-matched peptide-specific CTL and IgG responses increased in combination with docetaxel and dexamethasone in CRPC patients. Subgroup analysis suggested that this treatment is favorable for CRPC patients with ≥ 26% lymphocytes or PSA levels of < 11.2 ng/ml, but further clinical trials comparing OS are required.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Vacinas Anticâncer/administração & dosagem , Calicreínas/sangue , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/terapia , Linfócitos T Citotóxicos/imunologia , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/imunologia , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Docetaxel/administração & dosagem , Docetaxel/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Humanos , Infusões Intravenosas , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/imunologia , Neoplasias de Próstata Resistentes à Castração/mortalidade , Critérios de Avaliação de Resposta em Tumores Sólidos , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/efeitos adversos , Vacinas de Subunidades Antigênicas/imunologiaRESUMO
Peptide-based cancer vaccines are able to induce strong immune responses, but their clinical results are unsatisfactory. To determine clinically correlated peptides, we analyzed survival data from urological cancer patients treated by personalized peptide vaccination (PPV), in which different multiple peptides were used for individual patients based on human leukocyte antigen (HLA) type and pre-existing immunity. Survival data were obtained from a database of 265 urological cancer patients treated in 5 clinical PPV trials comprising 154 patients with castration-resistant prostate cancer (CRPC) and 111 patients with advanced urothelial cancer (UC). Expression of tumor-associated antigens (TAA) was evaluated in 10 prostate cancer tissues, 4 metastatic lymph nodes from prostate cancer, and 10 UC tissues using immunohistochemical staining. Clinical efficacy of individual peptides for overall survival was evaluated by the Cox proportional hazards regression model. All TAA coding candidate peptides used in PPV treatment were expressed in tumor cells from prostate cancer and UC samples except for p56Lck in both, and prostate-specific antigen (PSA), prostatic acid phosphatase (PAP) and prostate-specific membrane antigen (PSMA) in the UC samples. Patients with the following peptides had a significantly longer survival than patients without the peptides (hazard ratio <1.0, 95% confidence intervals <1.0 and P < .05): SART3-109, PTHrP-102, HNPRL-140, SART3-302 and Lck-90 in CRPC patients, and EGF-R-800, Lck-486, PSMA-624, CypB-129 and SART3-734 in advanced UC patients, respectively. Correlated peptides selected using both survival data and pre-existing immunity for PPV treatment may enhance the clinical benefits for urological cancer patients.
Assuntos
Vacinas Anticâncer/imunologia , Neoplasias Urológicas/terapia , Vacinação , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/análise , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Urológicas/imunologia , Neoplasias Urológicas/mortalidade , Vacinas de Subunidades Antigênicas/imunologiaRESUMO
This randomized phase II study investigated the immunological efficacy of herbal medicines (HM) using Hochu-ekki-to and Keishi-bukuryo-gan in combination with personalized peptide vaccination (PPV) for castration-resistant prostate cancer (CRPC). Seventy patients with CRPC were assigned to two arms; PPV plus HM or PPV alone. Two to four peptides were chosen from 31 peptides derived from cancer antigens for a s.c. injection of PPV given eight times according to the patient's human leukocyte antigen type and levels of antigen-specific IgG titer before PPV treatment. Peptide-specific CTL, IgG, regulatory T cells (Treg), monocytic myeloid-derived suppressor cells (Mo-MDSC), and interleukin-6 (IL-6) responses were measured before and at the eighth vaccination. Clinical outcomes were also analyzed. Combination therapy of PPV with HM was well tolerated without severe adverse events. There was no significant change in antigen-specific IgG, CTL, Treg or clinical outcomes. Combination therapy of PPV with HM stabilized the frequency of Mo-MDSC (1.91%-1.92%, P = 0.96) and serum levels of IL-6 (19.2 pg/mL to 16.1 pg/mL, P = 0.63) during the treatment. In contrast, the frequency of Mo-MDSC and levels of IL-6 in the PPV-alone group were significantly increased (0.91%-1.49% for Mo-MDSC and 9.2 pg/mL to 19.4 pg/mL for IL-6, respectively). These results suggest that the combined use of HM has the potential to prevent the immunosuppression induced by Mo-MDSC or IL-6 during immunotherapy. More research is needed to validate the findings of the present study.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Vacinas Anticâncer/administração & dosagem , Medicamentos de Ervas Chinesas/administração & dosagem , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Medicina de Precisão/métodos , Modelos de Riscos Proporcionais , Neoplasias de Próstata Resistentes à Castração/mortalidade , Vacinas de Subunidades Antigênicas/administração & dosagemRESUMO
This study investigated the applicability of personalized peptide vaccination (PPV) for patients with metastatic upper tract urothelial cancer (mUTUC) after failure of platinum-based chemotherapy. In this single arm, open-label, phase II clinical trial, patients with mUTUC received PPV at a single institution. Personalized peptide vaccination treatment used a maximum of four peptides chosen from 27 candidate peptides according to human leukocyte antigen types and peptide-reactive IgG titers, for six s.c. injections weekly as one cycle. The safety of PPV, as well as its influence on host immunity and effect on overall survival were assessed. Forty-eight patients were enrolled in this study. Personalized peptide vaccinations were well tolerated without severe adverse events. Median survival time was 7.3 months (95% confidence interval [CI], 5.3-13.1) with 13.0 months for patients receiving combined salvage chemotherapy (95% CI, 5.7-17.5) and 4.5 months for patients receiving PPV alone (95% CI, 1.7-10.1) (P = 0.080). Patients with positive CTL responses showed a significantly longer survival than patients with negative CTL responses (hazard ratio, 0.37; 95% CI, 0.16-0.85; P = 0.019). Multivariate Cox regression analysis showed that lower numbers of Bellmunt risk factors and lower levels of B-cell activating factor were significantly associated with favorable overall survival for patients under PPV treatment. This study indicated that PPV for patients with mUTUC after failure of platinum-based chemotherapy induced substantial peptide-specific CTL responses without severe adverse events and has the potential to prolong survival when combined with salvage chemotherapy. UMIN Clinical Trials Registry ID: 000001854.
Assuntos
Vacinas Anticâncer/uso terapêutico , Carcinoma de Células de Transição/terapia , Medicina de Precisão/métodos , Neoplasias da Bexiga Urinária/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células de Transição/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Terapia de Salvação/métodos , Vacinas de Subunidades Antigênicas/uso terapêuticoRESUMO
The HLA-A11 or -A33 allele is found in approximately 18% or 10% of the Asian population, respectively, but each of which is a minor allele worldwide, and therefore no clinical trials were previously conducted. To develop a therapeutic peptide vaccine for each of them, we investigated immunological responses of advanced cancer patients with the HLA-A11+ /A11+ (n = 18) or -A33+ /A33+ (n = 13) allele to personalized peptide vaccine (PPV) regimens. The primary sites of HLA-A11+/A11+ or -A33+/A33+ patients were the colon (n = 4 or 2), stomach (2 or 3), breast (3 or 2), lung and pancreas (2 or 2), and so on. For PPV, a maximum of four peptides were selected from nine different peptides capable of binding to HLA-A11 and -A33 molecules based on the pre-existing peptide-specific IgG responses. There were no severe adverse events related to PPV. At the end of the first cycle, peptide-specific CTL responses were augmented in 4/12 or 2/9 of HLA-A11+ /A11+ or -A33+ /A33+ patients, while peptide-specific IgG responses were augmented in 6/14 or 4/10 patients, respectively. Clinical responses consisted of four stable diseases and 14 progressive diseases in HLA-A11+ /A11+ patients, versus seven and six in -A33+ /A33+ patients, respectively. Further clinical study of PPV could be recommended because of the safety and positive immunological responses.
Assuntos
Vacinas Anticâncer/administração & dosagem , Antígenos HLA-A/genética , Neoplasias/terapia , Vacinação/métodos , Vacinas de Subunidades Antigênicas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Sequência de Aminoácidos , Anemia/etiologia , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/imunologia , Epitopos de Linfócito T/imunologia , Epitopos de Linfócito T/metabolismo , Antígenos HLA-A/imunologia , Humanos , Imunoglobulina G/imunologia , Interferon gama/imunologia , Interferon gama/metabolismo , Estimativa de Kaplan-Meier , Leucopenia/etiologia , Pessoa de Meia-Idade , Neoplasias/genética , Neoplasias/imunologia , Estudos Retrospectivos , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Vacinação/efeitos adversos , Vacinas de Subunidades Antigênicas/efeitos adversos , Vacinas de Subunidades Antigênicas/imunologia , Adulto JovemRESUMO
Prostate cancer is the most common cancer in men, and the second leading cause of cancer-related death in Western countries. Prostate cancer-related death occurs in patients with metastatic castration-resistant prostate cancer. Although several new drugs for castration-resistant prostate cancer have been approved, each of these has prolonged survival by just a few months. Consequently, new therapies are sorely needed. Recently, it has been recognized that immunotherapy is an effective treatment for prostate cancer patients. Several strategies, such as cancer vaccines and immune checkpoint inhibitors, have been investigated in clinical studies for prostate cancer patients. In the present review, the results of the most recent clinical studies investigating immunotherapy in prostate cancer patients are reported, and the future clinical development of immunotherapy for prostate cancer is discussed.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Imunoterapia/métodos , Neoplasias da Próstata/terapia , Microambiente Tumoral/efeitos dos fármacos , Animais , Antineoplásicos Imunológicos/farmacologia , Vacinas Anticâncer/imunologia , Ensaios Clínicos como Assunto , Receptores Coestimuladores e Inibidores de Linfócitos T/antagonistas & inibidores , Receptores Coestimuladores e Inibidores de Linfócitos T/imunologia , Modelos Animais de Doenças , Humanos , Imunoterapia/tendências , Masculino , Próstata , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/mortalidade , Extratos de Tecidos/imunologia , Extratos de Tecidos/uso terapêutico , Resultado do Tratamento , Microambiente Tumoral/imunologiaRESUMO
The immunological characteristics of carcinoma of unknown primary site (CUP) are not well established due to inclusion of heterogeneous types of metastatic tumors with the absence of any detectable primary site. We evaluated the immune responses in patients with histologically unfavorable CUP during personalized peptide vaccination (PPV). Ten patients with histologically unfavorable CUP who had been treated by PPV after chemotherapy failure were analyzed. In PPV treatment, up to four human leukocyte antigen-matched peptides of a total 31 peptides were selected according to preexisting host immunity before vaccination and administered subcutaneously. Peptides derived from the Lck antigen were most often chosen for use among all patients. CTL responses were increased in 8 of the 10 and 5 of the five patients tested at the end of the first and second PPV cycles, respectively. Increases in humoral responses after vaccination, including IgG, IgG1, IgG3, IgA, and IgM, were observed against not only the vaccinated peptides but also the non-vaccinated peptides. Severe adverse events due to PPV were not observed. Median overall survival was 13.9 months (95 % CI 4.0-22.5 months). PPV activated both cellular and humoral immune responses to short peptides derived from CTL epitopes in the majority of CUP patients. PPV with Lck-derived peptides may be a feasible, new treatment modality for histologically unfavorable CUP patients due to its safety and strong ability to boost immune responses, although its clinical efficacy remains to be investigated in larger-scale trials.
Assuntos
Adenocarcinoma/terapia , Vacinas Anticâncer/imunologia , Carcinoma de Células Escamosas/terapia , Epitopos de Linfócito T/metabolismo , Imunoterapia/métodos , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/metabolismo , Neoplasias Primárias Desconhecidas/terapia , Fragmentos de Peptídeos/metabolismo , Linfócitos T Citotóxicos/imunologia , Vacinação , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Citotoxicidade Imunológica , Resistencia a Medicamentos Antineoplásicos , Feminino , Antígenos HLA/metabolismo , Humanos , Imunidade Humoral , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias Primárias Desconhecidas/mortalidade , Neoplasias Primárias Desconhecidas/patologia , Medicina de Precisão , Análise de Sobrevida , Vacinas de Subunidades Antigênicas/imunologiaRESUMO
This study investigated the effect of metronomic cyclophosphamide (CPA) in combination with personalized peptide vaccination (PPV) on regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC), and whether it could improve the antitumor effect of PPV. Seventy patients with metastatic castration-resistant prostate cancer were randomly assigned (1:1) to receive PPV plus oral low-dose CPA (50 mg/day), or PPV alone. PPV treatment used a maximum of four peptides chosen from 31 pooled peptides according to human leukocyte antigen types and antigen-specific humoral immune responses before PPV, for 8 subcutaneous weekly injections. Peptide-specific cytotoxic T lymphocyte (CTL) and immunoglobulin G responses were measured before and after PPV. The incidence of grade 3 or 4 hematologic adverse events was higher in the PPV plus CPA arm than in the PPV alone arm. Decrease in Treg and increase in MDSC were more pronounced in PPV plus CPA treatment than in PPV alone (p = 0.036 and p = 0.048, respectively). There was no correlation between the changes in Treg or MDSC and CTL response. There was no difference in positive immune responses between the two arms, although overall survival in patients with positive immune responses was longer than in those with negative immune responses (p = 0.001). Significant differences in neither progression-free survival nor overall survival were observed between the two arms. Low-dose CPA showed no change in the antitumor effect of PPV, possibly due to the simultaneous decrease in Treg and increase in MDSC, in patients under PPV.
Assuntos
Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/imunologia , Ciclofosfamida/administração & dosagem , Medicina de Precisão , Neoplasias de Próstata Resistentes à Castração/imunologia , Neoplasias de Próstata Resistentes à Castração/terapia , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/imunologia , Administração Metronômica , Idoso , Idoso de 80 Anos ou mais , Vacinas Anticâncer/efeitos adversos , Terapia Combinada , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Peptídeos/administração & dosagem , Peptídeos/química , Peptídeos/imunologia , Medicina de Precisão/métodos , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/patologia , Análise de Sobrevida , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Resultado do Tratamento , Vacinas de Subunidades Antigênicas/efeitos adversosRESUMO
The present study attempted to identify T helper epitope long peptides capable of inducing cytotoxic T lymphocytes (CTL) from Lck antigen (p56(Lck) ), the src family tyrosine kinase, which is known to be aberrantly expressed in metastatic cancers cells, in order to develop a long peptide-based cancer vaccine for HLA-A2(+) cancer patients. Based on the biding motif to the HLA-DR and HLA-A2 alleles, 94 peptides were prepared from the Lck antigen. These peptides were screened for their reactivity to immunoglobulin G (IgG) from plasma of cancer patients, followed by testing of their ability to induce both CD4(+) and CD8(+) T lymphocytes showing not only peptide-specific IFN-γ production but cytotoxicity against HLA-A2(+) cancer cells from peripheral blood mononuclear cells (PBMC) of HLA-A2(+) cancer patients. Among 94 peptides tested, the three T helper epitope long peptides and their inner CTL epitope short peptides with HLA-A2 binding motifs were frequently recognized by IgG of cancer patients, and efficiently induced both CD4(+) IFN-γ(+) and CD8(+) IFN-γ(+) T lymphocytes. Patients' PBMC stimulated with these long peptides showed cytotoxicity against HLA-A2(+) Lck(+) cancer cells in HLA-class I and HLA-class II dependent manners. These three peptides might be useful for long peptide-based vaccines for HLA-A2(+) cancer patients with Lck(+) tumor cells.
Assuntos
Vacinas Anticâncer/imunologia , Epitopos de Linfócito T/imunologia , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/imunologia , Neoplasias/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Antígenos de Neoplasias/imunologia , Linhagem Celular Tumoral , Ensaio de Imunoadsorção Enzimática , ELISPOT , Citometria de Fluxo , Antígeno HLA-A2/imunologia , Humanos , Peptídeos/imunologiaRESUMO
To develop a peptide vaccine for cancer patients with the HLA-A26 allele, which is a minor population worldwide, we investigated the immunological responses of HLA-A26(+) /A26(+) cancer patients to four different CTL epitope peptides under personalized peptide vaccine regimens. In personalized peptide vaccine regimens, two to four peptides showing positive peptide-specific IgG responses in pre-vaccination plasma were selected from the four peptide candidates applicable for HLA-A26(+) /A26(+) cancer patients and administered s.c. Peptide-specific CTL and IgG responses along with cytokine levels were measured before and after vaccination. Cell surface markers in PBMCs and plasma cytokine levels were also measured. In this study, 21 advanced cancer patients, including seven lung, three breast, two pancreas, and two colon cancer patients, were enrolled. Their HLA-A26 genotypes were HLA-A26:01 (n = 24), HLA-A26:03 (n = 10), and HLA-A26:02 (n = 8). One, 14, and 6 patients received two, three, and four peptides, respectively. Grade 1 or 2 skin reactions at the injection sites were observed in the majority of patients, but no severe adverse events related to the vaccination were observed. Peptide-specific CTL responses were augmented in 39% or 22% of patients after one or two cycles of vaccination, respectively. Notably, peptide-specific IgG were augmented in 63% or 100% of patients after one or two cycles of vaccination, respectively. Personalized peptide vaccines with these four CTL epitope peptides could be feasible for HLA-A26(+) advanced cancer patients because of their safety and higher rates of immunological responses.
Assuntos
Vacinas Anticâncer/imunologia , Antígenos HLA-A/genética , Neoplasias/terapia , Linfócitos T Citotóxicos/imunologia , Idoso , Antígenos CD/metabolismo , Antígenos de Neoplasias/imunologia , Biomarcadores Tumorais/metabolismo , Antígeno CTLA-4/metabolismo , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/uso terapêutico , Feminino , Antígenos HLA-A/imunologia , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Neoplasias/genética , Receptor de Morte Celular Programada 1/metabolismo , Receptores Imunológicos/metabolismo , Estudos Retrospectivos , Resultado do Tratamento , Vacinação , Vacinas de Subunidades Antigênicas/efeitos adversos , Vacinas de Subunidades Antigênicas/imunologia , Vacinas de Subunidades Antigênicas/uso terapêutico , Proteína do Gene 3 de Ativação de LinfócitosRESUMO
The heterogeneity expression of tumor-associated antigens (TAA) and variability of human T cell repertoire suggest that effective cancer vaccine requires induction of a wide breadth of cytotoxic T lymphocyte (CTL) specificities. This can be achieved with vaccines targeting multiple TAA. We evaluated the safety and immune dynamics of a cancer vaccine consisting of 20 mixed peptides (KRM-20) designed to induce CTLs against 12 different TAA in patients with castration-resistant prostate cancer (CRPC). Patients received each of three different randomly assigned doses of KRM-20 (6, 20, or 60 mg) once a week for 6 weeks. KRM-20 was applicable for patients with positive human leukocyte antigen (HLA) A2, A3, A11, A24, A26, A31 or A33 alleles, which cover the majority of the global population. To evaluate the minimum immunological effective dose (MIED), peptide-specific CTL and immunoglobulin G (IgG) responses, and immune suppressive subsets were evaluated during the vaccination. Total of 17 patients was enrolled. No serious adverse drug reactions were encountered. The MIED of KRM-20 in CTL or IgG response calculated by logistic regression model was set as 16 or 1.6 mg, respectively. The frequency of immune suppressive subsets was fewer in the 20 mg cohort than that in 6 or 60 mg cohort. Clinical responses determined by prostate-specific antigen levels were two partial responses (from the 20 mg cohort), five no changes and ten progressive diseases. Twenty milligrams of KRM-20 could be recommended for further studies because of the safety and ability to augment CTL activity.
Assuntos
Antígenos de Neoplasias/imunologia , Neoplasias Ósseas/terapia , Vacinas Anticâncer/administração & dosagem , Fragmentos de Peptídeos/imunologia , Neoplasias de Próstata Resistentes à Castração/terapia , Linfócitos T Citotóxicos/imunologia , Idoso , Biomarcadores Tumorais/sangue , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/secundário , Antígeno CTLA-4/sangue , Estudos de Coortes , Seguimentos , Antígenos HLA/imunologia , Humanos , Imunoglobulina G , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Neoplasias de Próstata Resistentes à Castração/imunologia , Neoplasias de Próstata Resistentes à Castração/patologiaRESUMO
Personalized peptide vaccination (PPV) is an attractive approach to cancer immunotherapy with strong immune-boosting effects conferring significant clinical benefit. However, as with most therapeutic agents, there is a difference in clinical efficacy among patients receiving PPV. Therefore, a useful biomarker is urgently needed for prognosticating clinical outcomes to preselect patients who would benefit the most from PPV. In this retrospective study, to detect a molecular prognosticator of clinical outcomes for PPV, we analyzed whole-genome gene expression profiles of peripheral blood mononuclear cells (PBMCs) in castration-resistant prostate cancer (CRPC) patients before administration of PPV. Cox regression analysis revealed that mRNA expression of myeloperoxidase, haptoglobin, and neutrophil elastase was significantly associated with overall survival (OS) among vaccinated CRPC patients (adjusted P < 0.01). By promoter sequence analysis of these three genes, we found that rs5472 of haptoglobin (HP), an acute-phase plasma glycoprotein, was strongly correlated to OS of vaccinated CRPC patients (P = 0.0047, hazard ratio 0.47; 95 % confidence interval 0.28-0.80). Furthermore, both HP mRNA expression in PBMCs and protein level in plasma of CRPC patients before administration of PPV exhibited rs5472 dependence (P < 0.001 for mRNA expression and P < 0.05 for protein level). Our findings suggest that rs5472 may play an important role in the immune response to PPV via regulation of HP. Thus, we concluded that rs5472 is a potential prognostic biomarker for PPV.
Assuntos
Biomarcadores Tumorais/genética , Vacinas Anticâncer/uso terapêutico , Haptoglobinas/genética , Polimorfismo Genético , Neoplasias de Próstata Resistentes à Castração/terapia , Vacinas de Subunidades Antigênicas/uso terapêutico , Humanos , Masculino , Regiões Promotoras Genéticas/genética , Neoplasias de Próstata Resistentes à Castração/diagnóstico , RNA Mensageiro/genética , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Since both tumor cells and host immune cell repertoires are diverse and heterogeneous, immune responses against tumor associated antigens shall be substantially different among individual patients with prostate cancer. Subsequently, selection of suitable peptide vaccines for individual patients based on the pre-existing host immunity before vaccination could induce potent anti-tumor responses capable of providing clinical benefit for prostate cancer patients. We have developed a novel immunotherapeutic approach of personalized peptide vaccination (PPV) in which a maximum of four human leukocyte antigen (HLA)-class IA-matched peptides were selected for vaccination among pooled peptides based on both HLA-class IA type and the pre-existing host immunity before vaccination. We discuss our recent results of clinical studies of peptide vaccination for castration-resistant prostate cancer and the future direction of therapeutic cancer vaccines.
Assuntos
Vacinas Anticâncer/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/terapia , Vacinação , Ensaios Clínicos Fase III como Assunto , Células Dendríticas/imunologia , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/imunologia , Vacinas de Subunidades Antigênicas/uso terapêuticoRESUMO
Many clinical trials of peptide vaccines have been carried out since the first clinical trial of a melanoma antigen gene-1-derived peptide-based vaccine was reported in 1995. The earlier generations of peptide vaccines were composed of one to several human leukocyte antigen class I-restricted CTL-epitope peptides of a single human leukocyte antigen type. Currently, various types of next-generation peptide vaccines are under development. In this review, we focus on the clinical trials of the following categories of peptide vaccines mainly published from 2008 to 2012: (i) multivalent long peptide vaccines; (ii) multi-peptide vaccines consisting of CTL- and helper-epitopes; (iii) peptide cocktail vaccines; (iv) hybrid peptide vaccines; (v) personalized peptide vaccines; and (vi) peptide-pulsed dendritic cell vaccines.
Assuntos
Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/uso terapêutico , Neoplasias/tratamento farmacológico , Linfócitos T Citotóxicos/imunologia , Vacinas de Subunidades Antigênicas/uso terapêutico , Vacinas Sintéticas/uso terapêutico , Vacinas Anticâncer/imunologia , Células Dendríticas/imunologia , Epitopos de Linfócito T/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Neoplasias/imunologia , Vacinas de Subunidades Antigênicas/imunologia , Vacinas Sintéticas/imunologiaRESUMO
Since both tumor cells and host immune cell repertoires are diverse and heterogeneous, immune responses against tumor-associated antigens should differ substantially among individual cancer patients. Selection of suitable peptide vaccines for individual patients based on the preexisting host immunity before vaccination could induce potent anti-tumor responses that provide clinical benefit to cancer patients. We have developed a novel immunotherapeutic approach of personalized peptide vaccination (PPV) in which a maximum of four human leukocyte antigen (HLA) class IA-matched peptides are selected for vaccination among pooled peptides on the basis of both HLA class IA type and the preexisting host immunity before vaccination. In this review, we discuss our recent results of preclinical and clinical studies of PPV for various types of advanced cancer.
Assuntos
Vacinas Anticâncer/uso terapêutico , Neoplasias/terapia , Medicina de Precisão/métodos , Vacinas de Subunidades Antigênicas/uso terapêutico , Antígenos de Neoplasias/imunologia , Linhagem Celular Tumoral , Ensaios Clínicos como Assunto , Antígenos HLA/metabolismo , Humanos , Imunoterapia/métodos , Oncologia/tendências , Fatores de TempoRESUMO
BACKGROUND: Cancer vaccine is one of the attractive treatment modalities for patients with castration-resistant prostate cancer (CRPC). However, because of delayed immune responses, its clinical benefits, besides for overall survival (OS), are not well captured by the World Health Organization (WHO) and Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Several surrogate markers for evaluation of cancer vaccine, including prostate-specific antigen doubling time (PSADT), are currently sought. The purpose of this study was to assess prospectively the PSA kinetics and immune responses, as well as the efficacy, safety, and biomarkers of personalized peptide vaccination (PPV) in progressive CRPC. METHODS: One hundred patients with progressive CRPC were treated with PPV using 2-4 positive peptides from 31 candidate peptides determined by both human leukocyte antigen (HLA) class IA types and the levels of immunoglobulin G (IgG) against each peptide. The association between immune responses and PSADT as well as overall survival (OS) was studied. RESULTS: PPV was safe and well tolerated in all patients with a median survival time of 18.8 months. Peptide-specific IgG and T-cell responses strongly correlated with PSADT (p < 0.0001 and p = 0.0007, respectively), which in turn showed correlation with OS (p = 0.018). Positive IgG responses and prolongation of PSADT during PPV were also significantly associated with OS (p = 0.001 and p = 0.004) by multivariate analysis. CONCLUSIONS: PSADT could be an appropriate surrogate marker for evaluation of the clinical benefit of cancer vaccine. Further randomized trials are needed to confirm these results. TRIAL REGISTRATION: UMIN000001850.
Assuntos
Adenocarcinoma/terapia , Vacinas Anticâncer/uso terapêutico , Imunoterapia Ativa , Neoplasias de Próstata Resistentes à Castração/terapia , Vacinas de Subunidades Antigênicas/imunologia , Adenocarcinoma/sangue , Adenocarcinoma/imunologia , Adenocarcinoma/mortalidade , Idoso , Idoso de 80 Anos ou mais , Vacinas Anticâncer/imunologia , Humanos , Imunidade Celular , Imunidade Humoral , Calicreínas/sangue , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Medicina de Precisão , Modelos de Riscos Proporcionais , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/imunologia , Neoplasias de Próstata Resistentes à Castração/mortalidade , Resultado do TratamentoRESUMO
BACKGROUND: Docetaxel-based chemotherapy (DBC) showed limited clinical efficacy for castration-resistant prostate cancer (CRPC) patients. To explore cancer vaccine as a new treatment modality, we conducted a phase II study of personalized peptide vaccine (PPV) for DBC-resistant CRPC patients. METHODS: Twenty DBC-resistant CRPC patients and 22 patients with no prior DBC, as a control, were treated with PPV using peptides chosen from 31 peptides in patients, respectively. Cytokines, inflammatory markers, and immune responses were measured as candidate biomarkers. DBC-resistant CRPC patients without PPV was set as a historical control for evaluation of clinical benefit of PPV. RESULTS: Median overall survival (OS) time from the first vaccination was 14.8 months or not reached in DBC-resistant CRPC patients and patients with no prior DBC (log-rank; P = 0.07), respectively. Median OS time from the first day of progression disease was 17.8 and 10.5 months in DBC-resistant CRPC patients receiving PPV and those with no PPV (P = 0.1656), respectively. Elevated IL-6 levels before vaccination was an unfavorable factor for OS of DBC-resistant CRPC patients (P = 0.0161, hazard ratio (HR): 0.024, 95% CI:0.001-0.499) as well as all 42 patients with PPV(P = 0.0011, HR: 0.212, 95% CI:0.068-0.661) by multivariable analysis. CONCLUSIONS: Further clinical study of PPV is recommended for DBC-resistant CRPC patients, because of the safety and possible prolongation of MST. Control of elevated IL-6 by combined therapy may provide much better clinical outcome.
Assuntos
Antineoplásicos/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Orquiectomia , Medicina de Precisão , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/imunologia , Taxoides/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Citocinas/sangue , Progressão da Doença , Docetaxel , Humanos , Imunidade Humoral , Interleucina-6/sangue , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Neoplasias da Próstata/mortalidade , Falha de Tratamento , Resultado do TratamentoRESUMO
BACKGROUND: Because only a subset of patients show clinical responses to peptide-based cancer vaccination, it is critical to identify biomarkers for selecting patients who would most likely benefit from this treatment. METHODS: The authors characterized the gene expression profiles in peripheral blood of vaccinated patients to identify biomarkers to predict patient prognosis. Peripheral blood was obtained from advanced castration-resistant prostate cancer patients, who survived for >900 days (long-term survivors, n = 20) or died within 300 days (short-term survivors, n = 20) after treatment with personalized peptide vaccination. Gene expression profiles in prevaccination and postvaccination peripheral blood mononuclear cells (PBMCs) were assessed by DNA microarray. RESULTS: There were no statistically significant differences in the clinical or pathological features between the 2 groups. Microarray analysis of prevaccination PBMCs identified 19 genes that were differentially expressed between the short-term and long-term survivors. Among the 15 up-regulated genes in the short-term survivors, 13 genes, which were also differentially expressed in postvaccination PBMCs, were associated with gene signatures of granulocytes. When a set of 4 differentially expressed genes were selected as the best combination to determine patient survival, prognosis was correctly predicted in 12 of 13 patients in a validation set (accuracy, 92%). CONCLUSIONS: These results suggested that abnormal granulocytes present in the PBMC faction may contribute to poor prognosis in advanced prostate cancer patients receiving personalized peptide vaccination. Gene expression profiling in peripheral blood might thus be informative for devising better therapeutic strategies by predicting patient prognosis after cancer vaccines.
Assuntos
Vacinas Anticâncer/uso terapêutico , Perfilação da Expressão Gênica , Neoplasias da Próstata/genética , Neoplasias da Próstata/terapia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Granulócitos/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Seleção de Pacientes , Prognóstico , Neoplasias da Próstata/sangueRESUMO
We conducted personalized peptide vaccination (PPV) for various types of advanced cancers in the past 10 years. A maximum of four HLA-matched peptides, which were selected based on the pre-existing host immunity before vaccination, were subcutaneously administered at PPV trials. Randomized phase II trial for patients with castration resistant prostate cancer showed the favorite clinical responses in the PPV group. PPV was also conducted for recurrent or progressive glioblastoma multiforme patients with median overall survival of 10.6 months, resulting in the initiation of randomized phase III clinical trial. A randomized phase III trial is essential to prove clinical benefits of PPV.
Assuntos
Vacinas Anticâncer/uso terapêutico , Neoplasias/tratamento farmacológico , Fragmentos de Peptídeos/uso terapêutico , Medicina de Precisão/métodos , Vacinas Anticâncer/imunologia , Ensaios Clínicos como Assunto , Humanos , Neoplasias/imunologia , Neoplasias/mortalidade , Fragmentos de Peptídeos/imunologia , Resultado do TratamentoRESUMO
BACKGROUND: To evaluate the safety, tolerability, immune response, and antitumor activity of a combination of personalized peptide vaccination (PPV) and estramustine phosphate (EMP) in patients with castration-resistant prostate cancer (CRPC). METHODS: In a phase I dose-escalation study, four peptides showing the highest levels of peptide-specific immunoglobulin G (IgG) to 14 vaccine candidates (ITK-1) were subcutaneously injected every week in three different dose settings (1, 3, and 5 mg per peptide) for 6 weeks with a low dose of EMP, and the patients were followed by maximum 2 years extension study either weekly or bi-weekly six times PPV as one course with a low dose of EMP. RESULTS: Fifteen patients were enrolled in the phase I study. No serious treatment-related adverse events were observed. The most common adverse events were grade 2 skin reactions at the injection sites. The maximum acceptable dose of ITK-1 was 8.643 mg. There were no treatment-related systemic adverse events of grade 3 or more, and maximum tolerated dose could not be determined. Cytotoxic T lymphocyte responses measured by interferon-γ release assay were boosted in 10 of 15 (67%) patients, and IgG responses were boosted in 7 of 15 (47%) patients. Twelve patients proceeded to the extension study, and the median survival time was 23.8 months during a median follow-up of 23.8 months. CONCLUSIONS: PPV treatment for HLA-A24 positive patients with CRPC could be recommended for further stages of clinical trials because of its safety and the higher frequency of boosting immune responses.