RESUMO
We undertook an early phase II study of mixed 19-peptide cancer vaccine monotherapy for 14 advanced metastatic triple-negative breast cancer (mTNBC) patients refractory to systemic chemotherapy to develop a new type of cancer vaccine. The treatment protocol consisted of a weekly vaccination for 6 weeks, and there were no severe adverse events related to the vaccination throughout the trial. Increase of peptide-specific IgG against the vaccinated human leukocyte antigen-matched peptides, but not against the nonmatched peptides, was positively correlated with overall survival (OS) (P < .01). The median OS was 11.5 or 24.4 months in all 14 patients or the 10 patients who completed the vaccination. The patients with lower C-reactive protein levels or 3 or fewer systemic chemotherapies were favorable candidates for this treatment. Advancement of this therapy to the next stage of study could be warranted based on the safety and immune boosting determined herein (clinical trial registration number: UMIN000014616).
Assuntos
Antígenos de Neoplasias/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Vacinas Anticâncer/administração & dosagem , Neoplasias de Mama Triplo Negativas/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/imunologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Esquemas de Imunização , Pessoa de Meia-Idade , Peptídeos/administração & dosagem , Peptídeos/genética , Peptídeos/imunologia , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/patologia , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/efeitos adversos , Vacinas de Subunidades Antigênicas/imunologiaRESUMO
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
BACKGROUND: The monoclonal antibody zolbetuximab (formerly IMAB362), which is being developed as a potential treatment for gastric cancer (GC), targets Claudin 18.2 (CLDN18.2), a GC biomarker. This study aimed to determine the prevalence of CLDN18.2 in primary tumors and lymph node (LN) metastases of Japanese patients with GC. METHODS: CLDN18.2 expression was investigated in tissue samples from patients with gastric adenocarcinoma archived at Kurume University Medical Center, Japan, between 2000 and 2012. Expression of CLDN18.2 in tumor samples was evaluated by immunohistochemistry using the same detection antibody (43-14A) and assay used in the FAST clinical trial (NCT01630083), a phase 2 randomized trial that compared the safety and antitumor activity of the zolbetuximab-chemotherapy combination with chemotherapy alone. Samples showing any specific staining with ≥1+ intensity were defined as CLDN18.2-positive. RESULTS: Of 263 samples analyzed (134 primary gastric tumors and corresponding LN metastases; 128 primary tumors only; one LN metastases only), CLDN18.2 was detected in 87% (n = 228/262) of all primary tumors and 80% (n = 108/135) of LN metastases. Moderate-to-strong CLDN18.2 expression (≥2+ membrane staining intensity in ≥40% of tumor cells [FAST eligibility criterion]) was observed in 52% (n = 135/262) of primary tumors and 45% (n = 61/135) of (LN) metastases. CLDN18.2 expression was significantly higher in GCs of the diffuse histological subtype per Lauren classification and in high grade (G3) tumors. CONCLUSIONS: The high prevalence of CLDN18.2 among Japanese patients with GC supports the therapeutic assessment of zolbetuximab in this population.
Assuntos
Adenocarcinoma/genética , Anticorpos Monoclonais/uso terapêutico , Claudinas/genética , Regulação Neoplásica da Expressão Gênica , Metástase Linfática/genética , Neoplasias Gástricas/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Povo Asiático , Humanos , Imuno-Histoquímica , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologiaRESUMO
Although humoral responses against CTL epitope peptides from lymphocyte-specific protein tyrosine kinase (Lck) antigen have been observed in the majority of healthy donors and cancer patients, the biological activity of the antibody has not been determined. We investigated the biological activity of mAb against CTL epitope peptide of Lck antigen at positions 486-494 (anti-Lck-486 mAb). This mAb induced dendritic cell maturation from murine bone marrow cells by the immune complex form in vitro, and inhibited tumor growth in association with a suppression of tumor-infiltrating T cells, including T regulatory cells in a murine model using female BALB/cCrlCrlj mice (H-2Kd ). More potent tumor inhibition was observed when this mAb was given prior to peptide vaccination. These results may help to unveil the biological activity of anti-Lck peptide antibodies against CTL epitope peptides.
Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Neoplasias do Colo/tratamento farmacológico , Epitopos de Linfócito T/imunologia , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/química , Animais , Antineoplásicos Imunológicos/farmacologia , Linhagem Celular Tumoral , Neoplasias do Colo/imunologia , Células Dendríticas/efeitos dos fármacos , Humanos , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/imunologia , Camundongos , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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
Overall survival of patients with hepatocellular carcinoma (HCC) refractory to locoregional therapy is dismal, even following treatment with sorafenib, a multikinase inhibitor. To develop a more efficacious treatment, we undertook a feasibility study of personalized peptide vaccination (PPV) for HCC, in which the peptides were selected from 31 peptide candidates based on the pre-existing immunity. Twenty-six HCC patients refractory to locoregional therapies (cohort 1) and 30 patients refractory to both locoregional and systemic therapies (cohort 2) were entered into the study. There were no severe adverse events related to PPV except for one injection site reaction. At the end of the first cycle of six vaccinations, successful CTL or IgG boosting was observed in 57% or 46% of patients in cohort 1 and in 54% or 52% of patients in cohort 2, respectively. Successful IgG boosting at the end of the second cycle was observed in the majority of patients tested. Median overall survival was 18.7 months (95% confidence interval, 12.2-22.5 months) in cohort 1, and 8.5 months (95% confidence interval, 5.9-12.2 months) in cohort 2. Based on the higher rates of immune boosting and the safety profile of PPV, further clinical studies of PPV would be warranted for patients with HCC refractory to not only locoregional therapy but also both locoregional and systemic therapies. The protocol of this study was registered with the UMIN Clinical Trials Registry (UMIN000001882 and UMIN000003590).
Assuntos
Vacinas Anticâncer/administração & dosagem , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Carcinoma Hepatocelular/mortalidade , Quimioembolização Terapêutica , Terapia Combinada , Resistencia a Medicamentos Antineoplásicos , Estudos de Viabilidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Niacinamida/administração & dosagem , Niacinamida/análogos & derivados , Compostos de Fenilureia/administração & dosagem , Medicina de Precisão , Sorafenibe , Linfócitos T Citotóxicos/fisiologia , Resultado do Tratamento , Vacinação , Vacinas de Subunidades Antigênicas/administração & dosagemRESUMO
The aim of this research was to investigate the correlation of immunologic factors in the tumor environment of breast cancer, using immunohistological staining to evaluate the expression of programmed death 1/programmed death ligand 1 (PD-1/PD-L1), phosphatase and tensin homolog (PTEN), tumor infiltrating lymphocytes (TILs), and macrophages, and to analyze the association between the immunologic factors and clinical outcome for patients with early stage breast cancer (EBC). A total of 97 EBC patients who underwent standard surgery were investigated. Expression of PD-1/PD-L1 and PTEN and the density of CD3+ TILs, CD8+ TILs, and CD163+ macrophages were evaluated by immunohistochemical analysis. The association between the immunologic factors and clinical outcome was statistically analyzed. The density of CD3+ TILs, CD8+ TILs, and CD163+ macrophages and non-expression of PTEN was significantly higher in cases of triple negative breast cancer. CD8+ TIL density and CD8+ /PD-L1+ expression were predictive factors for disease-free survival and overall survival (OS). Human epidermal growth factor 2 (HER2)-positive patients with PTEN expression and luminal/HER2-negative patients without PD-L1 expression had significantly longer OS compared to patients without PTEN expression (P = 0.049) and with PD-L1 expression (P = 0.036), respectively. Furthermore, patients with PD-L1+ /CD8+ expression had worse median progression-free survival (P = 0.022) and median OS (P = 0.037) compared with patients without PD-L1+ /CD8+ expression. The CD3+ TILs, CD8+ TILs, and CD163+ macrophages were shown to infiltrate the tumor area of EBC. In particular, triple negative breast cancer had a higher rate of TIL infiltration within the tumor environment. Expression of PTEN and lack of PD-L1 expression were associated with favorable survival in HER2-positive and luminal/HER2-negative EBC patients, respectively. The PD-L1 expression combined with CD8+ density was significantly associated with an aggressive clinical outcome.
Assuntos
Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Microambiente Tumoral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Antígeno B7-H1/metabolismo , Complexo CD3/metabolismo , Antígenos CD8/metabolismo , Feminino , Seguimentos , Humanos , Japão , Linfócitos do Interstício Tumoral/citologia , Linfócitos do Interstício Tumoral/metabolismo , Macrófagos/metabolismo , Pessoa de Meia-Idade , Estadiamento de Neoplasias , PTEN Fosfo-Hidrolase/metabolismo , Prognóstico , Receptor de Morte Celular Programada 1/metabolismo , Modelos de Riscos Proporcionais , Receptores de Superfície Celular/metabolismo , Resultado do TratamentoRESUMO
Since the prognosis of advanced biliary tract cancer (aBTC) still remains very poor, new therapeutic approaches, including immunotherapies, need to be developed. In the current study, we conducted an open-label randomized phase II study to test whether low dose cyclophosphamide (CPA) could improve antigen-specific immune responses and clinical efficacy of personalized peptide vaccination (PPV) in 49 previously treated aBTC patients. Patients with aBTC refractory to at least one regimen of chemotherapies were randomly assigned to receive PPV with low dose CPA (100 mg/day for 7 days before vaccination) (PPV/CPA, n = 24) or PPV alone (n = 25). A maximum of four HLA-matched peptides were selected based on the pre-existing peptide-specific IgG responses, followed by subcutaneous administration. T cell responses to the vaccinated peptides in the PPV/CPA arm tended to be greater than those in the PPV alone arm. The PPV/CPA arm showed significantly better progression-free survival (median time: 6.1 vs 2.9 months; hazard ratio (HR): 0.427; P = 0.008) and overall survival (median time: 12.1 vs 5.9 months; HR: 0.376; P = 0.004), compared to the PPV alone arm. The PPV alone arm, but not the PPV/CPA arm, showed significant increase in plasma IL-6 after vaccinations, which might be associated with inhibition of antigen-specific T cell responses. These results suggested that combined treatment with low dose CPA could provide clinical benefits in aBTC patients under PPV, possibly through prevention of IL-6-mediated immune suppression. Further clinical studies would be recommended to clarify the clinical efficacy of PPV/CPA in aBTC patients.
Assuntos
Neoplasias do Sistema Biliar/tratamento farmacológico , Vacinas Anticâncer/uso terapêutico , Ciclofosfamida/uso terapêutico , Peptídeos/uso terapêutico , Idoso , Neoplasias do Sistema Biliar/metabolismo , Intervalo Livre de Doença , Feminino , Humanos , Imunoterapia/métodos , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Medicina de Precisão/métodos , Vacinação/métodosRESUMO
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
A phase I study of a new cancer vaccine (KRM-10), consisting of a mixture of 10 different short peptides, was conducted for patients with advanced gastrointestinal cancers. Primary or secondary endpoints included the dose-limiting toxicity (DLT), or safety and immune responses, respectively. Peptide-specific cytotoxic T lymphocytes (CTL) and immunoglobulin G (IgG), together with soluble inflammatory factors, were measured before and after vaccination. Twenty-one patients were vaccinated with KRM-10 at dose levels of 10 (n = 6), 20 (n = 8) or 30 mg (n = 7) of peptides every week for 6 weeks. No DLT were observed in the dose range evaluated. Common treatment-related adverse events were a grade 1 injection site reaction in 15 patients, and fever in three patients (grade 1 in two patients and grade 2 in one patient). CTL activity to at least one peptide at the time of the third and sixth vaccination increased in 2 and 3 of 6 (10 mg), 2 of 8 and 4 of 6 (20 mg), or 2 and 1 of 6 (30 mg) patients, respectively. IgG levels, at the third and sixth vaccination, were also increased in 1 and 1 of 6 (10 mg), 2 of 8 and 4 of 6 (20 mg), or 1 and 3 of 6 (30 mg) patients, respectively. The KRM-10 vaccine consisting of 20 mg of peptides was determined as the optimal dose for a coming phase II trial because of its safety, and also for demonstrating the most potent activity for augmenting the immune response of the three doses tested. This trial was registered at the UMIN Clinical Trials Registry as UMIN000008820.
Assuntos
Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Neoplasias Gastrointestinais/imunologia , Neoplasias Gastrointestinais/terapia , Peptídeos/imunologia , Idoso , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/efeitos adversos , Citocinas/imunologia , Feminino , Humanos , Imunoglobulina G/imunologia , Mediadores da Inflamação/imunologia , Masculino , Pessoa de Meia-Idade , Linfócitos T Citotóxicos/imunologia , VacinaçãoRESUMO
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
Our previous phase II clinical trial showed that therapeutically selected personalized peptide vaccines(PPVs)were effective at boosting anticancer immunity; the immune response after PPV was associated with a clinical outcome as a prognostic factor for metastatic breast cancer(mBC). We conducted an early phase II study to evaluate the safety and efficacy of a new regimen using multiple peptide vaccines(KRM-19)for patients with metastatictriple -negative breast cancer. KRM-19 consisted of 19 mixed peptides chosen from the previously reported 31 PPVs according to their anti-tumor immunologiceffec ts and safety profiles for patients with mBC. All patients had histologically confirmed measurable ER-PgR-HER2- mBC and their human leukocyte antigen(HLA) / -A molecules were A2, A3, A11, A24, A26, A31, or A33. KRM-19(19mg/mL)was administrated subcutaneously every week for a total of 6 doses. Concurrent conventional chemo- and/or endocrine therapy were not permitted during treatment. This was an open-label, early phase II study. The primary endpoint was safety and anti-tumor immunologic effect, while the secondary endpoints were clinical responses and progression-free survival(PFS). The estimated enrollment was 10-15 and 8 patients were enrolled(Clinical trial registry number: UMIN000014616). Measurement of peptide-specific cytotoxic T lymphocyte and IgG responses were conducted before and after vaccination. The correlation between PFS and the increased IgG response and/or CTL levels were investigated.
Assuntos
Vacinas Anticâncer/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/imunologia , Ensaios Clínicos como Assunto , Humanos , Neoplasias de Mama Triplo Negativas/imunologia , Vacinas de Subunidades Antigênicas/efeitos adversos , Vacinas de Subunidades Antigênicas/imunologia , Vacinas de Subunidades Antigênicas/uso terapêuticoRESUMO
A feasibility study was performed to evaluate the immunological efficacy and safety of a personalized peptide vaccine (PPV) for cervical cancer patients who have received platinum-based chemotherapy. A total of 24 patients with standard chemotherapy-resistant cervical cancer, including 18 recurrent cases, were enrolled in this study and received a maximum of 4 peptides based on HLA-A types and IgG levels to the vaccine candidate peptides in pre-vaccination plasma. The parental protein expression of most of the vaccine peptides was confirmed in the cervical cancer tissues. No vaccine-related systemic grade 3 or 4 adverse events were observed in any patients. Due to disease progression, 2 patients failed to complete the first cycle of vaccinations (sixth vaccination). Cytotoxic T-lymphocyte (CTL) or IgG responses specific for the peptides used for vaccination were augmented in half of cases after the first cycle. The median overall survival was 8.3 months. The clinical responses of the evaluable 18 cases consisted of 1 case with a partial response and 17 cases with disease progression; the remaining 6 cases were not evaluable. Performance status, injection site skin reaction and circulating PD-1(+) CD4(+) T-cells were significantly prognostic of overall survival, and multivariate analysis also indicated that the performance status and circulating PD-1(+) CD4(+) T-cells were prognostic. Because of the safety and immunological efficacy of PPV and the possible prolongation of overall survival, further clinical trials of PPV at a larger scale in advanced or recurrent cervical cancer patients who have received prior platinum-based chemotherapy are recommended.
Assuntos
Vacinas Anticâncer/imunologia , Compostos Organoplatínicos/uso terapêutico , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/imunologia , Vacinas de Subunidades Antigênicas/imunologia , Adulto , Idoso , Progressão da Doença , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Medicina de Precisão/métodos , Prognóstico , Linfócitos T Citotóxicos/imunologia , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/terapia , Vacinação/métodosRESUMO
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.