Evaluation of the Immunological Response of Childhood Cancer Patients Treated with a Personalized Peptide Vaccine for Refractory Soft Tissue Tumor: A Four-Case Series.

This case series aimed to evaluate the peptide-specific immunoglobulin G (IgG) response, clinical effectiveness, and the safety of a personalized peptide vaccine (PPV) in four children with refractory solid cancer. Although the pre-vaccination IgG responses were suppressed, IgG levels against the vaccinated peptides after 12 vaccinations were increased in all three cases who received at least 12 vaccinations. Vaccination-related adverse effects were grade 1 injection-site local skin lesions. One patient, whose diagnosis was relapsed rhabdomyosarcoma, remains in sustained remission after 37 months. Although the pre-vaccination immune response in this patient was low, IgG levels against 2 of the 4 peptide vaccines were increased after the sixth vaccination, followed by a strong increase at the eighteenth vaccination against all 4 peptides, with a >100-fold increase vs. 2 peptides. The remaining three patients exhibited progressive disease and eventually died of their original cancer. The results of the current case series suggest that in cases of childhood solid tumors, when the tumor is controlled at the time of entry PPV may have some consolidation effect. Therefore, PPV could be a new immunotherapy modality for refractory childhood solid tumors.

Immune responses of patients without cancer recurrence after a cancer vaccine over a long term.

The present study aimed to clarify the humoral and cellular immune responses of patients with cancer who experienced no recurrence over a long term after receiving a cancer vaccine. The immune kinetics were investigated in response to a personalized peptide vaccination (PPV) among 44 Japanese patients without an active tumor at entry to the vaccination: Lung adenocarcinoma (n=11); colon (n=18); and breast cancer (n=15) (9, 10, 12, 8 and 5 patients with stage I, II, III and IV recurrences, respectively). The patients' immunoglobulin G (IgG) and cytotoxic T lymphocyte (CTL) activities were measured using a multiplexed Luminex assay and an interferon-γ release assay, respectively. There were no severe adverse events related to the PPV other than a grade III injection site reaction. A potent boost in IgG or CTL at the end of the 1st vaccination cycle was observed in 77% of the patients (n=84). The IgG levels were sustained throughout the follow-up period, whereas the CTL levels declined and were transient. A total of 37 of the 44 patients (84%) had no recurrence, with a median follow-up of 67.6 months (interquartile range, 45.6-82.8 months). Overall, the PPV induced long-term humoral immunity with transient cellular immunity in the majority of patients with cancer without an active tumor at their entry to the PPV.

Investigation of factors associated with reduced clinical benefits of personalized peptide vaccination for pancreatic cancer.

The aim of the present study was to determine the factors associated with reduced clinical benefits of personalized peptide vaccination (PPV) for pancreatic cancer. Phase II PPV clinical trials comprising 309 (8 non-advanced and 301 advanced-stage) patients with pancreatic cancer were conducted. Two to four peptides were selected among a set of 31 different peptides as vaccine candidates for personalized peptide vaccination based on human leukocyte antigen types and preexisting peptide-specific IgG levels, and subcutaneously injected. The selected peptides were subcutaneously injected. Of the 309 patients, 81 failed to complete the 1st PPV cycle due to rapid disease progression, and their median overall survival [2.1 months; 95% confidence interval (CI), 1.8-2.7] was significantly shorter than that of the remaining 228 patients (8.4 months; 95% CI, 8.4-9.9; P<0.01). 'Immune boosting' was defined when IgG levels before vaccination increased more than 2-fold after vaccination. Immune boosting was observed in the majority of patients with PPV irrespective of whether or not they received concomitant chemotherapy. Additionally, patients demonstrating immune boosting exhibited longer survival rates. Although the positive-response rates and peptide-specific IgG levels in pre- and post-vaccination samples differed among the 31 peptides, patients exhibiting immune boosting in response to each of the vaccinated peptides demonstrated longer survival times. Pre-vaccination factors associated with reduced clinical benefits were high c-reactive protein (CRP) levels, high neutrophil counts, lower lymphocyte and red blood cell counts, advanced disease stage and the greater number of chemotherapy courses prior to the PPV treatment. The post-vaccination factors associated with lower clinical benefits were PPV monotherapy and lower levels of immune boosting. In conclusion, pre-vaccination inflammatory signatures, rather than pre- or post-vaccination immunological signatures, were associated with reduced clinical benefits of personalized peptide vaccination (PPV) for pancreatic cancer.

Identification of biomarkers for personalized peptide vaccination in 2,588 cancer patients.

Peptide­based cancer vaccines have failed to provide sufficient clinical benefits in order to be approved in clinical trials since the 1990s. To understand the mechanisms underlying this failure, the present study investigated biomarkers associated with the lower overall survival (OS) among 2,588 patients receiving personalized peptide vaccination (PPV). Survival data were obtained from a database of 2,588 cancer patients including 399 patients with lung, 354 with prostate and 344 with colon cancer. They entered into phase II clinical trials of PPV in which 2 to 4 of 31 warehouse peptides were selected for vaccination on an individual patient basis based on human leukocyte antigen (HLA) class IA­types and pre­existing peptide­specific IgG levels. Higher pre­vaccination neutrophil, monocyte and platelet counts, and lower pre­vaccination lymphocyte and red blood cell counts were inversely associated with OS, with higher sensitivities in the proportions of neutrophils and lymphocytes, respectively. The most potent unfavorable and favorable factors for OS were the median percentage of neutrophils (≥64.8%) or percentage of lymphocytes (≥25.1%) with correlation coefficients (R2) of 0.98 and 0.92, respectively. Higher pre­vaccination levels of c­reactive protein and other inflammatory soluble factors were inversely associated with OS. Pre­vaccination peptide­specific immunity levels had no effect on OS, although lower immune boosting levels were inversely associated with OS. None of the 31 peptides was inversely associated with OS, although a few peptides were positively associated with it. On the whole, the findings of the present study suggested that pre­vaccination inflammatory signatures, but not those of post­vaccination immune induction, were associated with lower clinical benefits of PPV.

Development of Lobular Panniculitis Long After Completing the Personalized Peptide Vaccine Therapy.

BACKGROUND Personalized peptide vaccine therapy is regarded as a well-tolerated, safe and effective immunotherapy for patients with advanced cancers. Herein we report an exceptional case of a patient with advanced pancreatic cancer who developed delayed lobular panniculitis at sites corresponding to vaccine injections. CASE REPORT A 64-year-old Japanese female visited our clinic due to thirst and polydipsia; she was diagnosed as having type 2 diabetes. Simultaneously, she was diagnosed as having advanced pancreatic cancer; and a distal pancreatectomy and splenectomy were performed. Afterwards, she received adjuvant chemotherapy with titanium silicate-1 and personalized peptide vaccination using Montanide® ISA-51 by a subcutaneous injection to her abdomen over a total of 30 times. Thirteen months after the vaccine therapy had come to an end, lobular panniculitis appeared at the vaccination sites. At this point, corticosteroid was administered, resulting in significant improvement in the condition of the subcutaneous nodules. CONCLUSIONS This case report highlights the importance of careful patient explanation before initiation of cancer vaccine therapy about the possibilities of lobular panniculitis as an adverse event. It also highlights that it is important that physicians have a greater awareness of the possibility of panniculitis in patients with concerns regarding subcutaneous indurations even long after the end of peptide vaccine therapy.

Survival analysis of multiple peptide vaccination for the selection of correlated peptides in urological cancers.

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.

Personalized peptide vaccination as second-line treatment for metastatic upper tract urothelial carcinoma.

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.

Feasibility study of personalized peptide vaccination for hepatocellular carcinoma patients refractory to locoregional therapies.

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).

A randomized phase II trial of personalized peptide vaccine with low dose cyclophosphamide in biliary tract cancer.

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.

Immunological evaluation of peptide vaccination for cancer patients with the HLA -A11+ or -A33+ allele.

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.

Personalized Kampo Medicine Facilitated Both Cytotoxic T Lymphocyte Response and Clinical Benefits Induced by Personalized Peptide Vaccination for Advanced Esophageal Cancer.

We retrospectively evaluated if personalized Kampo medicine (PKM) could facilitate CTL responses and clinical benefits induced by personalized peptide vaccination (PPV), in which HLA-matched vaccines were selected and administered based on the preexisting host immunity, for advanced esophageal cancer (aEC) patients. Among 34 aEC patients entered in the clinical study, 23 patients received PKM and PPV without (n = 12) or with chemotherapy (n = 11), while the remaining 11 patients did not receive PKM but received PPV without (n = 6) or with chemotherapy (n = 5), respectively. Incidence of adverse events was significantly lower or higher in PKM and PPV arm (n = 23) or PPV and chemotherapy arm (n = 16) as compared to that of the counter arm (n = 11 or 18), respectively. Postvaccination PBMCs from the patients undergoing PKM and PPV showed significantly higher CTL responses as compared to the counter arm. The median progression-free survival (PFS) or median survival time (MST) of 34 patients was 2.9 or 7.6 months, respectively. The combination therapy in PPV and PKM arm, but not that in PPV and chemotherapy arm, significantly (P = 0.02) prolonged MST. These results could warrant a next step of prospective clinical study of PKM and PPV for aEC patients.

Immunological evaluation of personalized peptide vaccination for patients with histologically unfavorable carcinoma of unknown primary site.

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.

Phase II Study of Personalized Peptide Vaccination with Both a Hepatitis C Virus-Derived Peptide and Peptides from Tumor-Associated Antigens for the Treatment of HCV-Positive Advanced Hepatocellular Carcinoma Patients.

Objective. To evaluate safety and immune responses of personalized peptide vaccination (PPV) for hepatitis C virus- (HCV-) positive advanced hepatocellular carcinoma (HCC). Patients and Methods. Patients diagnosed with HCV-positive advanced HCC were eligible for this study. A maximum of four HLA-matched peptides were selected based on the preexisting IgG responses specific to 32 different peptides, which consisted of a single HCV-derived peptide at core protein positions 35-44 (C-35) and 31 peptides derived from 15 different tumor-associated antigens (TAAs), followed by subcutaneous administration once per week for 8 weeks. Peptide-specific cytotoxic T lymphocyte (CTL) and IgG responses were measured before and after vaccination. Results. Forty-two patients were enrolled. Grade 3 injection site skin reaction was observed in 2 patients, but no other PPV-related severe adverse events were noted. Peptide-specific CTL responses before vaccination were observed in only 3 of 42 patients, but they became detectable in 23 of 36 patients tested after vaccination. Peptide-specific IgG responses were also boosted in 19 of 36 patients. Peptide-specific IgG1 responses to both C-35 and TAA-derived peptides could be potentially prognostic for overall survival. Conclusion. Further clinical study of PPV would be warranted for HCV-positive advanced HCC, based on the safety and strong immune induction.

Evaluation of prognostic significance of granulocyte-related factors in cancer patients undergoing personalized peptide vaccination.

Since cancer vaccines do not always elicit beneficial effects in treated patients, identification of biomarkers for predicting clinical outcomes would be highly desirable. We previously reported that abnormal granulocytes present in peripheral blood mononuclear cells (PBMC) may contribute to poor prognosis in advanced prostate cancer patients receiving personalized peptide vaccination (PPV). In the current study, we examined whether soluble factors derived from granulocytes, such as matrix metalloproteinase 9 (MMP-9), myeloperoxidase (MPO), and arginase 1 (ARG1), and inhibitory cytokine TGFß in pre-vaccination plasma were useful for predicting prognosis after PPV in advanced cancer patients. In biliary tract cancer (n=25), multivariate Cox regression analysis demonstrated that patients with higher plasma MMP-9 levels had a significantly worse overall survival (OS) [hazard ratio (HR) = 4.637, 95% confidence interval (CI) = 1.670 - 12.877, P = 0.003], whereas MPO, ARG1, or TGFß levels were not correlated with OS. Similarly, patients with higher MMP-9 levels showed worse prognosis than those with lower MMP-9 levels in other types of advanced cancers, including non-small cell lung cancer (n=32, P = 0.037 by log-rank test), and pancreatic cancer (n=41, P = 0.042 by log-rank test). Taken together, plasma MMP-9 levels before vaccination might be potentially useful as a biomarker for selecting advanced cancer patients who would benefit from PPV.

Immunological evaluation of peptide vaccination for cancer patients with the HLA-A26 allele.

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.

Phase II study of personalized peptide vaccination for previously treated advanced colorectal cancer.

The prognosis of advanced colorectal cancer (aCRC) remains poor, and development of new therapeutic approaches, including immunotherapy, is needed urgently. Herein we report on our phase II study of personalized peptide vaccination (PPV) in 60 previously treated patients with aCRC, who had failed at least one regimen of standard chemotherapy and/or targeted therapy. For PPV, a maximum of four HLA-matched peptides were individually selected from a pool of 31 different peptide candidates based on preexisting host immunity, and administered subcutaneously without severe adverse events. Boosting of IgG and cytotoxic T lymphocyte (CTL) responses specific to the administered peptides was observed in 49% and 63%, respectively, of the patients, who completed the first cycles of six vaccinations. Median overall survival (OS) time was 498 days, with 1- and 2-year survival rates of 53% and 22%, respectively. Multivariate Cox regression analysis of prevaccination factors showed that plasma IL6, IP-10, and BAFF levels were significantly prognostic for OS [hazard ratio (HR), 1.508, P = 0.043; HR, 1.579, P = 0.024; HR, 0.509, P = 0.002, respectively]. In addition, increased peptide-specific CTL responses after vaccination were significantly predictive of favorable OS (HR, 0.231; P = 0.021), suggesting a causal relationship between biologic and clinical efficacy of PPV. On the basis of the safety profile and potential clinical efficacy, we believe that clinical trials of PPV would be warranted for previously treated patients with aCRC.

Long-term outcome of elderly patients (75 years or older) with hepatocellular carcinoma.

AIM: The aim of this study was to evaluate the long-term outcome of elderly patients with hepatocellular carcinoma (HCC) aged 75 years or older. METHODS: The study included 422 patients with HCC, who were divided into two age groups: 75 years or older (n = 140) and younger than 75 (n = 282). Outcomes were compared between the two groups. RESULTS: The number of elderly patients treated with supportive care alone (33 patients; 24%) was significantly higher than younger patients (30 patients; 11%, P < 0.01). The 1-, 3-, 5- and 7-year overall survival rates of the elderly patients (81%, 55%, 39% and 23%, respectively) were worse than those of younger patients (85%, 64%, 49% and 36%, respectively, P = 0.042). However, the overall survival rate of the elderly group after excluding 63 patients treated with supportive care alone, was similar to that of the younger group (P = 0.615). Multivariate analysis identified age, total bilirubin levels, albumin levels, serum des-γ-carboxy prothrombin levels, tumor size, number of HCC nodules, vascular invasion, extrahepatic metastasis and treatment modality as independent and significant factors of overall survival. CONCLUSION: Advanced age is a negative prognostic factor in patients with HCC due to the tendency for frequent use of conservative treatment rather than locoregional or surgical treatment.

Radiofrequency ablation combined with transarterial chemoembolization for intermediate hepatocellular carcinoma.

AIM: Radiofrequency ablation therapy (RFA) combined with transarterial chemoembolization (TACE) (combination therapy) is effective for early-stage hepatocellular carcinoma (HCC). The aim of this study was to compare the long-term effects of combination therapy with supportive care alone for intermediate HCC. METHODS: The study included 58 patients with intermediate HCC who received combination therapy (n = 34) or supportive care alone (n = 24). The inclusion criteria were a single nodule of more than 50 mm in diameter or two to three nodules, each measuring more than 30 mm in diameter, or more than three nodules, no vascular invasion and no extrahepatic metastasis. RESULTS: The overall survival rates at 1, 2, 3 and 5 years of the combination therapy group (91%, 65%, 53% and 27%, respectively) were significantly better (P < 0.0001) than those of the supportive care group (42%, 8%, 8% and 0%, respectively). Multivariate analysis identified treatment modality (combination therapy vs supportive care alone: P < 0.0001, risk ratio [RR] = 4.290 [95% confidence interval [CI] = 2.157-8.529]) and serum α-fetoprotein (P = 0.017, RR = 2.318 [95% CI = 1.166-4.610]) as independent and significant factors of overall survival. CONCLUSION: The combination of TACE and RFA is a safe and effective therapy in patients with intermediate HCC.

Juzentaihoto Failed to Augment Antigen-Specific Immunity but Prevented Deterioration of Patients' Conditions in Advanced Pancreatic Cancer under Personalized Peptide Vaccine.

Juzentaihoto (JTT) is a well-known Japanese herbal medicine, which has been reported to modulate immune responses and enhance antitumor immunity in animal models. However, it is not clear whether JTT has similar effects on humans. In particular, there is little information on the effects of JTT in antigen-specific immunity in cancer patients. Here we conducted a randomized clinical study to investigate whether combined usage of JTT could affect antigen-specific immunity and clinical findings in advanced pancreatic cancer patients undergoing personalized peptide vaccination (PPV), in which HLA-matched vaccine antigens were selected based on the preexisting host immunity. Fifty-seven patients were randomly assigned to receive PPV with (n = 28) or without (n = 29) JTT. Unexpectedly, JTT did not significantly affect cellular or humoral immune responses specific to the vaccine antigens, which were determined by antigen-specific interferon-γ secretion in T cells and antigen-specific IgG titers in plasma, respectively. Nevertheless, JTT prevented deterioration of patients' conditions, such as anemia, lymphopenia, hypoalbuminemia, plasma IL-6 elevation, and reduction of performance status, which are frequently observed in advanced cancers. To our knowledge, this is the first clinical study that examined the immunological and clinical effects of JTT in cancer patients undergoing immunotherapy in humans.

A phase II study of a personalized peptide vaccination for chemotherapy-resistant advanced pancreatic cancer patients.

Pancreatic cancer is one of the most aggressive cancers with a median survival time (MST) of <6 months in chemotherapy-resistant patients. Therefore, the development of novel treatment modalities is needed. In the present study, a phase II study of personalized peptide vaccination (PPV) was conducted, in which vaccine antigens were selected and administered based on the pre-existing IgG responses to 31 different pooled peptides, for 41 chemotherapy-resistant advanced pancreatic cancer patients. No vaccine-related severe adverse events were observed. IgG responses specific to at least one of the vaccine peptides were augmented in 14 of 36 patients (39%) and in 18 of 19 patients (95%) tested after the 5th and 11th vaccination, respectively. MST from the first vaccination was 7.9 months with a 1-year survival rate of 26.8%. Higher serum amyloid A (SAA) and C-reactive protein (CRP) levels in pre-vaccination plasma were unfavorable factors for overall survival (OS). Due to the safety profile and the potential clinical efficacy, the conduction of additional clinical trials of PPV for chemotherapy-resistant advanced pancreatic cancer patients is warranted.