Personalized Peptide Vaccination Research Articles

A phase I study of personalized peptide vaccination for advanced urothelial carcinoma patients who failed treatment with methotrexate, vinblastine, adriamycin and cisplatin

• To investigate the safety and immune responses of 12 consecutive weeks of once-weekly personalized peptide vaccine (PPV) administration in patients with advanced urothelial carcinoma (UC) for whom therapy with methotrexate, vinblastine, adriamycin and cisplatin (MVAC) has failed. • A phase I trial was designed. Ten patients with MVAC-refractory advanced or metastatic UC were treated with weekly personalized peptide vaccine 12 times using positive peptides chosen from 14 and 16 peptides in patients with human leucocyte antigens A24 and A2, respectively. • Peptide-specific cytotoxic T lymphocyte precursor analysis by interferon-γ production and peptide-reactive immunoglobulin G (IgG) using an enzyme-linked immunosorbent assay was monitored during the treatment. • The peptide vaccination was safe and well tolerated with no major adverse effects. Increased cytotoxic T lymphocyte response and the anti-peptide IgG titre were revealed by the post-vaccination sera in eight patients. • Clinical responses were as follows: one complete response, one partial response, two stable disease and six progressive disease. • Median progression-free survival and overall survival were 3.0 and 8.9 months, respectively. In the four responders, median progression-free survival and overall survival were 21 and 24 months, respectively. • This phase I study showed the safety of and boosted immune responses in response to PPV for advanced UC. • The potential efficacy of 12 consecutive weekly vaccinations with PPV in patients with advanced UC merits further investigation based on these findings.

Assessment of immunological biomarkers in patients with advanced cancer treated by personalized peptide vaccination

To investigate immunological biomarkers to predict overall survival of advanced cancer patients under treatment with personalized peptide vaccination, correlations between overall survival and biomarkers, including cytotoxic T lymphocyte (CTL) and immunoglobulin G (IgG) responses to the vaccinated peptides, were investigated in 500 advanced cancer patients who received personalized peptide vaccination from October 2000 to October 2008. The best clinical response was assessed for in 436 patients, 43 patients (10%) had partial response, 144 patients (33%) had stable disease and 249 patients (57%) had progressive, with a median overall survival of 9.9 months. Both lymphocyte counts prior to the vaccination (P = 0.0095) and increased IgG response (P = 0.0116) to the vaccinated peptides, along with performance status (P < 0.0001), well correlated with overall survival. To confirm the superiority of IgG response to CTL response, the samples from advanced castration-resistant prostate cancer patients who survived more than 900 days (n=20) and those who died within 300 days (n=23) were analyzed further. As a result, both the numbers of peptides, to which increased IgG responses were observed, and the fold increases in IgG levels were significantly higher in long-term survivors (P = 0.000282 and P = 0.00045). In contrast, CTL responses were not statistically different between the two groups. Both lymphocyte numbers and IgG response were thus suggested to be biomarkers of cancer vaccine for advanced cancer patients.

Phase I Trial of a Personalized Peptide Vaccine for Patients Positive for Human Leukocyte Antigen–A24 With Recurrent or Progressive Glioblastoma Multiforme

Personalized selection of suitable peptides for patients could offer a novel approach to developing cancer vaccines that boost anticancer immunity. We present the results of a phase I trial of 14 kinds of vaccine candidates (ITK-1) in patients with recurrent or progressive glioblastoma multiforme (GBM). From January 2006 to January 2008, 12 patients from eight Japanese hospitals who were positive for human leukocyte antigen-A24, including 10 patients refractory to temozolomide (TMZ), were enrolled. The dose escalation trial included three dose groups (1, 3, and 5 mg) to determine the safety and tolerability of ITK-1 peptides. Immunologic response was monitored by measuring levels of cytotoxic T-lymphocyte precursors and peptide-specific immunoglobulin G. In another ITK-1 phase I trial for advanced prostate cancer, the vaccination schedule was skipped or discontinued in all three patients receiving the highest dose (5 mg/peptide) because of injection site reactions. This trial was therefore ended without enrollment for the highest dose, and data were analyzed by intention to treat. No serious adverse drug reactions were encountered, and treatment was well tolerated. The vaccine induced dose-dependent immune boosting. The recommended dose of ITK-1 peptides is 3 mg/peptide. Personalized vaccination with ITK-1 peptides could be recommended in further stages of clinical trials. The safety and increased frequency of immune boosting offers potential clinical benefits in cases of recurrent or progressive GBM, even in TMZ-refractory settings.

Phase I clinical study of a personalized peptide vaccination available for six different human leukocyte antigen (HLA-A2, -A3, -A11, -A24, -A31 and -A33)-positive patients with advanced cancer

The majority of peptide-based cancer vaccines under development are for human leukocyte antigen (HLA)-A2- or -A24-positive patients. To overcome this limitation, we conducted a phase I clinical study of peptide vaccines designed for cancer patients with six different HLA-A types. Eligible patients were required to have failed prior standard cancer therapies and to be positive for the HLA-A2, -A24 or -A3 (A3, A11, A31 and A33) supertype. Three sets of 8 candidate peptides (24 peptides in total) were provided for vaccination to HLA-A2(+), HLA-A24(+) and HLA-A3(+) patients, respectively. Personalization of the vaccination peptides from the candidate pool was made by considering the patients' HLA types and pre-existing levels of IgGs to the candidate peptides. Seventeen patients were enrolled in this study. The peptide vaccinations were well tolerated in all patients with no vaccine-related severe adverse events. Augmentation of cytotoxic T lymphocyte (CTL) or IgG responses specific to the vaccinated peptides was observed in 11 or 10 out of 13 cases tested, respectively. This new type of vaccine is recommended for phase II clinical trial because of its tolerability and the immune responses to the vaccinated peptides.

Characteristics of severe adverse events after peptide vaccination for advanced cancer patients: Analysis of 500 cases

The purpose of this study was to investigate severe adverse events (SAEs) after therapeutic peptide vaccination for advanced cancer patients. We investigated SAEs following personalized peptide vaccinations in 500 advanced cancer patients, including 174 prostate, 74 colon, 51 pancreatic and 43 gastric cancer patients. The number of vaccination cycles varied widely, from 3 to 112. The severity of adverse events was scored according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3, and events with a grade of >3 were defined as SAEs and were evaluated by the Institutional Safety Evaluation Committee. A total of 215 SAEs in 102 patients were recorded during the vaccine trials. The main causes for these events were cancer progression (152 SAEs in 78 patients), combined cancer treatments other than vaccination (35 in 21 patients), diseases other than cancer (20 in 19 patients), peptide vaccines (6 in 6 patients) and suicide (1 in 1 patient). The 6 vaccine-related SAEs, all grade 3, consisted of skin reactions at each injection site, cellulitis around the injection site, edemas of the head and neck regions, colitis, rectal bleeding and bladder-vaginal fistulae. Both cellular and humoral responses to the vaccinated peptides were highly boosted in all 6 of these patients, indicating the involvement of augmented immune responses in these SAEs. The clinical responses in these 6 patients consisted of 2 partial responses and 4 stable diseases. The majority of SAEs after peptide vaccination for advanced cancer patients were caused by cancer progression. The appearance of vaccine-related SAEs, except inflammatory injection site reactions, was unexpected, and fortunately the incidence was very low. Our results suggest that physicians should be on guard for these rare SAEs associated with augmented immune responses.

A phase I study of personalized peptide vaccination using 14 kinds of vaccine in combination with low‐dose estramustine in HLA‐A24‐positive patients with castration‐resistant prostate cancer

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). 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. 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. 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.

Chest Wall and Axillary Lymph Node FDG Uptake Associated With Cancer Vaccine Therapy for Lung Cancer

Cancer vaccines are now undergoing clinical investigations, and clinical trials of therapeutic cancer vaccines have been conducted mainly for advanced cancer patients. We experienced 2 cases of multifocal F-18 fluoro-2-deoxy-D-glucose uptake in the chest wall and axillary lymph nodes associated with personalized peptide vaccine therapy for recurrent lung cancer. In this article, we report fluoro-2-deoxy-D-glucose -positron emission tomography and positron emission tomography/computed tomography findings.

A phase II study of personalized peptide vaccination combined with gemcitabine for non-resectable pancreatic cancer patients

We evaluated the safety of, and clinical and immune responses to personalized peptide vaccination with gemcitabine (GEM) as the first line therapy in patients with non-resectable pancreatic cancer. Pre-vaccination peripheral blood mononuclear cells (PBMCs) and plasma were prepared to examine cellular and humoral responses to 14 and 16 peptides in human leukocyte antigen (HLA)-A24+ or -A2+ patients, respectively. Only the reactive peptides (maximum of 4) were administered weekly at 3 mg/peptide. GEM was administered at 1000 mg/m(2) per week for 3 weeks, followed by 1 week of rest. Twenty-one patients with untreated and non-resectable pancreatic cancer were enrolled. The combination therapy was generally well tolerated. Boosting of cellular and humoral responses to the vaccinated peptides was observed in the post-vaccination (eighth) PBMCs and plasma from 14 of 18 and 13 of 18 patients tested, respectively. The best clinical responses were 7 cases of partial response, 9 cases of stable disease, and 5 cases of progressive disease. Median survival time of all 21 patients was 9.0 months (95% CI, 6-15.5 months) with a one year survival rate of 38%. Immune boosting in both cellular and humoral responses was well correlated with overall survival with a hazard ratio of 0.2 (95% CI, 0.06-0.73; log-rank p=0.0239). These results suggest a potential clinical benefit of this combination therapy for non-resectable pancreatic cancer patients as the first line therapy. Further exploration of this approach is warranted.

Evaluation of a new oil adjuvant for use in peptide‐based cancer vaccination

Vaccine therapies are increasingly being used for the treatment of various diseases, and the antigen molecules themselves are being expanded from whole microorganisms to fine molecules such as peptides. Accordingly, there is a need for new adjuvants to support these new applications. In this paper, we used pharmaceutical grade mineral oil and sorbitan monooleate to develop a new oil adjuvant formula, NH(2) , and investigated its effects on peptide vaccination at both the pre-clinical and clinical levels. The adjuvant effect of NH(2) on peptide-induced cellular immunity in mice was superior to that of Montanide ISA51VG, a commercially available incomplete Freund's adjuvant for clinical use, although no significant difference was observed between the two adjuvants on peptide-induced humoral immunity. The adjuvant effects of NH(2) were also confirmed in a Phase-I clinical trial of peptide vaccines for patients with advanced cancers. These results suggest that NH(2) is a suitable adjuvant for peptide vaccination, particularly for cancer vaccines (Phase-I clinical trial of pan-HLA type personalized peptide vaccine for advanced cancer patients, UMIN clinical trial registry number: UMIN 000000619).

Assessment of immunological biomarkers in patients with advanced cancer treated by personalized peptide vaccination.

e13043 Background: To investigate immunological biomarkers to predict overall survival of advanced cancer patients under treatment with personalized peptide vaccination. Methods: Between October 2000 and October 2008, pre- and post- (sixth) vaccination peripheral blood lymphocytes and plasma from 500 advanced cancer patients under treatment with personalized peptide vaccination were analyzed for measurement of cytotoxic T lymphocyte (CTL) activity and IgG reactive to the vaccinated peptides, respectively. All 500 patients suffered from advanced cancer originating in the prostate (n = 174), colon and rectum (n = 74), pancreas (n = 50), stomach (n = 42), brain (n = 33), uterus (n = 28), lung (n = 22), kidney (n = 13), skin (n = 12), breast (n = 11), bladder and urinary tracts (n = 10), and elsewhere (n = 31).Correlations between overall survival and CTL or IgG response were investigated statistically. Results: The best clinical responses were for 43 PR, 144 SD, and 249 PD with a median overall survival of 9.9 months. Increased CTL or IgG response to at least one of the vaccinated peptides was observed in 199 of 332 (60%) or 187 of 300 (62%) patients tested, respectively. IgG response (P = 0.0015) was superior to CTL response (p = 0.167) with regard to correlation with overall survival. To statistically confirm the superiority of IgG response, the samples from advanced hormone-refractory prostate cancer patients (n = 20) who survived more than 900 days and those from those (n = 23) who died within 300 days were analyzed further. As a result, the number of peptides and the increase in IgG levels were found to be significantly higher in long-term survivors (p = 0.000282 and p = 0.00045, respectively). In contrast, those of CTL responses were not statistically different between the two groups. Conclusions: The measurement of IgG response was suggested as an immunological biomarker for prediction of the overall survival of advanced cancer patients under treatment with personalized peptide vaccination. No significant financial relationships to disclose.

A phase II study of personalized selection of peptide vaccines combined with conventional chemo- or endocrine therapy for refractory breast cancer.

TPS173 Background: Immunotherapy using selected personalized peptide vaccines (PPV) has been reported to be effective for boosting anticancer immunity in many patients (pts) even in an advanced status. This study evaluate the anti-tumor immunologic effect and safety of PPV for pts with refractory breast cancer. Methods: Patient eligibility criteria: all patients had histologically confirmed measurable metastatic breast cancer and their HLA A molecules should be each of HLA-A2, A3, A11, A24, A26, A31 or A33. The following criteria were also required: age > 20 years, life expectancy of at least 3 months, ECOG performance status of 0 or 1, adequate vital organ function (WBC > 2,500/μ L; platelets > 80,000/μ L; serum creatinine < 1.5 mg/dL or creatinine clearance > 50 mL/min; AST and ALT < 2 times the upper limit of the institution's normal range; and total bilirubin < 2.5 mg/dL. All subjects provided written informed consent and the clinical protocol was approved by each institutional review board before patient enrollment. Treatment schedule:Pre- vaccination plasma was measured for their IgG levels reactive to each of the previously reported 31 candidate peptides followed by administration subcutaneously of the four peptides at maximum showing higher levels of IgG in order with schedule of every 1-2 week for a total of 6-24 doses. The concurrent conventional chemotherapy or endocrine therapy was available for the combination of PPV. Study design: This is an open-label, multicenter, single-arm, phase II study. The primary endpoint was anti-tumor immunologic effect and safety, and the secondary endpoints were clinical responses. The planned sample size was 60-80. Immune and clinical response assessment : Levels of IgG reactive to each of the 31 peptides in the pre- and post-treatment plasma at every 6 times of vaccination were measured using LUMNEX system. Clinical response was evaluated by RECIST criteria. Correlation between overall survival and the increased IgG levels was also investigated. No significant financial relationships to disclose.

Immunological evaluation of personalized peptide vaccination monotherapy in patients with castration‐resistant prostate cancer

We previously reported that personalized peptide vaccine (PPV) therapy in combination with leutenizing hormone-releasing hormone (LH-RH) analog and estramustine phosphate in certain cases is safe and capable of inducing both immune responses and clinical responses for metastatic castration-resistant prostate cancer (CRPC) patients. In the present study, PPV monotherapy was given to CRPC patients. Twenty-three patients with metastatic CRPC were treated with PPV without any additional treatment modalities, including LH-RH analogs. Samples were analyzed for peptide-specific cytotoxic T-lymphocyte (CTL) precursor analysis and peptide-reactive IgG. Toxicity and immunological and clinical responses were assessed on a three-monthly basis. Seventeen patients were available for immunological and clinical evaluation. The vaccines were well tolerated, with grade 3 erythema at injection sites in only one patient. Augmentation of CTL or IgG responses to at least one of the peptides was observed in six of 17 (35%) and 15 of 17 (88%) patients tested, respectively. Among 57 peptides used, 9 and 36 peptides induced CTL and IgG responses, respectively. Delayed-type hypersensitivity reaction was observed in eight of 17 patients. More than 30% prostate-specific antigen (PSA) decline was observed in four of 17 patients. Of these, one patient achieved a complete PSA response and another patient showed a partial PSA response with profound shrinking of lymph node metastases and prostate. The overall median survival time was 24 months (range, 5-37 months). These results suggest that PPV monotherapy appears to be safe and capable of inducing peptide-specific immune responses and clinical responses in CRPC patients. This trial was registered with University Hospital Medical Information Network (UMIN) number R000003339.

A randomized trial of personalized peptide vaccine (PPV) plus low-dose estramustine (EMP) versus full-dose EMP in patients with hormone-refractory prostate cancer

3007 Background: Personalized selection of the right peptides for each patient could be a novel peptide-based immunotherapy for boosting anti-cancer immunity in many patients (pts). This randomized study evaluated the anti-tumor effect and safety of PPV plus a low-dose EMP compared with full dose EMP for patients with hormone-refractory prostate cancer (HRPC). Methods: This was a randomized (1:1), open labeled, cross-over study in pts with HRPC. Pts were randomized to arm A; PPV plus low-dose EMP (280 mg/day) or arm B; full dose EMP (560 mg/day) according to age and PSA levels. In arm A, prevaccination plasma were measured for their IgG levels for each of the 14 or 12 candidate peptides which can induce HLA-A2 or A24-restricted CTL activity against cancer cells followed by biweekly subcutaneous administration of the top four peptides (3mg each) showing the strongest IgG responses. Disease progression (PD) was defined as three consecutive and 125% increase from baseline PSA levels at least two weeks apart or objective PD by RECIST criteria. After PD, pts were treated with the opposite regime. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival and toxicity. The planned sample size was 80. Results: A total of 54 pts from 4 institutions were enrolled between June 2006 and December 2008. The accural into arms A and B was 27 and 27 pts, respectively. The main pts characteristics are (arm A/B): median age 71/69 years, EOCG performance status 0/1 96%/4% and 100%/0%, HLA A2/A24/A2A24 40%/32%/28% and 54%/27%/19%, median PSA 27/25 ng/ml, and metastatic HRPC 96%/85%. All pts were evaluable for their response at the time of interim analysis. The personalized peptide vaccination was well tolerated with no major adverse effects. Increased levels of IgG responses to the vaccinated peptides were observed in 20 of 23 (87%) patients tested. The median PFS time was 246 days in the arm A group and 85 days in the arm B, respectively. The PFS time in the arm A was statistically longer than that in the arm B (log-rank test: p = 0.0007, hazard ratio: 0.27, 95%CI: 0.12 to 0.615). Conclusions: PPV plus low-dose EMP was associated with improvement in PSA-based PFS compared to full-dose EMP alone. No significant financial relationships to disclose.

Immunological evaluation of personalized peptide vaccination in combination with UFT and UZEL for metastatic colorectal carcinoma patients.

To investigate the safety and immunological responses of personalized peptide vaccination in combination with oral administration of UFT and UZEL for metastatic colorectal carcinoma (mCRC), fourteen patients were enrolled in the present study. Peptides were determined based on the presence of peptide-specific cytotoxic T lymphocyte precursors and IgG in each patient. A maximum of four peptides were subcutaneously administered weekly with UFT (300 mg/m2 day(-1)) and UZEL (75 mg/day) for 4 weeks, followed by 1 week of rest. This therapy was well-tolerated although there was a grade-3 skin reaction at the vaccination site in one patient. An increase in peptide-specific interferon-gamma production or peptide-specific IgG after the tenth vaccination was observed in nine of ten or eight of ten patients tested, respectively. IgG responses were well correlated with overall survival (P = 0.0215). The safety and immunological responsiveness of the present therapy suggest that this combination would be of clinical benefit for mCRC patients, and further trials are merited.

Dexamethasone did not suppress immune boosting by personalized peptide vaccination for advanced prostate cancer patients

To evaluate the immunological responses of personalized peptide vaccination combined with low-dose glucocorticoids for advanced hormone refractory prostate cancer (HRPC) patients (pts). Eleven pts with advanced HRPC were treated with the vaccination and low-dose glucocorticoids; 6 pts with 10 mg/day of prednisolone (PDL) followed by 1 mg/day of dexamethasone at the time of progression, 1 pt with PDL, and 4 pts with dexamethasone. Peptide-specific cellular and humoral responses were employed to monitor pre- and post- (6th) vaccination samples. The vaccination combined with glucocorticoids was well tolerated with no severe adverse effects. Increments of IgG responses were observed in 1 of 4 or 8 of 10 pts tested who received PDL or dexamethasone, respectively, increment of cytotoxic T lymphocyte activity was observed in 2 of 4 or 5 of 7 pts tested, respectively. Vaccination with PDL or dexamethasone resulted in a decline of PSA (at least 50%) in 1 of 7 or 6 of 10 pts with significantly longer median TTP in the dexamethasone group, respectively. Vaccination combined with dexamethasone could be recommended for further clinical trials from both immunological and clinical points of view.

Immunologic and clinical effects of personalized selection of peptide vaccines in HLA-A2 positive patients with advanced cancer

3031 Background: Personalized selection of the right peptides for each patient could be a novel peptide-based immunotherapy for boosting anticancer immunity in many patients (pts). Here we describe immunologic and clinical effects of a personalized peptide vaccine for HLA-A2 positive advanced cancer pts who mostly failed the standard therapy. Methods: To evaluate safety and immune responses of vaccination, 74 HLA-A2 positive advanced cancer pts, including 27 hormone refractory prostate cancer (HRPC), 13 colon cancer (CC), 8 pancreatic cancer (PC), 6 gastric cancer (GC), 4 brain tumor (BT), and 16 other types of cancer (Others) pts were enrolled in a phase I/II clinical trial. Pre-vaccination peripheral blood mononuclear cells and/or plasma were measured for their CTL or IgG levels for each of the 14–20 candidate peptides which can induce HLA-A2-restricted CTL activity against cancer cells followed by weekly or bi-weekly subcutaneous administration of the top four peptides (3mg each) showing the strongest immune responses. The protocol was approved by each ethics committee. Results: Vaccination-related adverse events were mainly grade 1 or 2 skin reactions at the injection sites, and there were no severe adverse events except for rectal bleeding in a cervical cancer pt. In the post (6–8th)-vaccination samples, CTL responses were boosted in 46 of 70 pts tested, while IgG responses were boosted in 55 of 73 pts tested, respectively. Best clinical responses were 1 CR, 11 PR, 31 SD, and 31 PD. Objective responses were obtained in urologic and gynecologic cancers or brain tumors by vaccination in the thigh or upper back regions, respectively, suggesting that location of sentinel lymph node near to tumor site is a pivotal factor for tumor regression. Median survival times in all pts are 14.3 months: 25 months in HRPC, 9.7 in BT, 8 in GC, 7 in PC, 6 in CC, and 17 in Others, respectively. Conclusions: This personalized peptide vaccine could be recommended for further stages of clinical trials because of safety, boosting of immune responses, and potential clinical benefits. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GreenPeptide GreenPeptide GreenPeptide GreenPeptide

A multicenter phase I/II study of gemcitabine and personalized peptide vaccination combination therapy for metastatic pancreatic cancer patients

4633 Background: The present multicenter phase I/II study was conducted to confirm the efficacy and toxicity of immunochemotherapy for metastatic pancreatic cancer. Methods: HLA-A2 or A24 positive patients with histologically or cytologically proven pancreatic adenocarcinoma with at least one measurable metastatic lesion were eligible for the study. Other eligibility criteria included: age of 20–80 years, ECOG performance status (PS) of 0 or 1, and adequate organ function. Gemcitabine was given intravenously at a dose of 1,000 mg/m2 over 30 min once a week for three weeks, followed by 1 week of rest, and three or four peptides that had been positive for pre-existing peptide-specific immune responses in the circulation (personalized peptide vaccine) were injected subcutaneously in the femoral area once a week. The objective response rate was assessed according to RECIST. Results: Twenty patients from 2 institutions were enrolled in this study. The median age was 63 years (range: 41–80 years). The PS was 0 in 10 patients (50%) and 1 in 10 patients (50%). The efficacy and toxicity were analyzed in 20 patients who received at least one course (8 weeks) of immunochemotherapy. Although no complete response was seen, a partial response was achieved in 5 patients, resulting in an overall response rate of 25%. Eleven patients (55%) had stable disease. The median overall survival was 8.5 months with a 1-year survival rate of 33%. The major grade 3–4 toxicities using CTCAE criteria were neutropenia (25%), anemia (20%), thrombocytopenia (20%) and anorexia (5%). All 17 dermatologic reactions at the vaccination site were scored as grade 1 or 2. No treatment-related deaths occurred during the study. Augmentation of peptide-specific CTL responses in the post-vaccination peripheral blood mononuclear cells was observed in 72%, while increased titer of peptide-specific IgG antibodies was observed in the post-vaccination plasma in 78%. Conclusions: This study could be recommended for further stages of clinical trials because of safety, boosting of immune responses, and potential clinical benefits. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GreenPeptide GreenPeptide GreenPeptide Grant-in-Aid for Scientific Research from Research Center of Innovative Cancer Therapy of the 21st Century COE Program for Medical Science of Japan, Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan

Phase I trial of personalized peptide vaccine for HLA-A24 positive patients with advanced cancer

3079 Background: A personalized selection of the right peptides for each patient could be a novel approach of cancer vaccine for boosting anti-cancer immunity in the majority of patients. Our approach is a pre-vaccination measurement of peptide-specific IgG in cancer patients reactive to 14 kinds of vaccine candidates (ITK-1) with the ability to induce CTLs, followed by administration of only reactive peptides (personalized peptide vaccine). Methods: To evaluate safety, tolerability and immune responses of the vaccination, 27 HLA-A24 positive patients with advanced cancer, 12 recurrent glioblastoma multiforme (GBM) and 15 advanced hormone-refractory prostate cancer (HRPC) patients, were enrolled in a phase I clinical trial. Pre-vaccination plasma was measured for their IgG levels to each of ITK-1 peptides followed by weekly subcutaneous administration of the top four peptides showing the strongest antibody responses for 6 times at the 3 different dose settings (1mg, 3mg, and 5mg per peptide). The protocol was approved by each ethics committee. Results: There were no severe adverse events, but grade 2 skin reactions at the injection sites were observed in 3 of 12 patients receiving 1mg/peptide, and 8 of 12 patients receiving 3mg. Vaccination schedule was skipped or disconnected in 3 of 3 patients receiving 5mg because of both grade 2 skin reactions in wider regions and patients’ claim. The recommended dose of ITK-1 peptides is 3mg/peptide in patients with advanced cancer. In the post (6th)-vaccination samples, CTL responses measured by IFN-γ release assay were boosted in 8 of 12 patients with 1mg/peptide and 9 of 11 patients with 3mg/peptide tested, while IgG responses were boosted in 5 of 12 and 5 of 11 pts, respectively. After the 6th vaccination, a prostate-specific antigen decline of at least 30 percent occurred in 1 and 3 of each 6 HRPC patients with 1mg and 3 mg/peptide, respectively. Two recurrent GBM patients showed partial response by RECIST criteria when received continuing vaccination. Conclusions: This personalized vaccine with ITK-1 peptides could be recommended for further stages of clinical trials because of safety, higher frequency of immune responses with potential clinical benefits. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GreenPeptide GreenPeptide GreenPeptide GreenPeptide GreenPeptide GreenPeptide

Phase I trial of personalized peptide vaccination for cytokine‐refractory metastatic renal cell carcinoma patients

The aim of this clinical trial was to investigate the toxicity and immunological responses of personalized peptide vaccination for cytokine-refractory metastatic renal cell carcinoma patients. Patients were confirmed to be human leukocyte antigen (HLA)-A24 or HLA-A2 positive and had histologically confirmed renal cell carcinoma. Ten patients were enrolled in the present study. The peptides to be administered were determined based on the presence of peptide-specific cytotoxic T lymphocyte precursors in peripheral blood mononuclear cells (PBMC) and peptide-specific IgG in the plasma of cancer patients. Patients received subcutaneous injections of four different peptides (3 mg/peptide) every 2 weeks. Vaccinations were well tolerated without any major adverse events. A minimal increase in peptide-specific interferon-gamma production in postvaccination PBMC was observed, regardless of higher levels of cytotoxic T lymphocyte activity in prevaccination PBMC. In contrast, an increase in peptide-specific IgG levels of postvaccination (sixth) plasma was observed in the majority of patients. After progression, five patients received interleukin-2 therapy and continuous vaccination, with survival of 31, 25, 23, 17, and 15 months, but interleukin-2 did not impede humoral responses boosted by the vaccination. These results encourage further clinical trials of personalized peptide vaccinations.

Phase I clinical study of a personalized peptide vaccination for patients infected with hepatitis C virus (HCV) 1b who failed to respond to interferon-based therapy

To assess the safety and immune responses to a personalized peptide vaccination of hepatitis C virus (HCV) 1b-derived peptides, 12 HCV1b-positive patients, who were unresponsive to interferon-based therapy, were enrolled in this study. The reactivity of the pre-vaccination peripheral blood T cells and plasma IgG to four vaccine candidate peptides capable of inducing cytotoxic T lymphocytes (CTLs) in HLA-A24 + patients was examined and only the reactive peptides were then administered bi-weekly at three different dose settings. The study was well tolerated with no severe toxicity. Augmentation of peptide-specific CTL activity and IgG in response to at least one of the vaccinated peptides was observed after the 7th vaccination. Decrease of serum alanine aminotransferase and HCV-RNA levels after the 14th vaccination was also observed in five and three patients, respectively.