Telomerase Peptide Vaccination Research Articles

A phase II study of chemotherapy in combination with telomerase peptide vaccine (GV1001) as second-line treatment in patients with metastatic colorectal cancer.

Background: GV1001 is a human telomerase peptide vaccine that induces a CD4/CD8 T-cell response against cancer cells, thereby affording an immunological anti-tumor effect. Here, we evaluated the efficacy and safety of GV1001 in combination with chemotherapy in patients with metastatic colorectal cancer who had failed first-line chemotherapy.Methods: This multicenter, non-randomized, single-arm phase II study recruited recurrent or metastatic colorectal cancer patients with measurable disease who had failed first-line chemotherapy. Patients received GV1001 and chemotherapy concomitantly based on a pre-established schedule. Cytotoxic chemotherapy and targeted agents (bevacizumab, cetuximab, or aflibercept) were allowed to be used at the discretion of the investigator. The primary endpoint was the disease control rate; secondary endpoints were the objective response rate, progression-free survival, overall survival, and safety outcomes. The baseline serum eotaxin level (a potential predictive biomarker of GV1001) was analyzed. To determine whether an adequate immune response had been induced, a delayed-type hypersensitivity test and a T-cell proliferation test were performed.Results: From May 13, 2015 to October 13, 2020, 56 patients with recurrent or metastatic colorectal cancer treated in seven hospitals of South Korea were enrolled. The median patient age was 64 years (range, 29-82 years); 67.9% were men. Of all patients, 66.1% had left-side colorectal cancer and the RAS mutation was present in 25%. The disease control rate and the objective response rates were 90.9% (95% confidence interval [CI]: 82.4-99.4%) and 34.1% (95% CI, 20.1-48.1%), respectively. The median progression-free survival was 7.1 months (95% CI, 5.2-9.1 months) and the median overall survival was 12.8 months (95% CI, 9.9-15.8 months). The most common all-grade adverse events were neutropenia (48.2%), nausea (26.8%), neuropathy (25.0%), stomatitis (21.4%), and diarrhea (21.4%). Immune response analysis showed that no patient had positive delayed-type hypersensitivity test results; antigen-specific T-cell proliferation was observed in only 28% of patients. The baseline eotaxin level was not associated with any efficacy outcome.Conclusion: Although no clear GV1001-specific immune response was observed, the addition of GV1001 vaccination to chemotherapy was tolerable and associated with modest efficacy outcomes.

1154P - Telomerase peptide vaccine combined with ipilimumab in metastatic melanoma: Reports from a phase I trial

1154P - Telomerase peptide vaccine combined with ipilimumab in metastatic melanoma: Reports from a phase I trial

1154P - Telomerase peptide vaccine combined with ipilimumab in metastatic melanoma: Reports from a phase I trial

1154P - Telomerase peptide vaccine combined with ipilimumab in metastatic melanoma: Reports from a phase I trial

The anti-fibrotic effect of GV1001 combined with gemcitabine on treatment of pancreatic ductal adenocarcinoma.

GV1001 is a telomerase-based cancer vaccine made of a 16-mer telomerase reverse transcriptase (TERT) peptide, and human TERT, the rate-limiting subunit of the telomerase complex, is an attractive target for cancer vaccination. The aim of this study was to evaluate the effect of telomerase peptide vaccination, GV1001 combined with gemcitabine in treatment of pancreatic ductal adenocarcinoma (PDAC). Human PDAC cell lines were used in vitro experiment and also, PDAC xenograft mice model was established using PANC1, AsPC1 and CD133+ AsPC1 (PDAC stem cell). Treatment groups were divided as follows; control, gemcitabine, GV1001, gemcitabine and GV1001 combination. The inflammatory cytokines were measured from the blood, and xenograft tumor specimens were evaluated. GV1001 treatment alone did not affect the proliferation or the apoptosis of PDAC cells. Gemcitabine alone and gemcitabine with GV1001 groups had significantly reduced in tumor size and showed abundant apoptosis compared to other treatment groups. Surprisingly, xenograft PDAC tumor specimens of gemcitabine alone group had been replaced by severe fibrosis whereas gemcitabine with GV1001 group had significantly less fibrosis. Blood levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β increased in gemcitabine alone group, however, it was decreased in gemcitabine with GV1001 group. GV1001 combined with gemcitabine treatment showed significant loss of fibrosis in tumor tissue as well as tumor cell death. Therefore, further investigation of GV1001 effect combined with gemcitabine treatment may give us useful insights to overcome the hurdle in anti-cancer drug delivery over massive fibrosis around PDACs.

Abstract B141: Combining the telomerase peptide cancer vaccine UV1 with CTLA-4 blockade in patients with metastatic malignant melanoma: Proof of principle and early clinical reports from a phase I/IIa trial

Abstract The purpose of this clinical phase I/IIa, open label, single arm, interventional study (EudraCT No 2013-005582-39) is to investigate the safety, clinical and immunological responses of a therapeutic telomerase peptide vaccine, UV1, combined with ipilimumab in patients with metastatic melanoma (MM). The CTLA-4 antibody ipilimumab produces long term survival benefits in ca.20% of patients with MM. The mechanism of action of ipilimumab suggests that combinations with therapies inducing tumor-specific immune responses, such as vaccines, may lead to additive and even synergistic anti-tumor activity. We hypothesized that a telomerase peptide-based vaccine in combination with ipilimumab would improve therapeutic efficacy in patients with MM. Telomerase promotes elongation of telomeres after each cell division, representing the key enzymatic process in preventing telomere shortening. It is responsible for human cell immortalization and cancer pathogenesis, and is present in 85-90% of cancer tissues. Thus, telomerase-based immunotherapy has been investigated in several tumor types. Available blood samples from long term cancer survivors previously treated with different types of human telomerase reverse transcriptase subunit (hTERT) vaccines identified a new set of peptide epitopes. T cell responses to these peptides form spontaneously after vaccination by epitope spreading and are found only in patients with remarkable clinical courses, suggesting a role in tumor eradication. This led to the development of UV1, a therapeutic cancer vaccine consisting of a mixture of 3 synthetic peptides representing naturally occurring fragments of human hTERT. Ongoing phase I/IIa trials with UV1 in non-small-cell lung cancer and prostate cancer (EudraCT No 2012-001852-20 and 2012-002411-26, respectively) have shown potent, durable T cell responses against UV1 peptides and low toxicity (unpublished data). In the present protocol, patients with a histologically or cytologically confirmed diagnosis of unresectable AJCC stage III/IV MM, ECOG 0-1 and an adequate renal, hepatic and hematological function are eligible. Any previous treatment is allowed. Patients with active brain metastases, a history of autoimmune disease, splenic surgery or irradiation, allogenic stem cell transplantation, known hypersensitivity to the investigational products, uncontrolled infectious disease, pregnant or breastfeeding, will be excluded. Intradermal UV1 vaccines of 300 mcg and 75 mcg GM-CSF are administered 7, 5, and 3 days before and 11 days after the first dose of ipilimumab, then 3 days before every dose of ipilimumab, and subsequently every 4th week until week 48 or treatment cessation. Ipilimumab 3 mg/kg is given IV every 3rd week for a total of 4 doses. Each patient will be followed up 5 weeks after the completion of the last study treatment. Adverse events are recorded in coherence with CTCAE vs. 4.0. Tumor response is evaluated according to RECIST vs.1.1. Immune responses against UV1 peptides are monitored by standard immunoassays. Potential predictive biomarkers will be explored in an extensive program involving sequential tumor biopsies, DNA sequencing and mRNA expression. The first patient was enrolled 16 January 2015, estimated completed recruitment by one year. 3 out of 20 patients have been recruited so far. Data from the first 3 patients until week 16 will be reported. Citation Format: Elin Aamdal, Tormod Kyrre Guren, Else Marit Inderberg Suso, Gunnar Kvalheim, Jon Amund Kyte, Øyvind Kongstun Arnesen, Steinar Aamdal, Gustav Gaudernack. Combining the telomerase peptide cancer vaccine UV1 with CTLA-4 blockade in patients with metastatic malignant melanoma: Proof of principle and early clinical reports from a phase I/IIa trial. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B141.

Immunological factors influencing clinical outcome in lung cancer patients after telomerase peptide vaccination.

We have previously reported two trials in non-small cell lung cancer (NSCLC) evaluating vaccine therapy with the telomerase peptide GV1001. The studies demonstrated considerable differences in survival among immune responders, highlighting that an immune response is not necessarily beneficial. In the present study, we conducted long-term clinical follow-up and investigated immunological factors hypothesized to influence clinical efficacy. Peripheral blood mononuclear cells from 33 NSCLC trial patients and 15 healthy donors were analyzed by flow cytometry for T regulatory cells (Tregs, CD4(+)CD25(+)CD127(low/-)FOXP3(+)) and two types of myeloid-derived suppressor cells (MDSCs, HLA-DR (low) CD14 (+) or Lin (-/lo) HLA-DR (-) CD33 (+) CD11b (+)). T cell cultures were analyzed for 17 cytokines. The results demonstrated that immune responders had increased overall survival (OS, p < 0.001) and progression-free survival (p = 0.003), compared to subjects without immunological response. The mean OS advantage was 54 versus 13 months. Six patients were still alive at the last clinical update, all belonging to the immune responders. No serious toxicity had developed (maximum observation 13 years). Most patients developed a polyfunctional cytokine profile, with high IFNγ/IL-4 and IFNγ/IL-10 ratios. Low Treg levels were associated with improved OS (p = 0.037) and a favorable cytokine profile, including higher IFNγ/IL-10 ratios. High CD33(+) MDSC levels were associated with poorer immune response rate (p = 0.005). The levels of CD14(+) MDSC were significantly higher in patients than in healthy controls (p = 0.012). We conclude that a randomized GV1001 trial in NSCLC is warranted. The findings suggest that Tregs and MDSCs are associated with a tolerogenic cytokine milieu and impaired clinical efficacy of vaccine responses.

Gemcitabine and capecitabine with or without telomerase peptide vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer (TeloVac): an open-label, randomised, phase 3 trial

We aimed to assess the efficacy and safety of sequential or simultaneous telomerase vaccination (GV1001) in combination with chemotherapy in patients with locally advanced or metastatic pancreatic cancer. TeloVac was a three-group, open-label, randomised phase 3 trial. We recruited patients from 51 UK hospitals. Eligible patients were treatment naive, aged older than 18 years, with locally advanced or metastatic pancreatic ductal adenocarcinoma, and Eastern Cooperative Oncology Group performance status of 0-2. Patients were randomly assigned (1:1:1) to receive either chemotherapy alone, chemotherapy with sequential GV1001 (sequential chemoimmunotherapy), or chemotherapy with concurrent GV1001 (concurrent chemoimmunotherapy). Treatments were allocated with equal probability by means of computer-generated random permuted blocks of sizes 3 and 6 in equal proportion. Chemotherapy included six cycles of gemcitabine (1000 mg/m(2), 30 min intravenous infusion, at days 1, 8, and 15) and capecitabine (830 mg/m(2) orally twice daily for 21 days, repeated every 28 days). Sequential chemoimmunotherapy included two cycles of combination chemotherapy, then an intradermal lower abdominal injection of granulocyte-macrophage colony-stimulating factor (GM-CSF; 75 μg) and GV1001 (0·56 mg; days 1, 3, and 5, once on weeks 2-4, and six monthly thereafter). Concurrent chemoimmunotherapy included giving GV1001 from the start of chemotherapy with GM-CSF as an adjuvant. The primary endpoint was overall survival; analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN4382138. The first patient was randomly assigned to treatment on March 29, 2007, and the trial was terminated on March 27, 2011. Of 1572 patients screened, 1062 were randomly assigned to treatment (358 patients were allocated to the chemotherapy group, 350 to the sequential chemoimmunotherapy group, and 354 to the concurrent chemoimmunotherapy group). We recorded 772 deaths; the 290 patients still alive were followed up for a median of 6·0 months (IQR 2·4-12·2). Median overall survival was not significantly different in the chemotherapy group than in the sequential chemoimmunotherapy group (7·9 months [95% CI 7·1-8·8] vs 6·9 months [6·4-7·6]; hazard ratio [HR] 1·19, 98·25% CI 0·97-1·48, p=0·05), or in the concurrent chemoimmunotherapy group (8·4 months [95% CI 7·3-9·7], HR 1·05, 98·25% CI 0·85-1·29, p=0·64; overall log-rank of χ(2)2df=4·3; p=0·11). The commonest grade 3-4 toxic effects were neutropenia (68 [19%] patients in the chemotherapy group, 58 [17%] patients in the sequential chemoimmunotherapy group, and 79 [22%] patients in the concurrent chemoimmunotherapy group; fatigue (27 [8%] in the chemotherapy group, 35 [10%] in the sequential chemoimmunotherapy group, and 44 [12%] in the concurrent chemoimmunotherapy group); and pain (34 [9%] patients in the chemotherapy group, 39 [11%] in the sequential chemoimmunotherapy group, and 41 [12%] in the concurrent chemoimmunotherapy group). Adding GV1001 vaccination to chemotherapy did not improve overall survival. New strategies to enhance the immune response effect of telomerase vaccination during chemotherapy are required for clinical efficacy. Cancer Research UK and KAEL-GemVax.

An exploratory phase I trial of immunochemoradiotherapy in locally advanced and borderline resectable (LA/BR) pancreatic adenocarcinoma (PC).

174 Background: The primary aim of this exploratory trial was to determine the feasibility and safety of chemoradiotherapy (CRT) with combinatorial immunotherapy in LA or BR PC. Methods: 10 patients (pts) with untreated, LA (n=6) or BR (n=4) biopsy-proven PC received gemcitabine (GEM) in combination with telomerase peptide vaccine (GV1001) and sargramostim (GM-CSF) both by intradermal injection. Tadalafil was taken once daily throughout the course of therapy for myeloid derived suppressor cell inhibition. The 2nd month of treatment included external beam radiation therapy (50.4 Gy, 28 fractions) and concurrent twice-weekly GEM 50 mg/m2. Disease response was assessed at 12 weeks. Following recovery from either concurrent CRT or resection, 8 weeks of GV1001 + GM-CSF, tadalafil and GEM completed treatment. Peripheral blood was analyzed by quantitative multiparameter whole blood flow cytometry of immune cell subtypes. Samples were also cryo-preserved for future analysis of peripheral blood mononuclear cell (PBMC) populations and ELISPOT analysis of antigen-specific T cell numbers. Tumor resection specimens were sectioned for immunohistological analysis of macrophage and T cell infiltration. Results: 9 of 10 pts completed therapy to assess response. Grade (Gr) 3-4 hematologic adverse events (AE) were observed during CRT. Immune-related AE were infrequent and mild. 3 of 4 pts with BR disease and 1 with initial LA (unresectable) disease achieved R0 resection. No unanticipated surgical complications were observed. Changes in monocytes and granulocytes occurred throughout treatment and may correlate with clinical benefit. At least 50% reduction in serum CA19-9 was observed in 8 pts. Partial response (n=2) or stable disease (n=7) was achieved in 9 pts. Conclusions: Combinatorial immunotherapy concurrent with GEM-based CRT is feasible and appears safe in LA or BR PC. Initial biochemical responses as well as disease control were observed in the majority of pts. Preliminary immune correlative data suggest a relationship between hematopoietic populations and clinical response.

Telomerase Peptide Vaccination in NSCLC: A Phase II Trial in Stage III Patients Vaccinated after Chemoradiotherapy and an 8-Year Update on a Phase I/II Trial

We report two clinical trials in non-small cell lung cancer (NSCLC) patients evaluating immune response, toxicity, and clinical outcome after vaccination with the telomerase peptide GV1001: a phase II trial (CTN-2006) in patients vaccinated after chemoradiotherapy and an 8-year update on a previously reported phase I/II trial (CTN-2000). CTN-2006: 23 inoperable stage III patients received radiotherapy (2 Gy × 30) and weekly docetaxel (20 mg/m(2)), followed by GV1001 vaccination. CTN-2000: 26 patients were vaccinated with two telomerase peptides (GV1001 and I540). The immune responses were evaluated by T-cell proliferation and cytokine assays. CTN-2006 trial: a GV1001-specific immune response developed in 16/20 evaluable patients. Long-term immunomonitoring showed persisting responses in 13 subjects. Serious adverse events were not observed. Immune responders recorded a median PFS of 371 days, compared with 182 days for nonresponders (P = 0.20). CTN-2000 trial update: 13/24 evaluable subjects developed a GV1001 response. The immune responders achieved increased survival compared with nonresponders (median 19 months vs. 3.5 months; P < 0.001). Follow-up of four long-time survivors showed that they all harbored durable GV1001-specific T-cell memory responses and IFNγ(high)/IL-10(low)/IL-4(low) cytokine profiles. Two patients are free of disease after 108 and 93 months, respectively. Vaccination with GV1001 is well tolerated, immunizes the majority of NSCLC patients and establishes durable T-cell memory. The considerable immune response rate and low toxicity in the phase II trial support the concept of combining chemoradiotherapy with vaccination. The survival advantage observed for immune responders warrants a randomized trial.

Telomerase Peptide Vaccination Combined with Temozolomide: A Clinical Trial in Stage IV Melanoma Patients

The study is a proof-of-principle trial evaluating toxicity, immune response, and clinical response in melanoma patients after combined therapy with temozolomide and the telomerase peptide vaccine GV1001. Our previous GV1001 trials showed immune responses in approximately 60% of lung or pancreatic cancer patients. Twenty-five subjects with advanced stage IV melanoma (M1B or M1C) received concomitant temozolomide and GV1001. Temozolomide was administered 200 mg/m² orally for 5 days every fourth week, and GV1001 as eight injections over 11 weeks. Immune response was evaluated by delayed type hypersensitivity, T-cell proliferation, and cytokine assays. The immunologic responders continued monthly vaccination. The treatment was well tolerated. A GV1001-specific immune response was shown in 18 of 23 evaluated subjects (78%). Patients developing long-term T-cell memory survived more than those rapidly losing their responses. The immune response exhibited several characteristics of possible clinical significance including high IFNγ/IL-10 ratios, polyfunctional cytokine profiles, and recognition of naturally processed antigens. Survival compared favorably with matched controls from a benchmark meta-analysis (1 year: 44% vs. 24%, 2 years: 16% vs. 6.6%). The clinical responses developed gradually over years, contrary to what is expected from chemotherapy. Five patients developed partial tumor regression and six more recorded stable disease. One patient has no remaining disease on fluorodeoxyglucose positron emission tomography scans after 5 years. The immunologic response rate is considerable compared with previous GV1001 trials without concomitant chemotherapy, although low toxicity is retained. The results warrant further studies of GV1001/temozolomide treatment and support the general concept of combining cancer vaccination with chemotherapy.

Highlights of This Issue

To explore the value of HER2 as a target in ovarian cancer, Faratian and colleagues evaluated the combination of the HER2-directed antibodies trastuzumab and pertuzumab in xenograft models. They found that the antibody combination was effective against high HER2-expressing tumors. Size, apoptosis, morphology, and estrogenregulated gene expression were modulated by the antibodies in a spatial and temporal manner. Further, trastuzumab increased ERα expression and enhanced sensitivity to letrozole. These results suggest that trastuzumab in combination with pertuzumab could be an effective treatment for high HER2-expressing ovarian cancers, and could also enhance sensitivity to endocrine therapy in ERα-positive ovarian cancer.Klotho is a transmembrane protein that can be shed and act as a circulating hormone. Here, Abramovitz and colleagues explored the expression and function of klotho in pancreatic cancer. They found that klotho expression was reduced in human pancreatic adenocarcinoma. Treatment with klotho or with KL1 internal repeat effectively slowed the growth of pancreatic cancer cells in vitro and in vivo and inhibited activation of the IGF-1 and FGF pathways. These findings indicate that klotho acts as a tumor suppressor and suggest that klotho may be used therapeutically or as a diagnostic marker in pancreatic cancer.In this issue, Kyte and colleagues report a trial evaluating combined therapy with temozolomide and the telomerase peptide vaccine GV1001 in advanced melanoma patients. They found that 18 of 23 subjects developed a telomerase-specific immune response, without notable toxicity. Patients developing longterm immunologic memory survived longer than those who rapidly lost immune response. Five patients developed partial tumor regression and overall survival (intention-totreat population) was extended compared with matched controls from a benchmark meta-analysis. These findings warrant further studies of GV1001/temozolomide treatment and support the concept of combining cancer vaccination with chemotherapy.Variable individual response to opioid therapy for cancer pain is an important problem in the clinical management of patients. In this issue, Galvan and colleagues carried out a genome-wide association study in 1,008 cancer patients undergoing opioid therapy. They identified eight genetic polymorphisms significantly associated with poor response to opioid therapy. Genes related to nerve impulse transmission rather than genes implicated in opioid pharmacology were tagged. These findings may represent a starting point to define therapeutic target(s) for countering poor pain relief, leading to improved quality of life for cancer patients.

Novel Therapies for Pancreatic Cancer: Setbacks and Progress

Pancreatic cancer continues to be one of the most difficult malignancies to treat. It is ranked tenth in cancer incidence but is the fourth leading cause of cancer mortality [1]. At present, surgery for resectable tumor and gemcitabine-based chemotherapy for advanced disease are the main forms of treatment; yet disturbingly, its 5-year survival rate of 5% has not improved over the last 30 years. Clearly, there is an urgent need for new therapeutic strategies. Years of intensive research have made pancreatic cancer one of the most described diseases in terms of its molecular biology and pathogenesis, and with that, many therapeutic targets have been identified [2]. One example is the activation of the EGF-receptor (EGFR) signaling pathway. Erlotinib, an EGFR tyrosine kinase inhibitor, was the first targeted therapy to be approved by the US FDA in 2005 for pancreatic cancer treatment. Although it has shown a statistically significant benefit in combination with gemcitabine in a Phase III trial of advanced pancreatic cancer, improvement in survival was small (median survival of 6.24 vs 5.91 months with gemcitabine alone) and appears to favor a subgroup of patients, such as males and those who developed a more severe skin rash [3]. However, cetuximab, a monoclonal antibody that also inhibits EGFR, was ineffective against advanced pancreatic cancer [4]. In fact, a number of other targeted agents have been tested in Phase III trials, including those against VEGF (bevacizumab), gastrin (G17DT), gastrin receptor (gastrazole), Ras farnesyltransferase (tipifarnib) and matrix metalloproteinases (marimastat and tanomastat), but have all failed to make any measurable impact on patient survival [2]. More recently, a Phase III trial of immunotherapy using the GV1001 telomerase peptide vaccine (telomerase is expressed in the majority of pancreatic cancers and contributes to cell immortalization) was stopped prematurely as results showed no survival benefit in combination with gemcitabine in advanced pancreatic cancer patients [5].

A phase II open label trial evaluating safety and efficacy of a telomerase peptide vaccination in patients with advanced hepatocellular carcinoma

BackgroundThe sole effective option for patients with advanced HCC is sorafenib and there is an urgent need to develop new therapeutic approaches. Immunotherapy is a promising option that deserves major investigation. In this open label, single arm clinical trial, we analyzed the effect of a low dose cyclophosphamide treatment in combination with a telomerase peptide (GV1001) vaccination in patients with advanced HCC.Methods40 patients with advanced HCC were treated with 300 mg/m2 cyclophosphamide on day -3 followed by GM-CSF + GV1001 vaccinations on days 1, 3, 5, 8, 15, 22, 36 followed by 4-weekly injections. Primary endpoint of this phase II trial was tumor response; secondary endpoints evaluated were TTP, TTSP, PFS, OS, safety and immune responses.ResultsNone of the patients had a complete or partial response to treatment, 17 patients (45.9%) demonstrated a stable disease six months after initiation of treatment. The median TTP was 57.0 days; the median TTSP was estimated to be 358.0 days. Cyclophosphamide, GV1001 and GM-CSF treatment were well tolerated and most adverse events, which were of grade 1 or 2, were generally related to the injection procedure and injection site reactions. GV1001 treatment resulted in a decrease in CD4+CD25+Foxp3+ regulatory T cells; however, no GV1001 specific immune responses were detected after vaccination.ConclusionsLow dose cyclophosphamide treatment followed by GV1001 vaccinations did not show antitumor efficacy as per tumor response and time to progression. Further studies are needed to analyze the effect of a combined chemo-immunotherapy to treat patients with HCC.Trial registrationNCT00444782

The way forward in treating pancreatic cancer

The way forward in treating pancreatic cancer

A randomized phase III study of gemcitabine (G) versus GV1001 in sequential combination with G in patients with unresectable and metastatic pancreatic cancer (PC)

4601 Background: A phase I/II study with GV1001, a telomerase peptide vaccine, showed a median overall survival (OS) of 8.6 months in non-resectable PC (Bernhardt SL et al, Br J Cancer. 2006;95:1474–1482). This phase III trial was conducted to determine the impact on overall survival of G monotherapy vs. GV1001 in sequential combination with G in unresectable and metastatic PC. Methods: Eligible patients (pts) had chemotherapy-naive, advanced PC and ECOG performance status 0–1. Pts were randomized 1:1 to receive arm A: G (1,000 mg/m2 30 min i.v.) weekly for 7 weeks (w), 1w off and then 3w during 4-weekly cycles, or arm B: GV1001 0.56 mg s.c. plus GM-CSF as immune adjuvant on days 1, 3, 5, 8, 15, 22, 36, then every 4 weeks. Patients who progressed clinically or radiologically during GV1001 continued on GV1001 and concomitant gemcitabine. CT scans were performed every 8 weeks. The primary end-point was OS. A sample size of 520 patients allowed the detection of a hazard ratio (HR) of 0.73 (B/A), with 2α = 0.05 and 90% power. Results: Between June 2006 and May 2008, 365 pts were enrolled (A / B; 182 / 183). The study was stopped prematurely due to a preliminary analysis with 178 events showing no survival benefit of GV1001. Pts were well balanced for baseline characteristics: male 59.3% / 62.8%; median age 61y / 61y; ECOG PS 0 34.3% / 36.7%; locally advanced 22.4% / 20.7%. As of August 2008, 238 pts (A / B : 114 / 124) had died. Median OS was 7.3 / 5.9 months (HR 0.8; 95% CI 0.6–1.0). Median progression-free survival (PFS) was 3.7 / 1.9 months (HR 0.5; 95%CI 0.4–0.7). Grade 3–4 AEs: gastrointestinal 6% / 8%, infection 5% / 5%, vascular disorders 2% / 3%, neutropenia 6% / 3%. Conclusions: GV1001 did not show efficacy in sequential combination with G in advanced PC. The advantage of G monotherapy over the sequential combination may be due to the delayed treatment with G in arm B. [Table: see text]

Telomerase peptide vaccination of patients with non-resectable pancreatic cancer: a dose escalating phase I/II study

Patients with inoperable pancreatic cancer have a dismal prognosis with a mean life expectancy of 3–6 months. New treatment modalities are thus urgently needed. Telomerase is expressed in 85–90% of pancreas cancer, and immunogenic telomerase peptides have been characterised. A phase I/II study was conducted to investigate the safety, tolerability, and immunogenecity of telomerase peptide vaccination. Survival of the patients was also recorded. Forty-eight patients with non-resectable pancreatic cancer received intradermal injections of the telomerase peptide GV1001 at three dose levels, in combination with granulocyte–macrophage colony-stimulating factor. The treatment period was 10 weeks. Monthly booster vaccinations were offered as follow-up treatment. Immune responses were measured as delayed-type hypersensitivity skin reaction and in vitro T-cell proliferation. GV1001 was well tolerated. Immune responses were observed in 24 of 38 evaluable patients, with the highest ratio (75%) in the intermediate dose group. Twenty-seven evaluable patients completed the study. Median survival for the intermediate dose-group was 8.6 months, significantly longer for the low- (P=0.006) and high-dose groups (P=0.05). One-year survival for the evaluable patients in the intermediate dose group was 25%. The results demonstrate that GV1001 is immunogenic and safe to use. The survival data indicate that induction of an immune response is correlated with prolonged survival, and the vaccine may offer a new treatment option for pancreatic cancer patients, encouraging further clinical studies.

A phase I/II study of telomerase peptide vaccination in combination with chemotherapy in patients with stage IV malignant melanoma

8031 Background: A phase I/II feasibility study was conducted to investigate the safety, tolerability and immunological response to vaccination with the telomerase peptide GV1001 (hTERT: 611–626) in combination with temozolomide (T). Methods: Twenty-five patients with malignant melanoma (15 stage M1c,10 stage M1b) received T day 1–5 every four weeks for 1–9 cycles. During the first cycle (4 weeks) they received i.d. injections of 560 μg GV1001 with local GM-CSF in week 2,3 and 4, followed by injections in week 6 and 7 in the second cycle and week 11 in the third cycle. The treatment period was 12 weeks (3 cycles). Booster vaccinations with 560 μg GV1001 were offered every third month. Monitoring of blood samples, clinical examination were performed regularly with radiological staging every 12th week. Immune responses were measured as DTH and in vitro T-cell proliferation. Results: The treatment was generally well tolerated with only grade 1–2 toxicity in most patients. Of 14 patients, 4 developed grade 3 toxicity and one grade 4 toxicity (neutropenia). Immune responses against GV1001 were detected in 17/21 patients (81%) at 12 weeks. Patients receiving up to 9 cycles of T exhibited stable proliferative responses to GV1001 throughout the treatment period. None of the patients had DTH response at trial entry and no DTH responses were observed in patients receiving T. This was not due to a shift in the cytokine profile since cloned GV1001-specific CD4+ T cells displayed a Th1 cytokine profile. Upon evaluation in week 12, 6 patients had SD, 10 PD. One patient had a PR with shrinkage or disappearance of multiple lung metastases. A patient continuing on vaccine alone developed significant DTH response when T therapy was stopped. Conclusions: Telomerase vaccination of patients receiving concomitant T treatment is feasible. The unexpected high proportion of patients showing an immune response indicates that regulatory T-cells may have been removed by T treatment. The chemotherapy may also have influenced effector cells required for development of skin reactions. In spite of lacking DTH response however, the majority of the patients demonstrated significant immune response indicating different regulation of DTH and T-cell response. No significant financial relationships to disclose.

Telomerase peptide vaccination: a phase I/II study in patients with non-small cell lung cancer

A phase I/II study was conducted to investigate the safety, tolerability and clinical response to vaccination with a combination of telomerase peptides GV1001 (hTERT: 611-626) and HR2822 (hTERT: 540-548) in patients with non-small cell lung cancer. Twenty-six patients with non-small cell lung cancer received intradermal administrations of either 60 nmole (112 microg) or 300 nmole (560 microg) GV1001 in combination with 60 nM (68.4 microg) HR2822 and granulocyte macrophage-colony stimulating factor. The treatment period was 10 weeks. Booster vaccinations with 300 nM GV1001 were offered as follow-up. Monitoring of blood samples, clinical examination and radiological staging were performed regularly. Immune responses were measured as delayed-type hypersensitivity skin reaction and in vitro T cell proliferation. Bone marrow function was monitored in long time survivors. The treatment was well tolerated with minor side effects. No bone marrow toxicities were observed in long time survivors with immune responses. Immune responses against GV1001 were detected in 11 of 24 evaluable patients during the primary regimen and in additional two patients following booster injections. Two patients responded to HR2822. Cloned GV1001-specific CD4+ T cells displayed a Th1 cytokine profile and recognized autologous antigen presenting cells pulsed with recombinant telomerase protein. A complete tumor response was observed in one patient who developed GV1001-specific cytotoxic T cells that could be cloned from peripheral blood. The results demonstrate that GV1001 and HR2822 are immunogenic and safe to use in patients with NSCLC. Induction of GV1001-specific immune responses may result in objective tumor responses. Based on these initial encouraging results, further clinical studies of GV1001 in NSCLC patients are warranted.

A phase I/II study of telomerase peptide vaccination of patients with non-small cell lung cancer

2580 Background: A phase I/II study was conducted to investigate the safety, tolerability and clinical response to vaccination with a combination of telomerase peptides GV1001 (hTERT: 611–626) and HR2822 (hTERT: 540–548).Methods: Twenty-six patients with non-small cell lung cancerreceived intradermal administrations of either 112 μg or 560 μg GV1001 in combination with 68.4 μg HR2822 and granulocyte macrophage-colony stimulating factor. The treatment period was ten weeks. Booster vaccinations with 560 μg GV1001 were offered as follow-up. Monitoring of blood samples, clinical examination and radiological staging were performed regularly. Immune responses were measured as delayed-type hypersensitivity skin reaction and in vitro T-cell proliferation. Bone marrow function was monitored in long time survivors. Our regional medical research ethics committee has approved the study and signed informed consent was obtained in all subjects. Results: The treatment was well tolerated with minor side effects. Immune responses against GV1001 were detected in 11 of 24 evaluable patients during the primary regimen and in an additional two patients following booster injections. Two patients responded to HR2822. Cloned GV1001-specific CD4+ T cells displayed a Th1 cytokine profile and recognized autologous antigen presenting cells pulsed with recombinant telomerase protein. No bone marrow toxicities were observed in long time survivors with immune responses. A complete tumor response was observed in one patient who developed GV1001-specific cytotoxic T cells that could be cloned from peripheral blood. Conclusions: Telomerase vaccination of patients with advanced treatment resistant NSCL cancer is feasible and results in potentially beneficial immune responses in about 50% of vaccinated patients. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GemVax GemVax