Telomerase Vaccination Research Articles

Outcome prediction based on [18F]FDG PET/CT in patients with pleural mesothelioma treated with ipilimumab and nivolumab +/- UV1 telomerase vaccine.

The introduction of immunotherapy in pleural mesothelioma (PM) has highlighted the need for effective outcome predictors. This study explores the role of [18F]FDG PET/CT in predicting outcomes in PM treated with immunotherapy. Patients from the NIPU trial, receiving ipilimumab and nivolumab +/- telomerase vaccine in second-line, were included. [18F]FDG PET/CT was obtained at baseline (n = 100) and at week-5 (n = 76). Metabolic tumour volume (MTV) and peak standardised uptake value (SUVpeak) were evaluated in relation to survival outcomes. Wilcoxon rank-sum test was used to assess differences in MTV, total lesion glycolysis (TLG), maximum standardised uptake value (SUVmax) and SUVpeak between patients exhibiting an objective response, defined as either partial response or complete response according to the modified Response Criteria in Solid Tumours (mRECIST) and immune RECIST (iRECIST), and non-responders, defined as either stable disease or progressive disease as their best overall response. Univariate Cox regression revealed significant associations of MTV with OS (HR 1.36, CI: 1.14, 1.62, p < 0.001) and PFS (HR 1.18, CI: 1.03, 1.34, p = 0.02), while multivariate analysis showed a significant association with OS only (HR 1.35, CI: 1.09, 1.68, p = 0.007). While SUVpeak was not significantly associated with OS or PFS in univariate analyses, it was significantly associated with OS in multivariate analysis (HR 0.43, CI: 0.23, 0.80, p = 0.008). Objective responders had significant reductions in TLG, SUVmax and SUVpeak at week-5. MTV provides prognostic value in PM treated with immunotherapy. High SUVpeak was not associated with inferior outcomes, which could be attributed to the distinct mechanisms of immunotherapy. Early reductions in PET metrics correlated with treatment response. The NIPU trial (NCT04300244) is registered at clinicaltrials.gov. https://classic. gov/ct2/show/NCT04300244?cond=Pleural+Mesothelioma&cntry=NO&draw=2&rank=4.

Clinical research progress of telomerase targeted cancer immunotherapy: a literature review.

Telomerase is activated or overexpressed in 85-90% of tumors, which maintains the length of telomere and has become an important anti-cancer target. Increasing clinical and preclinical data suggest that telomerase-targeted cancer immunotherapy could achieve effective killing of tumor cells in vivo. This article reviews the research progress of telomerase targeted cancer immunotherapy in clinical and pre-clinical trials, aiming to provide a reference for further clinical research and treatment of cancers. We investigated the research progress of telomerase immunotherapy in the last 20 years from four electronic databases. Telomerase-targeted immunotherapies have been developed with the arising of a new era in immuno-oncology, including peptide vaccines, DNA vaccines, dendritic cells (DCs), adoptive cell transfer (ACT) therapies, antibodies, etc. Some of them have been approved for undergoing clinical trials by the Food and Drug Administration (FDA) for the treatment of various cancers, such as pancreatic cancer, non-small cell lung cancer, melanoma, leukaemia. Of all the treatment modalities, vaccines are the primary treatment methods, some of which have been even entered into phase III clinical trials. The main clinical application direction of telomerase vaccine is the combination with other drugs and treatment modalities, including combination with other vaccines targeting human telomerase reverse transcriptase (hTERT), traditional chemotherapy drugs and immunosuppressors. We also summarized the recent findings of immunotherapy targeting hTERT, focusing on various vaccines and the current status of associated clinical trials. We further discussed the advantages, disadvantages and potential developmental directions of various telomerase-targeted immunotherapies. Telomerase-targeted cancer immunotherapy has promising prospects in improving patient survival expectancy. This review may provide data support and design ideas for all researchers and pharmaceutical enterprises in this field.

UV1 telomerase vaccine with ipilimumab and nivolumab as second line treatment for pleural mesothelioma – A phase II randomised trial

PurposeThe NIPU-trial investigates the effect of adding the telomerase vaccine UV1 to treatment with ipilimumab and nivolumab for patients with pleural mesothelioma (PM). MethodsIn this phase 2 open-label trial, patients with PM progressing after first-line chemotherapy were randomised to receive ipilimumab and nivolumab alone (arm B) or combined with UV1 (arm A). The primary endpoint was progression-free survival (PFS) as determined by BICR. It was estimated that 69 PFS events were needed to detect a hazard ratio (HR) of 0.60 with 80% power and a one-sided alpha level of 0.10. Results118 patients were randomised. The median PFS determined by blinded independent central review (BICR) was 4.2 months (95%CI 2.9–9.8) in arm A and 4.7 months (95%CI 3.9–7.0) in arm B (HR 1.01, 80%CI 0.75–1.36 P = 0.979), after a median follow-up of 12.5 months (95%CI 9.7–15.6). The investigator-determined median PFS was 4.3 months (95%CI 3.0–6.8) in arm A and 2.9 months (95%CI 2.4–5.5) in arm B (HR 0.60, 80%CI 0.45–0.81 P = 0.025). Confirmed objective response rate (ORR) by BICR was 31% in arm A and 16% in arm B (odds ratio 2.44 80%CI 1.35–4.49 P = 0.056). After a median follow-up time of 17.3 months (95%CI 15.8–22.9), the OS was 15.4 months (95%CI 11.1–22.6) in arm A and 11.1 months (95%CI 8.8–18.1) in arm B, (HR 0.73, 80%CI 0.53–1.0, P = 0.197). ConclusionThe primary endpoint was not met. Predefined analyses of response rates are in favour of adding the vaccine.

Telomerase inhibitors induce mitochondrial oxidation and DNA damage-dependent cell death rescued by Bcl-2/Bcl-xL

BackgroundReactivation of telomerase is a hallmark of cancer and the majority of cancers over-express telomerase. Telomerase-dependent telomere length maintenance confers immortality to cancer cells. However, telomere length-independent cell survival functions of telomerase also play a critical role in tumorigenesis. Multiple telomerase inhibitors have been developed as therapeutics and include anti-sense oligonucleotides, telomerase RNA component targeting agents, chemical inhibitors of telomerase, small molecule inhibitors of hTERT, and telomerase vaccine. In general, telomerase inhibitors affect cell proliferation and survival of cells depending on the telomere length reduction, culminating in replicative senescence or cell death by crisis. However, most telomerase inhibitors kill cancer cells prior to significant reduction in telomere length, suggesting telomere length independent role of telomerase in early telomere dysfunction-dependent cell death. MethodsIn this study, we explored the mechanism of cell death induced by three prominent telomerase inhibitors utilizing a series of genetically encoded sensor cells including redox and DNA damage sensor cells. ResultsWe report that telomerase inhibitors induce early cell cycle inhibition, followed by redox alterations at cytosol and mitochondria. Massive mitochondrial oxidation and DNA damage induce classical cell death involving mitochondrial transmembrane potential loss and mitochondrial permeabilization. Real-time imaging of the progression of mitochondrial oxidation revealed that treated cells undergo a biphasic mitochondrial redox alteration during telomerase inhibition, emphasizing the potential role of telomerase in the redox regulation at mitochondria. Additionally, silencing of hTERT confirmed its predominant role in maintaining mitochondrial redox homeostasis. Interestingly, the study also demonstrated that anti-apoptotic Bcl-2 family proteins still confer protection against cell death induced by telomerase inhibitors. ConclusionThe study demonstrates that redox alterations and DNA damage contribute to early cell death by telomerase inhibitors and anti-apoptotic Bcl-2 family proteins confer protection from cell death by their ability to safeguard mitochondria from oxidation damage.

NIPU: a randomised, open-label, phase II study evaluating nivolumab and ipilimumab combined with UV1 vaccination as second line treatment in patients with malignant mesothelioma

BackgroundMalignant pleural mesothelioma (MPM) is a rare and aggressive tumour. For patients with inoperable disease, few treatment options are available after first line chemotherapy. The combination of ipilimumab and nivolumab has recently shown increased survival compared to standard chemotherapy, but most patients do not respond and improvements are called for. Telomerase is expressed in mesothelioma cells, but only sparsely in normal tissues and is therefore an attractive target for therapeutic vaccination. Vaccination against telomerase is tolerable and has shown to induce immune responses associated with increased survival in other cancer types. There is a well-founded scientific rationale for the combination of a telomerase vaccine and checkpoint inhibition to improve treatment response in MPM patients.MethodsNIPU is a randomized, multi-centre, open-label, phase II study comparing the efficacy and safety of nivolumab and ipilimumab with or without telomerase vaccine in patients with inoperable malignant pleural mesothelioma after first-line platinum-based chemotherapy. Participants (n = 118) are randomized 1:1 into two treatment arms. All participants receive treatment with nivolumab (240 mg every 2 weeks) and ipilimumab (1 mg/kg every 6 weeks) until disease progression, unacceptable toxicity or for a maximum of 2 years. Patients randomised to the experimental arm receive 8 intradermal injections of UV1 vaccine during the first three months of treatment. Tumour tissue, blood, urine, faeces and imaging will be collected for biomarker analyses and exploration of mechanisms for response and resistance to therapy.DiscussionCheckpoint inhibition is used for treatment of mesothelioma, but many patients still do not respond. Increasing therapy response to immunotherapy is an important goal. Possible approaches include combination with chemotherapy, radiotherapy, targeted therapy and other immunotherapeutic agents. Predictive biomarkers are necessary to ensure optimal treatment for each patient and to prevent unnecessary side effects. This trial seeks to improve treatment response by combining checkpoint inhibition with a telomerase vaccine and also to explore mechanisms for treatment response and resistance. Knowledge gained in the NIPU study may be transferred to the first line setting and to other cancers with limited benefit from immunotherapy.Trial registration: ClinicalTrials.gov: NCT04300244, registered March 8th, 2020, https://clinicaltrials.gov/ct2/show/NCT04300244?term=NIPU&draw=2&rank=1.

A phase I clinical trial investigating the telomerase vaccine UV1 in combination with pembrolizumab in patients with advanced melanoma.

2620 Background: UV1, a telomerase peptide-based vaccine, consists of 3 long peptides (15-30 aa) representing a 54 aa sequence in the catalytic unit of the reverse transcriptase subunit of telomerase (hTERT). UV1 contains both CD4 and CD8 epitopes, and immunogenicity is shown in 78% of HLA unselected patients (pts.) in prior studies. UV1 induced expansion of hTERT specific CD4+ T cells that might be relevant in tumors expressing telomerase, theoretically enabling enhanced checkpoint efficacy in pts. with insufficient spontaneously primed T cells. Reciprocally, checkpoint inhibitor may support the UV1-induced T cells and provide increased effector activity, as these cells may be restricted by intrinsic and tumor-induced suppressor mechanisms. Methods: UV1 was combined with standard of care pembrolizumab in pts. with advanced melanoma. The primary objective of this phase I, multicenter study (NCT03538314), was to evaluate safety and tolerability of UV1 in combination with standard pembrolizumab. Secondary objective was evaluation of response rate (RR) according to iRECIST. Pts. received, in a serial manner, adjuvant GM-CSF and UV1 (300μg) intradermally followed by pembrolizumab. The first 3 UV1/GM-CSF doses were given during week 1, and from week 2 in combination with pembrolizumab (Q3W). Two different doses of GM-CSF were investigated: 37.5μg (20 pts. cohort 1) and 75μg (10 pts. cohort 2). Totally 8 UV1/GM-CSF vaccinations per pt. were planned (14 weeks). Results: In total 30 pts. were enrolled; cohort 1 (N = 20); cohort 2 (N = 10). The abstract reports cohort 1 results. The majority of adverse events (AEs) reported was grade 1 or 2 (48%, 41%). Main AEs were fatigue (8%), injection site reaction (5%), diarrhea (4%) and pyrexia (3%). 18% and 30% of AEs were possibly/definitely related to UV1 or pembrolizumab, respectively. Three patients experienced SAE, one (inflammatory arthritis) was considered possibly related to UV1. No severe allergic reactions were observed. Pembrolizumab was continued after completion of UV1 treatment in 14 pts. for a mean of 8.2 months (range 3-21). Four pts. discontinued pembrolizumab due to PD, one for irAE and one for unknown reason. The RR was 60%, with 5 CRs, and the 1-year survival rate 85 %. Conclusions: Results from cohort 1 (N = 20) show that the treatment of UV1 together with pembrolizumab was safe and well tolerated in patients with advanced melanoma. Updated data with minimum 18 months follow-up will be presented at the conference. Cohort 2 results will be presented at a later stage. Clinical trial information: NCT03538314. [Table: see text]

Building on the Promise of Cancer Vaccines for Solid Tumors.

A novel telomerase vaccine (INVAC-1) has been evaluated in a phase I clinical trial (n = 26). It induced CD8+ and CD4+ T-cell responses and reduced circulating regulatory T cells. The findings support further development, especially in combination with vaccine adjuvants, plus therapies to increase immune infiltrates into solid tumor metastases.See related article by Teixeira et al., p. 588.

A DNA telomerase vaccine for canine cancer immunotherapy.

Telomerase reverse transcriptase (TERT) is highly expressed in more than 90% of canine cancer cells and low to absent in normal cells. Given that immune tolerance to telomerase is easily broken both naturally and experimentally, telomerase is an attractive tumor associated antigen for cancer immunotherapy. Indeed, therapeutic trials using human telomerase peptides have been performed. We have developed an immunogenic yet catalytically inactive human telomerase DNA construct that is in clinical trials with patients presenting solid tumors. Paralleling this human construct, we have developed a canine telomerase DNA vaccine, called pDUV5. When administered intradermally to mice combined with electrogene transfer, pDUV5 induced canine TERT specific cytotoxic T-cells as measured by IFN-γ ELISpot assay. Intradermal vaccination of healthy dogs with 400 μg of pDUV5 generated strong, broad and long lasting TERT specific cellular immune responses. In vitro immunization with cTERT peptides revealed the maintenance of cTERT specific T-cells in PBMCs from tumor bearing dogs showing that this repertoire was not depleted. This study highlights the potential of pDUV5 as a cancer vaccine and supports its evaluation for the treatment of spontaneous canine tumors.

Telomeres and Telomerase in Hematopoietic Dysfunction: Prognostic Implications and Pharmacological Interventions.

Leukocyte telomere length (TL) has been suggested as a marker of biological age in healthy individuals, but can also reflect inherited and acquired hematopoietic dysfunctions or indicate an increased turnover of the hematopoietic stem and progenitor cell compartment. In addition, TL is able to predict the response rate of tyrosine kinase inhibitor therapy in chronic myeloid leukemia (CML), indicates clinical outcomes in chronic lymphocytic leukemia (CLL), and can be used as screening tool for genetic sequencing of selected genes in patients with inherited bone marrow failure syndromes (BMFS). In tumor cells and clonal hematopoietic disorders, telomeres are continuously stabilized by reactivation of telomerase, which can selectively be targeted by telomerase-specific therapy. The use of the telomerase inhibitor Imetelstat in patients with essential thrombocythmia or myelofibrosis as well as the use of dendritic cell-based telomerase vaccination in AML patients with complete remissions are promising examples for anti-telomerase targeted strategies in hematologic malignancies. In contrast, the elevation in telomerase levels through treatment with androgens has become an exciting clinical intervention for patients with BMFS. Here, we review recent developments, which highlight the impact of telomeres and telomerase targeted therapies in hematologic dysfunctions.

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.

Telomerase (GV1001) vaccination together with gemcitabine in advanced pancreatic cancer patients.

Telomerase is expressed in 85-90 % of pancreatic adenocarcinomas and might be a target for active cancer immunotherapy. A study was conducted to investigate safety and immunogenicity in non-resectable pancreatic carcinoma patients using a 16-amino acid telomerase peptide (GV1001) for vaccination in combination with GM-CSF and gemcitabine as first line treatment. Three different vaccine treatment schedules were used; [A (n=6), B (n=6) and C (n=5)]. Groups A/B received GV1001, GM-CSF and gemcitabine concurrently. Group C received initially GV1001 and GM-CSF while gemcitabine was added at disease progression. Group D (n=4) was treated with gemcitabine alone. Adverse events (AE) related to vaccination were mild (grades I-II). Grade III AEs were few and transient. An induced GV 1001‑specific immune response was defined as an increase ≥2 above the baseline value in one of the assays (DTH, proliferation, ELISPOT and cytokine secretion assays, respectively). A telomerase‑specific immune response was noted in 4/6 patients in group A, 4/6 patients in group B and 2/5 patients in group C. An induced ras‑specific immune response (antigenic spreading) was seen in 5 of the 17 patients. The cytokine pattern was that of a Th1-like profile. A treatment induced telomerase or ras response was also noted in group D. All responses were weak and transient. A significant decrease in regulatory T-cells over time was noted in patients in groups A and B (p<0.05). Telomerase vaccination (GV1001) in combination with chemotherapy appeared to be safe but the immune responses were weak and transient. Measures have to be taken to optimize immune responses of GV1001 for it to be considered of clinical interest.

Predictive cytokine biomarkers for survival in patients with advanced pancreatic cancer randomized to sequential chemoimmunotherapy comprising gemcitabine and capecitabine (GemCap) followed by the telomerase vaccine GV1001 compared to concurrent chemoimmunotherapy in the TeloVac phase III trial.

4121 Background: The TeloVac trial randomized 1,062 patients with advanced pancreatic cancer to a control chemotherapy Arm1, using GemCap; sequential chemoimmunotherapy Arm 2, GemCap for 8 wks foll...

A phase III randomized trial of chemoimmunotherapy comprising gemcitabine and capecitabine with or without telomerase vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer.

LBA4004 Background: GV1001, a promiscuous class II epitope encompassing aa 611-626 of hTERT led to the development of CD4+ clones recognizing hTERT in patients with advanced pancreatic cancer (APC). Preclinically gemcitabine increases antigen cross-presentation, enhances T cell trafficking/activation, and reduces MDSCs and Tregs. Methods: Patients with APC were randomized 1:1:1 to: Arm 1 GemCap; 2 GemCap for 8/52 followed by GV1001 followed by further GemCap if no PD at week 8; 3 concurrent administration of GemCap and GV1001. 735 (69.2%) had metastatic disease and 948 (89.3%) had ECOG PS=0 or 1. Randomization was stratified by stage and PS. Primary endpoint was overall survival (OS); secondary endpoints included ORR, TTP, and AEs. Recruitment target was 1,110 patients (780 deaths) to permit detection of a hazard ratio of 0.748 between either GV1001 arm and Arm 1 using a 2-sided α=0.025 level of significance with at least 80% power. Results: 1,062 pts from 51 centers were randomized. Trial maturity was high (72.7% patients died): median follow-up was 6.11 months. The overall response rates were Arm 1=17.6%; Arm 2=8.9% (p=0.001); Arm 3: 15.5% (p=0.460 compared with Arm 1). Conclusions: OS with concurrent GemCap/GV1001 was not different to that with GemCap alone. OS with sequential GV1001 was not statistically different to GemCap alone as it did not meet the criterion for statistical significance (p&lt;0.0175). The addition of a T helper epitope vaccine to GemCap did not improve outcome compared to GemCap alone. Clinical trial information: 43482138. [Table: see text]

A phase III randomized trial of chemoimmunotherapy comprising gemcitabine and capecitabine with or without telomerase vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer.

LBA4004 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Monday, June, 3, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.

A multi-peptide, dual-adjuvant telomerase vaccine (GX301) is highly immunogenic in patients with prostate and renal cancer.

Anti-tumor vaccination is a new frontier in cancer treatment applicable to immunogenic neoplasms such as prostate and renal cancers. GX301 is a vaccine constituted by four telomerase peptides and two adjuvants, Montanide ISA-51 and Imiquimod. The aim of this study was to analyze safety and tolerability of GX301 in an open-label, phase I/II trial. Immunological and clinical responses were also evaluated as secondary endpoints. GX301 was administered by intradermally injecting 500μg of each peptide (dissolved in Montanide ISA-51) in the skin of the abdomen. Imiquimod was applied as a cream at the injection sites. The protocol included 8 administrations at days 1, 3, 5, 7, 14, 21, 35, 63. Eligible patients were affected with stage IV prostate or renal cancer resistant to conventional treatments. Patients were clinically and immunologically monitored up to 6months from the first immunization. No grade 3-4 adverse events were observed. Evidence of vaccine-specific immunological responses was detected in 100% of patients. Disease stabilization occurred in 4 patients. Prolonged progression-free survival and overall survival were observed in patients showing a full pattern of vaccine-specific immunological responses. GX301 demonstrated to be safe and highly immunogenic. Further studies are needed to determine its clinical efficacy.

Prolonged Administration of the Telomerase Vaccine GRNVAC1 Is Well Tolerated and Appears to Be Associated with Favorable Outcomes In High-Risk Acute Myeloid Leukemia (AML)

AbstractAbstract 2190 Background:Telomerase activity in leukemic blasts is frequently increased in high-risk AML patients, and the major protein catalytic subunit of telomerase (hTERT) includes immunogenic epitopes which can stimulate generation of hTERT-specific cytotoxic T cells. Methods:We evaluated the feasibility, safety, and immunologic effects of telomerase catalytic subunit (hTERT)-expressing autologous dendritic cells (DC) in adult AML patients. GRNVAC1 (VAC1) was produced at a central facility from patient-specific leukapheresis harvests. Immature DCs from monocyte-enriched PBMCs were electroporated with an mRNA construct encoding hTERT and a lysosomal targeting sequence (LAMP-1). Further culture with cytokines induced a mature DC phenotype. AML patients were eligible if in CR1 and with intermediate or high risk cytogenetics or in CR2. PBMCs were harvested after induction, and before or after completion of planned consolidation cycles. Patients in ongoing CR or early relapse (<20% marrow blasts) were vaccinated. Vials of VAC1 containing 1 × 107 cells were administered by intra-dermal injections weekly × 6, followed by 4 weeks off, then as boost vaccinations every other week × 6. In cases where additional vials were available, injections could then continue on a q28 day extended boost schedule. This abstract summarizes safety of administering VAC1 up through the extended boost schedule. Results:Between September 2007 and December 2009, 33 patients with a median age 61yrs (range, 30–75) were enrolled and leukapheresed. 21 patients received VAC1 vaccinations, 19 in CR (16 in CR1 and 3 in CR2) and 2 in early relapse. Eight of 16 in CR1 were at intermediate risk of relapse and 8 were at high risk of relapse. A median of 17 (6-32) vaccinations were administered to those 19 patients. VAC1 was well tolerated with no toxicities with the exception of one patient who developed ITP after 6 vaccinations. Local transient erythema at the site of injection was common in all patients.With a median follow-up of 10.5 months (range, 1.2–27.2) months, 4/19 relapsed and 7 continue to receive VAC1. The Kaplan-Meier estimate of disease free survival (DFS) at 12 months, measured from beginning with the first vaccination of VAC1, was 79% for the 19 CR patients (95% CI: 52%-91%), 75% (31%-93%) for the eight patients in the intermediate risk group, and 81% for the 11 patients in the high risk group. Median DFS was not reached. Conclusions:Prolonged administration of VAC1, up to 32 vaccinations (the maximum number administered so far), is well tolerated in patients with AML, and associated with favorable DFS, especially in high-risk patients. Disclosures:DiPersio: Genzyme: Honoraria.

Current status of GV1001 and other telomerase vaccination strategies in the treatment of cancer

GV1001 is a telomerase-specific, promiscuous class II peptide vaccine which is currently in an advanced stage of clinical development. This article reviews the biological rationale underpinning the design of ongoing studies with the vaccine as well as its immunogenicity and clinical activity. It places GV1001 in the context of other immunotherapeutic approaches targeting telomerase and assesses the chances of the vaccine becoming a future standard of care in the treatment of cancer.

Abstract 4780: CD4 T-lymphocyte responses to the human telomerase reverse transcriptase (hTERT) in patients (pts) with advanced non small cell lung cancer (NSCLC)

Abstract Background: hTERT is a potential target for cancer immunotherapy because it is highly expressed in tumor cells. To assess the applicability of hTERT-based immunotherapy in NSCLC, we aimed to analyse the natural anti-hTERT CD4 T-lymphocyte responses in advanced NSCLC pts. Methods: We included in a prospective, monocentric study chemonaive NSCLC pts. Pts were required to present stage III or IV tumor, without any immune deficiency or immunosuppressive drug. Before start of chemotherapy, the anti-hTERT T-lymphocyte responses were assessed in whole blood by ELISPOT test. We evaluated the presence or absence of hTERT-specific CD4 T lymphocytes. Thereafter, we analyzed its link with age (&amp;lt; 70 vs. ≥ 70 yrs), ECOG performance status PS (0-1 vs. 2-3), tumoral stage (IIIA vs. IIIb + IV), histological subtype (adenocarcinoma vs. other) and smoking status (never smoker vs. smoker). Statistical analysis was performed using chi-Square or Fischer test. Results: Between February 2008 and October 2009, fifty-one NSCLC pts were included. They presented a stage IIIa (n = 5), IIIb (n = 5) or IV (n = 41) disease. Median age was 66 yrs [39-89]. Nineteen pts presented anti-telomerase CD4 T lymphocytes (37 %); among them we found 14 stage IV (73 %), 13 pts &amp;lt; 70 yrs (68 %), 12 pts with PS 0/1 (63 %), 18 adenocarcinoma/undifferentiated carcinoma (94 %), 13 pts with stable disease/ partial response (68%). Furthermore, all non smokers have anti-telomerase immune response. Conclusions: These preliminary results demonstrate that natural anti-hTERT immune response exists in NSCLC pts, even in case of advanced disease. However the presence of immune response is more frequently found in pts less than 70 yrs with good PS, in non squamous cell carcinoma and in pts with non progressive disease. The study is ongoing to evaluate if baseline anti-hTERT immune response could be used as selection criteria for telomerase vaccination in NSCLC. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4780.

T-lymphocyte responses to the human telomerase reverse transcriptase (hTERT) in patients (pts) with advanced non-small cell lung cancer (NSCLC)

3061 Background: hTERT is a potential target for cancer immunotherapy because it is highly expressed in tumor cells. To assess the applicability of hTERT-based immunotherapy in NSCLC, we aimed to analyse the natural anti-hTERT T-lymphocyte responses in advanced NSCLC pts. Methods: We included in a prospective, monocentric study chemonaive NSCLC pts. Pts were required to present stage III or IV tumor, without any immune deficiency or immunosuppressive drug. Before start of chemotherapy, the anti-hTERT T-lymphocyte responses were assessed in whole blood by ELISPOT and thymidine proliferation test. We evaluated the presence or absence of hTERT-specific T lymphocytes. Thereafter, we analyzed its link with age (&lt; 60 vs. ≥ 60 yrs), ECOG performance status PS (0–1 vs. 2–3), tumoral stage (III vs. IV), histological subtype (adenocarcinoma vs. other), and smoking status (never smoker vs. smoker). Statistical analysis was performed using chi-square or Fischer test. Results: Between February and September 2008, 31 NSCLC pts were included. They presented a stage III (n = 6) or IV (n = 27) disease. Median age was 65 yrs (33–89). Eighteen pts presented anti-hTERT T lymphocytes (54%); among them we found 12 pts ≥ 60 yrs (70%), 14 adenocarcinoma (77%), 13 stage IV (72%), 7 pts with PS 2/3 (41%), and 13 smokers (72%). So far, univariate analysis showed no relationship between presence of anti-hTERT T-cell responses and pts’ characteristics. Conclusions: These preliminary results demonstrate that natural anti-hTERT immune response exists in NSCLC pts, even in case of poor prognosis. Thus, clinical trial using telomerase-based therapeutic vaccine may include NSCLC pts with advanced disease. The study is ongoing to evaluate if baseline anti-hTERT immune response could be used as selection criteria for telomerase vaccination in NSCLC. No significant financial relationships to disclose.

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.