bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vγ9Vδ2 T (γδ) lymphocytes: a promising approach for immunotherapy of solid tumors
Authors: Squiban P. J. , Bompas E. , Bennouna J. , Levy V. , Sicard H. , Lafaye de Micheaux S. , Viey E. , Salot S. , Tiollier J. , Calvo F. 
Published: March 2020

3064 Background: The Vγ9Vd2 T (γd) blood lymphocyte subset has a strong cytotoxic potential and can be selectively activated with chemically-synthesized, structural analogues of non-conventional antigens like BrHPP (IPH1101). Their proliferation requires low dose of Interleukin-2 (IL-2). Methods: We developed several in vitro and in vivo models to assess the immunotherapeutic potential of IPH1101-activated γd cells: - Direct cytotoxicity assays on patient-derived primary tumor cell lines - Extensive pharmacodynamics in the non human primate (NHP) - Small scale in vitro amplification assays for IPH1101-sensitive patient pre-selection Then, two Phase I clinical trials were performed in solid tumor patients: - Autologous cell therapy with ex vivo IPH1101- expanded γd cells (1, 4 or 8.109 cells) - Direct administration of IPH1101 (200 to 1800 mg/m2 i.v.) and low dose IL-2 (106 U/m2 s.c.). Results: In NHP, IPH1101 and low dose IL-2 induce early pro-inflammatory cytokine release and dose-dependent γd cell amplification in peripheral blood. In vitro, mRCC tumor cells are efficiently and selectively killed by autologous γd cells. In Phase I clinical trials, both ex vivo expanded γd cells and IPH1101 were well tolerated. - Cell therapy-related AEs included mainly gastrointestinal disorders, flu-like symptoms and hypotension. Six patients showed stabilized disease. Median duration of stabilization was 25.7 weeks. 2 pts treated with 4.109 or 8.109 cells showed substantial tumor shrinkage at the 14-week evaluation (-22% and -48%, respectively). - When IPH1101 was administered with low dose of IL-2, a significant increase of blood γd T cells was observed (up to 240 times the basal values) and in terms of clinical activity assessment, among the evaluable mRCC population (n=15), 8 patients presented disease stabilization for more than 35 weeks, including 6 for more than 51 weeks. Conclusions: For the first time, a specific γd immunotherapy was fully developed and led to Phase I clinical trials. It has been found well tolerated. Encouraging signs of disease stabilisation in mRCC patients suggest that γd may have a role in the treatment of cancers resistant to conventional therapies. A phase 2 is ongoing in mRCC patients. No significant financial relationships to disclose.
Phase II trial of a 10-epitope CTL vaccine, EP-2101, in metastatic NSCLC patients
Authors: Brown S. , Cunningham C. , Mary G. , Morse M. , Greco F. A. , McCune D. , Khong H. , Steis R. , Mills B. , Ishioka G. , Bender J. 
Published: March 2020

3068 Background: The 10-peptide EP-2101 vaccine is designed to induce multi-specific CTL responses against epitopes in CEA, p53, HER-2/neu and MAGE 2/3. Seven epitopes are modified for enhanced MHC binding or heteroclitic T-cell activation including the previously described CAP1–6D heteroclitic analog and 2 epitopes are native wild-type (WT) sequences. Also included is the helper epitope PADRE. We report here immunogenicity results from a Phase II trial of the EP-2101 vaccine. Methods: 66 HLA-A2+ good performance patients with Stage IIIB/IV NSCLC were enrolled. Patients received 6 induction doses (0.5 mg/epitope) q3 wks followed by maintenance treatments at 2–3 month intervals. Endpoints included survival and induction of immune responses. CTL responses in peripheral blood MNC were measured after a 10 day in vitro stimulation with peptide followed by an IFNγ ELISPOT assay. Results: 33 patients completed induction and the first 11 patients were monitored for CTL against all vaccine epitopes. Seven of 11 patients generated responses against ≥ 4 epitopes after 3 and 6 vaccine doses and 8 patients generated CTL against ≥ 3 WT vaccine epitopes and WT sequences of vaccine analogs. Responses ranged between 10–50 spots/5x10e4 cells with stronger responses of >100 spots observed. All 9 vaccine epitopes were immunogenic in at least 1 patient. CTL responses against epitopes were maintained at Wk 30 and/or Month 9 in 7 of 8 patients. At Month 12, 2 of 4 patients also had detectable CTL against the vaccine. The 22 remaining patients were monitored against 5 representative vaccine epitopes. 13 of these patients generated CTL responses to ≥ 2 epitopes and 7 patients generated responses to ≥ 3 epitopes. Th-cell responses against PADRE measured with a direct IFNγ ELISPOT assay were observed in 18 of the 33 patients tested. Toxicities attributable to vaccine were mild and consisted mostly of injection site reactions. Follow-up for survival is ongoing. Conclusions: The peptide vaccine EP-2101 is well-tolerated and induces broadly-specific CTL responses in metastatic NSCLC patients. [Table: see text]
Activity of MVA 5T4 alone or in combination with either interleukin-2 (IL-2) or interferon-α (IFN) in patients (Pts) with metastatic renal cell cancer (MRCC)
Authors: Cao A. , Hernandez-McClain J. , Willis J. , Harrop R. , Shingler W. , Chikoti P. , Drury N. , Amato R. 
Published: March 2020

3069 Background: MVA 5T4 consists of the highly attenuated modified Vaccinia Ankara virus containing the gene encoding the human TAA 5T4. Ninety percent or more of RCCs overexpress the 5T4 antigen. A series of clinical trials were conducted to evaluate the effectiveness of MVA 5T4 as a single agent or in combination with Interleukin-2 or Interferon Alpha 2B. Methods: Eligibility: pathologic diagnosis of clear cell or papillary RCC, progressive measurable metastases, any prior therapy, adequate physiologic parameters, Karnofsky performance status (KPS) = 80%, and no active CNS involvement. A regimen of MVA 5T4 alone or in combination with IFN or IL-2 was given. Results: A total of 41 patients received MVA 5T4 alone or in combination. 33 patients received MVA 5T4 with low dose IL-2 or IFN. 23 pts had clear cell; 12 papillary; 5 mixed clear cell; and 1 mixed papillary. 19 pts continue to receive therapy. 2 pts (both clear cell RCC) developed complete responses, 3 pts/partial responses (2 clear cell, 1 papillary) 8 pts/stable for 3+months and 6 pts are too early to be staged at this time. Median duration of therapy is 3.0+ (1+-13+) months. Conclusion: Although comparable antibody response were observed in papillary and clear cell histotypes, clear cell patients appeared to be more likely to respond in terms of clinical benefit parameters, to be presented. Of note is that preliminary analysis of clear cell patients suggests a relationship between the anti-5T4 immune response and tumor response. With the immunological potency and encouraging clinical activity, the future research will focus on the phase 3 randomized, double-blind, placebo controlled parallel group study to investigate whether MVA 5T4, added to first line standard of care therapy, prolongs the survival of patients with locally advanced or metastatic clear cell as well as studies to further optimize MVA 5T4 potency. [Table: see text]
A xenogeneic PSMA DNA vaccine for patients (pts) with non-castrate metastatic (NCMPC) and castrate metastatic prostate cancer (CMPC)—A phase I trial of proof of principle
Authors: Slovin S. , Gregor P. , Wolchok J. , Pedraza A. , Orlandi F. , Jefferson M. , Jefferson M. , Fernandez C. , Rudolph J. , Houghton A. , Scher H. 
Published: March 2020

3073 Background: Prostate Specific Membrane Antigen (PSMA) represents a target for both primary and metastatic prostate cancer and an anti-angiogenic approach for other solid tumors. Antitumor effects in PC have been observed using autologous dendritic cells pulsed with PSMA peptides. This is a pilot phase I trial of vaccination with a DNA encoding PSMA in patients with PC. The objective was to determine the safety and immunogenicity of vaccination with the genes encoding for mouse and human PSMA in patients with recurrent disease. The hypothesis was that xenogeneic DNA encoding a xenogeneic homologous antigen was a more potent immunogen than self DNA. Methods: Thirty-six HLA-A0201+ pts with either NCMPC or CMPC were randomly assigned to vaccination with either xenogeneic (mouse) or human (self) PSMA DNA delivered i.m. via a high pressure delivery system at 100μg, 1,500μg or 4,000μg every 3 weeks for 3 immunizations. Those pts randomized initially to receive human PSMA DNA received 3 immunizations with mouse PSMA DNA at three week intervals. Sera and peripheral blood mononuclear cells were analyzed for humoral and T cell responses Results: Twenty-nine of 36 pts were evaluable having received all six vaccines. Nine remain active without disease progression or significant change in PSA logslope. One of 6 pts treated at the 4,000μg cohort has been followed by > 92 weeks; at the 1,500μg cohort 1 of 2 pt has been monitored for > 110 weeks; and 1 pt at the 100μg dose has remained on study for > 169 weeks. No high titer antibodies against PSMA were detected by ELISA or FACS against 3T3 fibroblasts transduced to express PSMA. Conclusions: The vaccine was safe at all dose levels without evidence of autoimmune reactivity. While antibodies against PSMA were not detected, studies are ongoing to examine T cell responsiveness. The majority of pts who remain on study were treated at 4,000μg dose level which appears to be the optimal dose. Supported by The Prostate Cancer Foundation and MSKCC Prostate Cancer SPORE No significant financial relationships to disclose.
A multi-centre, open-label study to assess the safety of Stimuvax (BLP25 liposome vaccine or L-BLP25) in non-small cell lung cancer (NSCLC) patients (pts) with unresectable stage III disease
Authors: Soulieres D. , Smith C. , Ellis P. M. , Murray N. , Jasas K. , Maksymiuk A. , Goss G. , Falk M. H. , Butts C. 
Published: March 2020

3075 Background: L-BLP25 is an innovative cancer vaccine that incorporates a synthetic MUC1 lipopeptide in a liposomal delivery system. L-BLP25 is expected to elicit an immune response to cancer cells that express MUC1. Previous clinical studies have demonstrated that L-BLP25 has the potential to extend survival of pts with stage IIIB locoregional NSCLC (Butts C et al., JCO 2005; 23:6674–6681). The present ph I-II study was designed to assess the safety of the current formulation of L-BLP25 using a monophosphoryl lipid A in pts with unresectable stage IIIA and stage IIIB NSCLC. Methods: Pts with stable disease or an objective response to upfront radical therapy with chemoradiation for unresectable stage III NSCLC, plus ECOG 0–1 were eligible. All pts were vaccinated according to a previously described schedule (1). Maintenance immunizations were administered every 6-wks until disease progression. Primary and secondary endpoints were safety and survival respectively. Results: Twenty-two pts were recruited at 7 sites in Canada. 16 pts were evaluated for this interim safety analysis (8 stage IIIA, 8 stage IIIB, median age; 57, ECOG 0 56%, concurrent chemotherapy; 93.8%). Thirteen pts had a partial response and 3 had stable disease following chemoradiation. Thirteen pts experienced an adverse event (AE) during the first 4 vaccinations of which 7 pts had a L-BLP25 related adverse event. Grade 1/2 AEs related to L-BLP25 ≥10% included fatigue, dyspnea, insomnia, anorexia, headache, diarrhea, paresthesia, abdominal pain, influenza-like illness, urinary tract infection and peripheral neuropathy. No pts discontinued L-BLP25 due to an AE and no grade 3/4 AEs related to L-BLP25 were reported. Six pts (37.5%) had an injection site reaction. As of September 2006, 10 pts were still on study treatment. Conclusions: This formulation of L-BLP25 was well tolerated and the side effect profile was similar to that seen in previous studies (1). A controlled global multi-center phase III trial is underway to further evaluate L-BLP25 in this patient population. No significant financial relationships to disclose.
Vaccination with a CEA epitope mimic leads to reduced growth of tumor transplants
Authors: Brämswig K. , Knittelfelder R. , Gruber S. , Riemer A. B. , Kammerer R. , Zimmermann W. , Horvat R. , Zielinski C. C. , Scheiner O. , Jensen-Jarolim E. 
Published: March 2020

3076 Background: The carcinoembryonic antigen (CEA) is a glycoprotein which is overexpressed on nearly 50% of all human tumors. We aimed to establish an active immunotherapy by replacing the poorly immunogenic glycoprotein with highly immunogenic peptides. Methods: Col-1 is a monoclonal antibody directed against CEA on tumor cells. To generate structural mimics of the Col-1 epitope, we used the Col-1 antibody and the biopanning method in order to select immunreactive peptide mimotopes from random phage libraries. Subsequently, immunogenicity of a selected mimotope was examined in BALB/c mice. We assessed antibody-dependent cytotoxicity (ADDC) and complement-dependent cytotoxicity (CDC) mediated by the induced antibodies on CEA expressing HT29 cells. Furthermore, after immunisation the BALB/c mice were transplanted subcutaneously with Meth-A/CEA tumor cells. Results: All peptides selected were exclusively recognized by the anti-CEA antibody. In addition, true mimicry of the peptides with the natural antigen was confirmed by competition ELISA using purified human CEA. The best mimotope was chosen for synthesis in a multiple antigenic peptide (MAP) configuration rendering, therefore, a multiple antigenic mimotope (MAM). BALB/c mice immunized with the MAM developed antibodies against the immunogen and the original antigen CEA. In vitro, the anti-mimotope antibodies were capable of inducing high specific lysis of CEA-expressing HT29 cells via antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Moreover, after s.c tumor transplantation no tumor growth was seen in MAM immunized mice, compared to the groups receiving a control mimotope or the naïve group. The CEA-mimotope immunized group showed a capsuled necrotic region without tumor cells but granulocytes and limited vascularisation. The non treated group showed tumor cells in different proliferation stages and neovascularisation. Conclusions: We conclude that the Col-1 epitope of the glycoprotein CEA can be translated into an immunogenic peptide mimic. The mimotope-induced antibodies recognize CEA and do effectively inhibit growth of CEA positive tumors. Based on these findings we suggest that generated mimotopes are candidates for active immunotherapy of CEA- expressing tumors. No significant financial relationships to disclose.
Dendritic cell based vaccine therapy of melanoma
Authors: Petenko N. N. , Mikhaylova I. N. , Chkadua G. Z. , Ogorodnokova E. V. , Vishnyakova L. Y. , Hatirev S. A. , Cheremushkin E. A. , Kadagidze Z. G. , Demidov L. V. , Baryshnikov A. Y. 
Published: March 2020

3077 Background: Vaccination with dendritic cells (DC) expressing tumor antigens is considered to be a possible strategy to induce anti-tumour immune responses in treatment of melanoma. Methods: 42 stage III and IV melanoma patients were enrolled into the study receiving autologous monocyte-derived DCs primed with autologous tumor lysate. DCs displayed mature phenotype. 75% of recruited pts had disease progression after conventional treatments modalities. Pts demographic characteristics wear: age 26–82 years (mean 54), male/female ratio = 24/18. Arm A included 17 pts treated with DC vaccine in therapeutic regimen (III stage - 2 pts, IV stage - 15 pts). Arm B consisted of 25 pts receiving DC vaccine after radical metastasectomy (III stage - 10 pts, IV stage - 15 pts). DC were administered s.c. q 2–4 weeks until disease progression in a dose of 1,0–5,0x10(6) cells. Pts who received = 4 vaccinations were evaluated, totally - 33 pts (79%) were considered evaluable. The vaccine therapy was evaluated for safety, tolerability and clinical effectiveness. Results. DCs vaccine was safe and well tolerated. Toxicity included flu-like syndrome (1 grade CTC), transitory hyperemia and itching in the sites of injections (1 grade CTC). 13 of 17 pts were evaluable in arm A, they received 210 vaccinations (from 4 to 21 per pts, mean 10,5). We observed 15,4% overall clinical response (1 complete and 1 partial response) and 38% stabilization of disease (lasting = 2 mos). 1- year survival, median survival were 42,5% and 9,5 mos, respectively. Follow-up 4–39+ mos. Among 20 evaluable pts in arm B who received 205 vaccinations (from 4 to 38 per pts, mean 15,8) median time to progression was 10 mos, 1-year survival - 84%, at a median follow- up of 12 mos (3–20+) disease free survival was 45%. Conclusion: DCs vaccine therapy is safe and lacks serious adverse effects. Melanoma pts with regional and distant metastasis demonstrated moderate clinical effectiveness in response to specific vaccine therapy. No significant financial relationships to disclose.
Identification of sensitivity markers for BMS-536924, an inhibitor for insulin-like growth factor-1 receptor
Authors: Huang F. , Hurlburt W. , Hafezi R. , Han X. , Chen J. , Carboni J. , Attar R. M. , Helman L. , Clark E. , Dongre A. 
Published: March 2020

3506 Background: Insulin-like growth factor-1 receptor (IGF-1R) signaling is an important regulator of mitogenesis, transformation to the oncogenic phenotype and anti-apoptotic effects in malignant cells. Over-expression of IGF-1R, seen in many tumors, may confer a growth advantage or drug resistance. A potent small-molecule inhibitor (BMS-536924) of IGF-1R tyrosine kinase showed anti-tumor activity in sarcoma, prostate, colon and pancreatic tumor models. One of the integral goals in the development of BMS-536924 as a cancer therapeutic is to identify molecular biomarkers predictive of response to the drug that ultimately will aid in selecting the patients who are most likely to benefit. Methods: The sensitivity (IC50) to BMS-536924 was determined for a panel of 29 pediatric sarcoma and neuroblastoma cell lines. Both microarray and LC/MS based protein profiling were utilized to analyze the baseline gene or protein expression level. Drug treatment studies were performed using two rhabdomyosarcoma cell lines, Rh41 (sensitive to BMS-536924) and Rh36 (resistant to the drug) to identify markers that are modulated by BMS-536924. Results: (1). Sixteen out of the 29 cell lines were highly sensitive to BMS-536924; candidate markers that correlated with the sensitivity to BMS-536924 were identified by gene expression and protein profiling. (2). Histological correlation was also discovered, with specific subtypes of sarcoma having a low IC50 to BMS-536924. (3). Pathway analysis noted that some major candidate markers are common key steps in the EGF-R pathway and the IGF1-R pathway. This observation of cross-talk between the two pathways led to the hypothesis of synergy with combined inhibition of both pathways. Combination studies of BMS-536924 and EGFR inhibitors were performed and synergism was observed. (4). Markers modulated by BMS-536924 in a sensitive cell line were identified. Conclusions: This work has identified candidate markers correlating to BMS-536924 sensitivity in vitro. The possible mechanism of synergistic activity of IGF1-R and EGFR inhibitors will be presented. No significant financial relationships to disclose.
Circulating tumor cells expressing the insulin growth factor-1 receptor (IGF-1R): Method of detection, incidence and potential applications
Authors: de Bono J. S. , Adjei A. , Attard G. , Pollak M. , Fong P. , Haluska P. , Roberts L. , Chainese D. , Terstappen L. , Gualberto A. 
Published: March 2020

3507 Purpose: To detect IGF-1R on circulating tumor cells (CTCs) as a biomarker in the clinical development of a monoclonal human antibody, CP-751,871, targeting IGF-1R. Experimental Design: An automated sample preparation and analysis system for enumerating CTCs (Celltracks) was adapted for detecting IGF-1R positive CTCs with a diagnostic antibody targeting a different IGF-1R epitope to CP-751,871. This assay was utilized in three phase I trials of CP-751,871 as a single agent or with chemotherapy and was validated using cell lines and blood samples from healthy volunteers and patients with metastatic carcinoma. Results: There was no interference between the analytical and therapeutic antibodies. CP-751,871 was well tolerated as a single agent, and in combination with docetaxel or carboplatin and paclitaxel, at doses ranging from 0.05 mg/kg to 20 mg/kg. Eighty patients were enrolled on phase 1 studies of CP-751,871, with 47 (59%) patients having CTCs detected during the study. Prior to treatment 26 patients (33%) had CTCs, with 23 having detectable IGF-1R positive CTCs. CP-751,871 alone, and CP-751,871 with cytotoxic chemotherapy, decreased CTCs and IGF-1R positive CTCs; these increased towards the end of the 21-day cycle in some patients, falling again with retreatment. CTCs were commonest in advanced hormone refractory prostate cancer (11/20). Detectable IGF-1R expression on CTCs before treatment with CP-751,871 and docetaxel was associated with a higher frequency of PSA decline by more than 50% (6/10 vs 2/8 patients). A relationship was observed between sustained falls in CTCs counts and PSA declines by more than 50%. Conclusions: IGF-1R expression is detectable by immunofluorescence on CTCs. These data support the further evaluation of CTCs in pharmacodynamic studies and patient selection, particularly in advanced prostate cancer. No significant financial relationships to disclose.
Irestatin, a potent inhibitor of IRE1α and the unfolded protein response, is a hypoxia-selective cytotoxin and impairs tumor growth
Authors: Feldman D. , Koong A. C. 
Published: March 2020

3514 Background: The unfolded protein response (UPR) is an adaptive response to the toxic accumulation of misfolded proteins in the endoplasmic reticulum (ER), and is activated in solid tumors. IRE1a is a core component of the UPR and responds to ER stress through activation of its dual kinase and endonuclease domains. The IRE1a endonuclease splices the mRNA for XBP-1, generateing a potent transcription factor that is required for tumor growth. Methods: We developed a fibrosarcoma cell line expressing a fusion of unprocessed XBP-1 inserted upstream of firefly luciferase. Under ER stress, IRE1a catalyzes the removal of a 26-nt intronic sequence from the XBP-1 mRNA, introducing a shift in reading frame that permits translation of luciferase. We screened a chemical library of 66,000 small molecules for inhibitors of XBP-luciferase activity and identified 12 molecules, termed irestatins, which consistently inhibited the IRE1a signaling module without affecting the activity of a control CMV-luciferase reporter. We pursued several of the most potent irestatins, including irestatin 9389, which inhibited XBP-luciferase activity with an IC50 of ∼25 nM. Results: Irestatin-mediated inhibition of the IRE1a endonuclease impairs the growth of malignant myeloma cells and inhibits the survival of oxygen-starved tumor cells in vitro. Exposure to irestatin 9389 (2.5 μM) had a negligible effect on the survival of HT1080 cells cultured under normal oxygen conditions. However, in cells cultured under hypoxia for 48 hours, irestatin 9389 inhibited colony formation by nearly 80-fold (48% vs. 0.62%). A two-week course of treatment with single-agent irestatin 9389 (50 mg/kg) administered every other day by i.p. bolus injection was well tolerated and strongly inhibited the growth of subcutaneous HT1080 tumor xenografts (1790 ± 380 mm3 vs. 480 ± 210 mm3; P<0.01). Conclusion: Irestatins define a novel class of hypoxia- and ER stress-selective agents targeted to the underlying physiological response to the tumor microenvironment. Intratumoral inhibition of the UPR can potentiate cell death and impair tumor growth. Molecular intervention against central components of the UPR may represent an effective therapeutic strategy in cancer treatment. No significant financial relationships to disclose.