bluuebunny/crossref_metadata_2025_split huggingface dataset:
The in vivo targeting of tumor antigens to DCs by administration of transduced autologous lymphocytes results in robust and prolonged immunization: Pre-clinical validation and results of a pilot clinical studies of vaccination for metastatic melanoma
Authors: Russo V. , Cipponi A. , Fontana R. , Maggioni D. , Ciceri F. , Lunghi F. , Bregni M. , Bordignon C. , Traversari C. 
Published: March 2020

2525 Background: Genetically-modified-lymphocytes (GML) can induce a specific immune response against the transgene product (HSV-TK), when injected into immunocompetent patients (Science 276:1719, 1997). In tumor-bearing mice the infusion of tumor-associated-antigen (TAA)-transduced lymphocytes induced protective immunity and long-term memory. In this experimental setting, the T-cell effectors were generated by a cross-presentation pathway, mediated by host dendritic cells (DCs). Indeed, DCs isolated from lymph nodes of treated mice contained fragments of labeled GML and were able to elicit antigen-specific responses ex vivo. Methods: To validate this novel vaccination strategy in humans, we treated 10 patients affected by stage IIIc/IV MAGE-A3+ melanomas with escalating doses of autologous GML expressing MAGE-A3 and the tracer antigen HSV-TK. HSV-TK allows to monitor the immune status of the patients. Immune responses were monitored by DTH and in vitro T cell assays (semi-quantitative recall assays and ELISPOT). Tumor status was monitored by conventional imaging analyses. Results: No toxicity was reported. From the 10 patients, 9 were clinically evaluable because responding to the tracer antigen HSV-TK. We observed one complete response with vitiligo surrounding the lesions and one long lasting stable disease (50 mo). Moreover, one patient with no evidence of disease remained free of disease at >48 mo. The 3 responding patients experienced both DTH reactivity to MAGE-A3 and sustained increase of circulating CD8+ and CD4+ MAGE-A3-specific effectors. The immune response was long lasting since MAGE-A3-specific effectors were still detectable both in vivo and in vitro 1 year after the last vaccination. Conclusions: We describe a new method for in vivo loading of TAA on DCs that may circumvent the limitations of ex vivo manipulation of DCs. Genetically modified lymphocytes, acting as antigen carriers, efficiently target DCs in vivo in tumor-bearing mice and in melanoma patients, resulting in the generation of TAA-specific effectors that correlate with clinical benefit. [Table: see text]
A randomized pilot study of concurrent docetaxel plus vaccine versus vaccine alone in metastatic androgen independent prostate cancer
Authors: Arlen P. M. , Gulley J. L. , Parker C. , Skarupa L. , Pazdur M. , Tsang K. Y. , Schlom J. , Dahut W. L. 
Published: March 2020

2531 Background: Docetaxel has activity against androgen insensitive prostate cancer (AIPC) and preclinical studies have demonstrated that taxane-based chemotherapy can enhance antitumor response of vaccines. The primary objective of this study was to determine: if concurrent docetaxel (with dexamethasone) had any effect on generating an immune response to a prostate cancer vaccine in patients with metastatic AIPC; secondary endpoints werewhether vaccine could be given safely with docetaxel, and the clinical outcome of the treatment regimen. Methods: The vaccination regimen was composed of (1) recombinant vaccinia virus (rV) that expresses the prostate-specific antigen gene (rV-PSA) admixed with (2) rV that expresses the B7.1 costimulatory gene (rV-B7.1), and (3) sequential booster vaccinations with recombinant fowlpox virus containing the PSA gene (rF-PSA). Patients received GM-CSF with each vaccination. Twenty-eight patients with metastatic AIPC were randomized to receive either vaccine and weekly docetaxel or vaccine alone. Patients on the vaccine alone arm were allowed to cross over to receive docetaxel alone at time of disease progression. An ELISPOT assay for IFN-gamma production was used to monitor immune responses for PSA-specific T cells. Results: The median increase in these T-cell precursors to PSA was 3.33-fold in both arms following 3 months of therapy. In addition, immune responses to other prostate cancer associated tumor antigens were also detected post-vaccination. Eleven patients who progressed on vaccine alone crossed over to receive docetaxel at time of progression. Median PFS on docetaxel was 6.1 months after receiving vaccine compared to 3.7 months with the same regimen in a historical control. Conclusions: This is the first clinical trial to demonstrate that docetaxel can be administered safely with immunotherapy, and without inhibiting vaccine specific T-cell responses. Furthermore, patients previously vaccinated with an anticancer vaccine may respond longer to docetaxel compared with a historical control of patients receiving docetaxel alone. Larger prospective clinical studies will be required to validate these findings. No significant financial relationships to disclose.
Early results of a phase I clinical trial of an Ii-Key/Her2/neu MHC class II peptide-based vaccine in breast cancer patients
Authors: Mittendorf E. A. , Khoo S. , Storrer C. E. , Harris K. A. , Jama Y. H. , Dehqanzada Z. A. , Murray J. L. , Shriver C. D. , Von Hofe E. , Ponniah S. , Peoples G. E. 
Published: March 2020

2532 Background: HER2/neu is over-expressed in breast cancer (BCa) and is the source of immunogenic peptides currently being evaluated in clinical trials as cancer vaccines. Ii-Key is a 4-amino-acid modification of peptides that has been reported to increase their occupancy of MHC class II molecules and enhance CD4 T cell responses. We are currently conducting a phase I clinical trial with an Ii-Key/HER2/neu MHC class II peptide (AE37) in BCa patients. Methods: The dose escalation safety trial design is for 3 groups of 3 patients to receive either 100, 500, or 1,000 μg of AE37 with 250 μg of GM-CSF in 6 monthly inoculations. Six additional patients will then be vaccinated at the optimal dose. Local and systemic toxicity is monitored and graded by the Common Toxicity Criteria. Immunologic response is monitored by peptide-stimulated proliferation (3H-thymidine incorporation) and ELISPOT (IFN-γ) assays for both AE37 and AE36 [the unmodified peptide HER2 776–790 (GVGSPYVSRLLGICL)]. Thus far 6 BCa patients have been vaccinated. Results: The 100μg dose group has completed all 6 vaccinations with maximum local and systemic toxicities of grade 2 and 1, respectively. All 3 patients developed increasing peptide-specific proliferation post-vaccination to both AE37 and AE36. ELISPOT responses were more variable with 1 minimal responder (30 IFN-γ spot-forming cells (SFC)/106 cells), 1 moderate responder (600 IFN-γ SFC/106 cells), and 1 good responder (1500 IFN-γ SFC/106 cells) post-vaccination. The 500μg dose group has thus far experienced earlier and larger local reactions but limited systemic toxicity. All 3 patients have demonstrated >1500 IFN-γ SFC /106 cells after just 2 inoculations. Peptide-specific proliferation after 2 inoculations has ranged between 3200–11500 cpm for the 500μg patients compared with 1200–2000 cpm after 6 inoculations for the 100μg dose group. Conclusions: AE37 appears to be safe and well-tolerated. A dose-dependent immunologic response has been demonstrated to the Ii-Key modified peptide as well as the naturally occurring sequence. These encouraging early results suggest that AE37 may prove to be useful as a CD4-specific vaccine either alone or in combination with CD8-specific HER2/neu peptides for improved cancer immunotherapy. [Table: see text]
Systemic modulatory effects of the treatment with IL-2 of lung metastasis
Authors: Diaz D. , Chara L. , Chevarria J. , Navas V. , Esteban E. , Carballido J. , Muñoz A. , Torregrosa Z. , Arroyo M. , Alvarez-Mon M. 
Published: March 2020

2560 Background: IL-2 is a drug that is employed in the treatment of several tumors due to its capacity of restore or increase the regulatory and effector function of the immune system. These effects have been demonstrated with the administration of the drug by intravenous and subcutaneous ways. Recently, it has been observed that the inhaled IL-2 administration is effective in the treatment of lung and renal cell carcinoma metastasis. However, it is unknown if this therapeutic effect is accompanied of systemic and local modulatory effects. Objectives: To compare spontaneous and mitogen-induced apoptosis in lymphocytes of renal carcinoma patients before and after treatment with inhaled IL-2. Methods: Peripheral blood mononuclear cells were purified from 7 patients with renal carcinoma before and after treatment with inhaled IL-2. The cells were characterized in a FACScalibur analyzer using fluorocrome-labeled monoclonal antibodies. The AI (or percentage of apoptotic cells, AI x 100) was calculated for T-cells expressing CD3, CD4, CD8, CD56, HLA-DR, CD25 and CD45RO/CD45RA antigens and NK-cells (CD3-CD56+ or CD3-CD16+). These AI were determined after 24 hours of culture under two conditions: without exogenous apoptosis inducers and in the presence of phytohemagglutinin. Comparisons between patients were carried out using the Wilcoxon test and were considered significant when p < 0.05. Results: A significant decrease in spontaneous ex vivo apoptosis was found in peripheral blood lymphocytes from renal carcinoma patients after treatment with inhaled IL-2 with respect to pretreatment values. This decrease occurred in T-cells and also in CD45RO expressing cells from both CD4+ and CD8+ subsets. A decrease of apoptosis was also observed in CD25+ expressing cells from CD3+, CD4+ and CD8+ subsets. A decrease in AI was found in mitogen induced apoptosis of CD25+ cells from CD3+, CD4+ and CD8+ subsets. Conclusions: The treatment with inhaled IL-2 has immunomodulatory effects that are observed at systemic level reducing the apoptosis of cells from several memory and activated T-cell subsets. No significant financial relationships to disclose.
Blocking the regulatory T cell molecule LAG-3 augments in vivo anti-tumor immunity in an autochthonous model of prostate cancer
Authors: Drake C. G. , Kelleher C. , Bruno T. , Harris T. , Flies D. , Getnet D. , Hipkiss E. , Maris C. , Grosso J. 
Published: March 2020

2573 Background: LAG-3 is a CD4 homolog expressed on activated T cells, NK cells, tumor infiltrating lymphocytes (TIL), and plasmacytoid dendritic cells. Recently, we showed that LAG-3 was relatively overexpressed in specific T cells rendered unresponsive in vivo by the presence of cognate self-antigen. These anergic T cells display regulatory function both in vitro and in vivo, and blockade of LAG-3 with a non-depleting monoclonal antibody significantly mitigates their regulatory T cell activity. Methods: Using a novel model of prostate cancer in which a tumor-specific antigen is expressed in autochthonous tumors, we tested whether treatment with a non-depleting anti-LAG-3 antibody affected trafficking and function of tumor-specific T cells. Results: LAG-3 blockade significantly augments specific CD8 T cell trafficking to antigen-expressing tumors, but not to normal tissue. Most significantly, LAG-3 blockade functionally reversed CD8 T cell tolerance as assayed by an in vivo cytotoxic T lymphocyte (CTL) assay. Combining LAG-3 blockade with specific anti-tumor vaccination results in a dramatic increase in activated CD8 T cells in the tumor parenchyma. Conclusions: Taken together, these data support the concept that treatment with a LAG-3 blocking antibody may significantly delay disease progression in patients with cancer. We have recently generated a panel of monoclonal antibodies directed against human LAG-3; several of these antibodies significantly augment human T cell responses in vitro. No significant financial relationships to disclose.
Vaccine for prevention of breast cancer
Authors: Deisseroth A. , Tang Y. , Maynard J. , Akbulut H. 
Published: March 2020

2580 Background: Women with high risk breast cancer still succumb to their disease despite existing programs of adjuvant therapy. Thus, new approaches for adjuvant therapy are needed. Her-2-Neu overexpression on a breast cancer cells correlates with recurrence, metastasis and resistance to chemotherapy and radiation therapy. The immune response is tolerant of tumor associated antigens (TAA) like Her-2-Neu since they have been present on epithelial cells since birth. The immune response to vaccines in women with breast cancer is limited by the diminished number of CD4 and CD8 T cells and qualitative defects of CD4 cells in individuals above the age of 50. Methods: The following strains of mice were vaccinated: 6–8 week old hMUC-1.Tg mice, and rH2N.Tg mice, as well as 18 month and 2 month old C57BL/6J mice, by injecting subcutaneously the Ad-sig-TAA/ecdCD40L vector prime followed by sc injections of the TAA/ecdCD40L protein boost. Results: Vaccination of 18 month old mice with the Ad-sig-TAA/ecdCD40L vector prime protein boost produce regressions of TAA positive sc tumor and a 5 fold increase in antigen specific spleen cells, a 10X increase in subcutaneous tumor nodules of antigen specific effector CD8 T cells by tetramers, and a 2X decrease of CD4+CD25+FOXP3+ cells. Vaccination of rH2N.Tg mice starting at 6 weeks with the Ad-sig-rH2N/ecdCD40L vector prime/protein boost prevented the development of breast cancer in 50% of the mice. The Ad-sig-hMUC-1/ecdCD40L vector prime/ hMUC-1/ecdCD40L protein boost induced hMUC-1 specific antibodies in hMUC-1.Tg mice which bound to human breast cancer specimens. The rH2N/ecdCD40L vector prime/protein boost vaccine suppressed growth of rH2N positive tumor cells and this effect was potentiated by concomitant administration of chemotherapy. Conclusions: These results suggest that the Ad-sig-TAA/ecdCD40L platform can be used to suppress the growth of existing breast cancer even in old mice and prevent the development of breast cancer. We are preparing a phase I clinical trial of this approach in the setting of breast cancer patients who have failed first line adjuvant therapy. In this trial, the vaccine will be added to established salvage therapy and both in vivo evaluations of tumor response, in vitro assays of immune response and toxicity will be measured. No significant financial relationships to disclose.
Effect of dasatinib, a SRC kinase inhibitor, on lung cancer cells with defined epidermal growth factor receptor status
Authors: Haura E. B. , Song L. , Lee F. , Jove R. 
Published: March 2020

3019 Background: Mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) predict sensitivity to small molecule inhibitors of EGFR such as gefitinib and erlotinib. Importantly, mutant EGFR selectively activates Akt and STAT pathways that are important in NSCLC cell survival. SRC-family kinases can cooperate with receptor tyrosine kinases to signal through downstream molecules such as PI3K/PTEN/Akt and STATs. Despite the importance of EGFR signaling in lung cancer, the known cooperation between EGFR and SRC proteins, and evidence of elevated SRC activity in human lung cancers, the effect of SRC inhibition on cell fate is unknown. Methods: We evaluated the anti-tumor efficacy of a novel orally bioavailable SRC-ABL inhibitor dasatinib (BMS-354825) in non-small cell lung cancer cell lines with defined EGFR status including wildtype EGFR and mutant EGFR sensitive to gefitinib. Western blotting was used to evaluate the effect of dasatinib on downstream signaling pathways and in vitro assays were used to evaluate the effect cell cycle, apoptosis, and cell invasion. Results: Our results show that cell fate (death versus growth arrest) in lung cancer cells exposed to a SRC inhibitor is dependent on EGFR status. Dasatinib reduces mutant EGFR lung cancer cell viability through the induction of apoptosis and G1 cell cycle arrest while having no significant apoptotic effect on cell lines with wildtype EGFR. The induction of apoptosis in EGFR mutant cell lines corresponds to downregulation of phosphorylated Akt and Stat3 survival proteins. In cell lines without EGFR mutation, dasatinib induces a G1 cell cycle arrest with associated changes in cyclin D and p27 proteins as well as inhibits activated FAK and prevents tumor cell invasion. Conclusions: Our results demonstrate that novel SRC inhibitors could be effective therapy for patients with lung cancers through disruption of cell growth, survival and tumor invasion. Our results suggest EGFR status is critical in deciding cell fate in response to SRC inhibition. [Table: see text]
Bevacizumab plus erlotinib in patients (pts) with carcinoma of unknown primary site: A phase II trial of the Minnie Pearl Cancer Research Network
Authors: Hainsworth J. D. , Spigel D. R. , Thompson D. S. , Shipley D. L. , Zubkus J. D. , Toomey M. A. , Burkett E. , Greco F. A. 
Published: March 2020

3033 Background: Targeted therapies inhibiting tumor angiogenesis or the epidermal growth factor pathway have demonstrated efficacy in a variety of solid tumors. In this multicenter phase II trial, we evaluated the efficacy of combined targeted therapy with bevacizumab plus erlotinib in pts with carcinoma of unknown primary site. Methods: Eligibility criteria included: metastatic adenocarcinoma or poorly differentiated carcinoma of unknown primary site; 1 or 2 previous chemotherapy regimens (previously untreated pts were eligible only if considered poor candidates for chemotherapy due to advanced liver or bone metastases); measurable disease; ECOG PS 0–2; no previous anti-angiogenic or EGFR inhibitor therapy; no active brain metastases; no active thromboembolic disease or bleeding abnormalities; adequate organ function; informed consent. All pts received bevacizumab 10mg/kg IV q 2 weeks and erlotinib 150mg PO daily. Pts were evaluated for response after 8 weeks; treatment was continued until tumor progression. Results: 51 pts entered this clinical trial between 4/04 and 7/05. Pt characteristics: median age 57; male/female, 22/29; ECOG 0/1/2, 5/43/3; previous chemotherapy, 75%. 49 pts (96%) received at least 2 months therapy and were evaluable for response. Objective responses occurred in 4 pts (8%) (all ongoing at 5+ - 19+ months); 30 pts (59%) had stable disease/minor response. After median follow-up of 13 months, median progression-free survival for the entire group is 6.2 months. Median overall survival is 8.9 months, with 42% of pts alive at 1 year. 1-year survival for previously treated vs. untreated pts: 41% vs. 46%. Toxicity with this regimen was consistent with previous reports; other than fatigue (12%), no grade 3/4 toxicity was observed in > 10% of pts. Conclusions: The combination of bevacizumab and erlotinib has activity in pts with carcinoma of unknown primary site. Progression-free and overall survival results appear superior to our previous second-line results using a variety of chemotherapy regimens, and are similar to results with first-line chemotherapy. Future trials will evaluate bevacizumab/erlotinib as part of first-line therapy. [Table: see text]
Letrozole (L) with bevacizumab (B) is feasible in patients (pts) with hormone receptor-positive metastatic breast cancer (MBC)
Authors: Traina T. A. , Rugo H. , Caravelli J. , Yeh B. , Panageas K. , Bruckner J. , Norton L. , Park J. , Hudis C. , Dickler M. 
Published: March 2020

3050 Background: Bevacizumab added to chemotherapy (CRx) prolongs PFS in pts with MBC. Data suggest that estrogen (E2) modulates VEGF-induced angiogenesis in physiologic and pathologic conditions. E2-induced VEGF expression may promote breast cancer growth therefore combination therapy with an aromatase inhibitor (AI) and an antibody to VEGF may be more effective than either agent alone. We performed a feasibility study testing B with L for the treatment (tx) of hormone receptor-positive MBC. Methods: Eligible pts have MBC and are candidates for AI therapy. Prior non-steroidal AI (NSAI) use without progression is permitted. Premenopausal pts undergo ovarian suppression/oophorectomy prior to tx. Therapy consists of L (2.5 mg daily) and B (15 mg/kg IV q3 weeks). The primary endpoint is frequency of Grade (Gr) 4 toxicity. Secondary endpoints include response rate, stable disease (SD) ≥ 6 mo and time to tumor progression. Using a two-stage design, 19 pts were accrued. Because <3 pts had Gr 4 toxicity, the 2nd stage is now enrolling an additional 23 pts. If <5 of the 42 pts have Gr 4 toxicity, the regimen will be considered feasible. Results: Thirty two pts are currently accrued and 28 are now evaluable. Medians: Age 49.5 yrs (32–77) and ECOG PS 0 (0–1). Sites of MBC: bone only 11/28, visceral 16/28, chest wall/soft tissue/lymph nodes 11/28. All are ER and/or PR (+); none are HER2 (+). Prior therapy: adjuvant CRx 20; adjuvant tamoxifen 14. Twenty five pts received an NSAI as first-line tx of MBC, starting a median of 23 wks (1–213) before B. Three pts received first-line tamoxifen; one pt had prior CRx for MBC. After a median of 8 cycles (1–20), tx-related toxicities: Gr 2: hypertension (HTN) 4, headache (HA) 4, proteinuria 3, fatigue 6, joint pain 5, hot flashes 1, epistaxis 1; Gr 3: HTN 5, HA 1, proteinuria 1. There has been no tx-related Gr 4/5 toxicity. Tx-related withdrawals: HTN 1 and headache 1. Twenty five pts are evaluable for response: PR 2, SD ≥ 6 mo 13, SD 4, progression 6. Conclusions: Combination L and B is well tolerated and will be studied in a randomized CALGB trial. Circulating endothelial and tumor cell data is reported separately. Supported in part by Genentech and Novartis. [Table: see text]
Preliminary pharmacogenetic evaluation of toxicity data in the prospective multicentre EORTC trial 40015 in metastatic colorectal cancer (CRC)
Authors: Aust D. , Kohne C. , Goekkurt E. , De Greve J. , Hartmann J. , Van Cutsem E. , Debois M. , Bethe U. , Lutz M. P. , Stoehlmacher J. 
Published: March 2020

3072 Background: EORTC phase III study 40015 was initiated in 2003 to compare capecitabine (C) + irinotecan (CPT-11) vs 5FU/LV/irinotecan ± celecoxib in 1st line treatment of mCRC. The study was suspended after enrollment of 85 pts due to 8 fatal events not related to disease progression, 4 of which included thrombo-embolic events. Purpose: To test whether genetic polymorphisms involved in metabolism of the drugs are related to the increased toxicity observed in the study. Methods: 71 pts signed informed consent for genetic analyses and material was available for 58 pts. DNA was extracted from normal colonic mucosa or peripheral leukocytes. Polymorphisms were determined using PCR-based RFLP and direct sequencing. Genotypes known to be associated with increased toxicity (diarrhea, mucositis, leucopenia) were classified as unfavorable. Results: Unfavorable genotypes were distributed equally between C+CPT-11 and LV/5FU+CPT-11 arms. Baseline characteristics and treatment duration were similar in the pts with or without unfavorable genotypes. Unfavorable genotypes of thymidylate synthase (TS-5; TS-3) and UDP-glucuronosyltransferase 1A1 (UGT1A1) were associated with increased grade 3/4 toxicity. 18/35 (51%) pts with unfavorable UGT1A1 genotype experienced toxicity grade 3/4 compared to 3/23 (13%) pts with favorable genotype. 16/36 pts (44%) with unfavorable TS-5 genotype showed toxicity grade 3/4 compared to 5/22 (23%) pts with favorable genotype. Toxicity grade 3/4 was observed in 18/41 (44%) pts with unfavorable TS-3 genotype and 3/17 (18%) pts with favorable genotype. Increasing grade 3/4 toxicity rates were observed in the pts expressing 0/1 (2/16 [13%]), 2 (7/24 [29%]) or 3 (12/16 [75%]) unfavorable genotype(s) (p=0.0001). Among the 4 pts who died of a thrombo-embolic event, only one has been analysed at this stage and showed a Factor (V) Leiden mutation linked to 10-fold increased risk for thrombo-embolic events. Analyses are ongoing and complete data will be available for presentation. Conclusion: Our data suggest an association between polymorphisms of TS and UGT1A1 and toxicity. No differences of pharmacogenetic patterns were observed that could explain the increased rate of fatal events in the C/CPT-11 arm. [Table: see text]