bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tremelimumab in combination with exemestane as novel immunotherapy for patients with advanced breast cancer
Authors: Vonderheide R. H. , LoRusso P. M. , Khalil M. , Heath E. , Khaira D. , Soulieres D. , Dorazio P. , Mariani G. L. , Usari T. , Domchek S. M. 
Published: August 2020

3034 Background: Tremelimumab (CP-675, 206) is a fully human IgG2 anti-CTLA4 monoclonal antibody (mAb) with single-agent antitumor activity presumed to be related to immune stimulation following blockade of CTLA4. Here, we conducted a phase I, open-label, dose-escalation trial of the combination of tremelimumab and exemestane in patients (pts) with advanced hormone receptor (or unknown receptor status if prior response with hormone therapy) breast cancer. Methods: Twenty-five pts with ER+ and/or PR+ breast cancer and 1 pt with unknown receptor status who had relapsed after treatment for advanced disease were enrolled. Pts received escalating doses of tremelimumab (3 to 10 mg/kg) delivered either every 28 days (Q28D) or every 90 days (Q90D) in combination with continuous exemestane (25 mg/day). Primary endpoints were assessment of safety and determination of recommended phase II dose. Tumor response evaluation per RECIST was a secondary endpoint. Results: Overall, 65 cycles of tremelimumab were administered in combination with exemestane. Pts received 3 mg/kg tremelimumab Q28D (n=6), 6 mg/kg tremelimumab Q28D (n=1), 6 mg/kg tremelimumab Q90D (n=13), or 10 mg/kg Q90D (n=6). No pharmacokinetic interaction between tremelimumab and exemestane was observed. Dose-limiting toxicities included transient serum transaminase elevation in cycle 1 (grade 3 in 1 pt) and diarrhea in cycle 1 (grade 3 in 3 pts, 1 of whom was hospitalized with steroid-refractory diarrhea and given anti-tumor necrosis factor-α mAb, infliximab) and cycle 2 (grade 3 in 1 pt). One pt developed grade 2 autoimmune thyroiditis requiring chronic hormone replacement. Other toxicities included constipation (n=6), fatigue (n=8), and rash (n=9). The MTD was 6 mg/kg Q90D. For pts receiving ≥2 cycles of therapy, best response was stable disease in 8 pts lasting 3 to 14 months (median 8 months); no pts had objective responses. Conclusions: MTD of tremelimumab in combination with exemestane is estimated at 6 mg/kg Q90D, which is lower than the single-agent dose of 15 mg/kg Q90D used in phase II and III trials in pts with melanoma or colorectal cancer. This may suggest that there is a biological interaction between tremelimumab and exemestane. [Table: see text]
Safety of catumaxomab: Cytokine-release-related symptoms as a possible predictive factor for efficacy in a pivotal phase II/III trial in malignant ascites
Authors: Bokemeyer C. , Heiss M. , Gamperl H. , Linke R. , Schulze E. , Friccius-Quecke H. , Lindhofer H. , Parsons S. 
Published: August 2020

3036 Background: As a targeted immunotherapy, the trifunctional antibody catumaxomab specifically binds to epithelial cell-adhesion molecule (EpCAM) on tumor cells and attracts T-cells via CD3 and accessory cells via its FcγRI/III+ region. The clinical relevance of this mode of action was demonstrated by Parsons et al. (ASCO 2008) in a pivotal phase II/III trial. Catumaxomab treatment resulted in a clinically relevant prolongation of puncture-free survival (defined as time to next puncture or time to death, which ever occurred first) in patients with malignant ascites. One of the most common adverse events associated with catumaxomab is cytokine-release-related-symptoms (CRRSs), which might be of predictive value for efficacy. Methods: The safety profile of catumaxomab was identified in the pivotal study. CRRSs (pyrexia, nausea, and vomiting) were among the most common adverse events in the catumaxomab group. A correlation between CRRSs and puncture-free survival, the primary endpoint, was performed to investigate whether patients who had CRRSs benefited from catumaxomab treatment more than those who had no CRRSs. Results: Among 157 patients, CRRSs were limited to the duration of catumaxomab treatment, with a median onset of 1 day after catumaxomab administration and a median duration of 1–2 days. Most of these symptoms were mild to moderate and were manageable by standard symptomatic treatment. Only 6 of 101 patients with CRRSs who were treated with concomitant medication required systemic corticoid therapy. Puncture-free survival was longer (48 days) in patients with (81%) CRRSs during catumaxomab treatment than in patients without (19%) CRRSs (27 days), although the difference was not statistically significant (p=0.1546, log rank test). Conclusions: CRRSs are a common occurrence with catumaxomab, due to its mode of action, during the treatment of patients with malignant ascites. Since CRRSs appear to be correlated with efficacy, they may therefore be a predictive factor for catumaxomab efficacy. [Table: see text]
Targeting of glioblastoma with activated T cells armed with anti-CD3xanti-HER2/neu (HER2Bi) and anti-CD3xanti-EGFR (EGFRBi) bispecific antibodies
Authors: Zitron I. M. , Norkina O. , Al-Kadhimi Z. , Barger G. R. , Lum L. G. , Mittal S. 
Published: August 2020

3038 Background: Malignant gliomas are the most common primary brain tumors in adults. The prognosis for patients with glioblastoma remains poor despite aggressive multimodality treatment including surgery and chemoradiotherapy. The receptor tyrosine kinases EGFR, mutant EGFR (EGFRvIII), and HER2/neu are expressed on the majority of glioblastomas and are potential targets for activated T cells (ATCs) armed with bispecific antibodies (BiAbs). Methods: ATCs were generated from human peripheral blood mononuclear cells (PBMC) by culture for 14 days with monoclonal anti-CD3 and interleukin-2 and armed with HER2Bi and/or EGFRBi. HER2Bi- and/or EGFRBi-armed ATCs were examined for in vitro cytotoxicity (MTT and 51Cr release assays) against long-term malignant glioma lines (U87MG, U118MG, and U251MG) as well as primary glioblastoma lines derived from surgical specimens. Expression of EGFR and HER2/neu were evaluated by FACS. Anti-CD133 coated magnetic microbeads were used to separate CD133-positive and CD133-negative cell populations. Results: EGFRBi-armed ATCs killed up to 85% of U87, U118, and U251 targets. HER2Bi-armed ATCs exhibited comparable cytotoxicity against U118 and U251, but did not kill HER2-negative glioma U87. Cytotoxicity exhibited by either HER2Bi- or EGFRBi-armed ATCs against four primary glioblastoma cell lines was 50–80%. We found that both CD133-negative and CD133-positive cell populations were susceptible to killing by armed ATCs. When we armed ATCs simultaneously with HER2Bi and EGFRBi, killing by doubly armed ATCs was equal to or greater than that by EGFRBi-armed ATCs against the tested cell lines. Conclusions: BiAbs efficiently target ATCs to kill EGFR and/or HER2/neu expressing glioblastomas. Long-term malignant glioma cell lines and primary lines derived from surgical specimens are equally susceptible. Both CD133-negative and CD133-positive (the putative glioma stem cells) are killed. ATCs armed with BiAbs represent a potentially valuable adjuvant to current treatment. No significant financial relationships to disclose.
Investigation of constitutive and cytokine-induced expression of pSTAT 1, 3, and 5 in PBL of breast cancer patients
Authors: Konjevic G. , Stankovic S. , Srdic T. , Jelic S. , Inic M. 
Published: August 2020

3042 Background: Although cytokines mediate their effects by latent transcription factors, STATs, their dysregulation has not been much investigated in peripheral blood lymphocytes (PBL) of breast cancer patients. As alterations in the JAK-STAT pathway contribute to immunosuppression in cancer patients in this study, aside from baseline-level, we investigated the level and cytokine-mediated activation of STAT1, 3, and 5 in healthy controls and breast cancer patients. Methods: PBL (5x106/ml) of breast cancer patients in all four clinical stages, as well as healthy controls, were treated in vitro with culture medium (CM) alone, IFNα (250 IU/ml CM) and IL-2 (500 IU/ml) for 24h at 37°C. Induction of phosphorylated STAT proteins was assessed in cellular lysates by Western blotting using monoclonal anti-STAT1, 3, and 5 antibodies. Treated PBL were also analyzed for IFNγ using an intracellular flow cytometry assay. Results: Our results indicate that untreated PBL of breast cancer patients, compared to healthy controls, express a significantly lower baseline level of pSTAT1, 3, and 5. The induction of pSTAT1 expression by IFNα, similar to the induction of pSTAT3 and pSTAT5 by IL-2, is significant for healthy controls and breast cancer patients, although the effect in patients is significantly below that for healthy controls. Moreover, the induction of pSTAT5 by IL-2 is of a higher magnitude than pSTAT3. PBL of breast cancer patients, compared to healthy controls, have a lower level of IFNγ. The production of IFNγ in PBL is enhanced by IFNα, as well as IL-2, although in breast cancer patients to a much lower level than in healthy controls. Conclusions: These results provide evidence that evaluation of STAT expression in PBL of breast cancer patients could be of diagnostic and therapeutic significance for cytokine-based therapy. No significant financial relationships to disclose.
Association of immune-regulatory (FoxP3+)-T-cell tumor infiltration status with benefit from chemoimmunotherapy with gemcitabine, oxaliplatin, 5-FU/FA plus GM-CSF and aldesleukine (GOLFIG) in metastatic colon cancer patients
Authors: Correale P. , Tagliaferri P. , Del Vecchio M. T. , Remondo C. , Migali C. , Tsang K. Y. , Rotundo M. S. , Fulfaro F. , Tassone P. , Francini G. 
Published: August 2020

3045 Background: GOLFIG is a novel chemoimmunotherapy regimen, combining gemcitabine, oxaliplatin, 5-FU/FA with immunoadjuvant GM-CSF and aldesleukine, which resulted safe and very active in colon cancer patients. Antitumor activity and immunity feedback to the treatment resulted strictly correlated. The best outcome was observed in patients showing autoimmunity signs, rise in central-memory-T cells, and decline in peripheral and tumor infiltrating immuno-regulatory T (Treg) cells. On these bases, we investigated a possible correlation between Treg tumor infiltration at diagnosis and clinical outcome of these patients. Methods: An immunohistochemistry study was carried out to quantify the infiltration of Treg (FoxP3+) lymphocytes in tumor samples of 41 colon cancer patients who received FOLFOX-4 chemotherapy or GOLFIG chemo-immunotherapy as enrolled in the ongoing phase III GOLFIG-2 trial. Treg tumor infiltration score (range 0 to 5) was then correlated with survival (OS) and time to progression (TTP). Results: A higher Treg tumor infiltration score (score 3–5) was associated to a longer OS and TTP in the whole patient population (high vs low score; TTP=18 vs 9.4 months; p=0.002; OS=55.7 vs 28.9 months; p=0.001); however, those patients with high tumor infiltration of FoxP3+-T cells who received GOLFIG regimen showed the most favorable outcome (high vs low score; TTP=20.8 vs 11.6 months; p=0.04; OS=68.1 vs 41 months; p=0.04). A Cox regression model demonstrated in these patients that a high Treg tumor infiltration score is an independent variable of long survival and prolonged TTP. Conclusions: Our results suggest that GOLFIG chemoimmunotherapy is highly effective in colon carcinoma patients with high FoxP3+ infiltration score and that Treg-tumor infiltration score may be a favorable prognostic marker in colon cancer patients. No significant financial relationships to disclose.
MMP-2: A novel target for antitumor immune therapy
Authors: Godefroy E. , Guilloux Y. , Jotereau F. , Bhardwaj N. 
Published: August 2020

3053 Background: Over the last two decades, a large array of antigens expressed by melanoma cells (MAA) has been identified and used in various immunization strategies to treat cancer patients. However, the therapeutic efficacy of these approaches remains limited. Because MMP-2 (matrix metalloproteinase-2) activity is critical for melanoma progression, this protein represents a unique antigen for vaccine therapy. Methods: Antigen-specific T cell clones were obtained from healthy donors. CD4+ cells were stimulated with overlapping MMP-2 peptides pulsed with irradiated autologous CD4- fraction. After 12 days, MMP-2-specific responses were determined by intracellular staining for cytokines. Specific T cells from positive samples were enriched, using the IFNγ-capture assay (Miltenyi), followed by cloning using limiting dilution. Cytokine production was assessed by ELISA, intracellular staining, or cytometric bead array method. Results: We identified 11 novel CD4 MMP-2-derived epitopes, and showed that the corresponding T cells displayed an inflammatory TH2 profile, i.e., mainly secreting TNF, IL-4 and IL-13 and expressing the TH2-specific transcription factor GATA-3. In contrast, CD4+ T cells that recognize other associated MAAs were typically TH1. MMP-2-specific responses were detected in the CD45RO+/CD62L- T cell memory fraction. Interestingly, naïve T cells primed with active MMP-2 gave rise to TH2 specific cells, while naïve T cells primed with peptides generated IFNγ-secreting specific cells, consistent with a TH1 profile. Accordingly, we showed that the enzymatic activity of MMP-2 inhibited IL-12 secretion by mature DCs, possibly explaining the TH2 skewing of MMP-2-specific T cells. Furthermore, MMP-2 specific TH2 cells were found in at least 18 tumor-infiltrating lymphocyte populations out of the 31 melanoma patients tested. Conclusions: The protease activity of MMP-2 blocks DC maturation, more precisely IL-12 production, which could be responsible for the observed TH2 lineage commitment of MMP-2-specific T cells. These findings open the way to therapeutic strategies skewing these already frequent and diverse MMP-2-specific responses towards a more efficient antitumor TH1 phenotype to treat melanoma patients. No significant financial relationships to disclose.
T-lymphocyte responses to the human telomerase reverse transcriptase (hTERT) in patients (pts) with advanced non-small cell lung cancer (NSCLC)
Authors: Fabre E. , Medioni J. , Dosset M. , Dosset M. , Tartour E. , Oudard S. , Riquet M. , Adotevi O. 
Published: August 2020

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 (< 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.
Evaluation of recombinant bacillus Calmette-Guerin expressing pertussis toxin in bladder cancer
Authors: Chade D. C. , Borra R. , Leite K. R. , Villanova F. E. , Nascimento I. , Liete L. C. , Srougi M. , Andrade P. M. 
Published: August 2020

3064 Background: Pertussis toxin (S1PT) was combined to BCG, creating a recombinant variant (rBCG-S1PT) with the capacity to promote an immune response targeted to the T helper type 1 (Th1), which may increase the effectiveness of its antitumor effect. Objective: Compare the antitumor effects of rBCG-S1PT and BCG in an experimental model of bladder cancer. Methods: The development of the animal model of bladder cancer was conducted by transurethral instillation of bladder tumor cell line MB49 of the mouse strain C57BL/6. The animal models were divided into three groups, which received 4 weekly intravesical applications of rBCG-S1PT, BCG, or saline. After 7 days of the last instillation, bladders were extracted and weighed in order to infer the tumor weight. Then, the bladders were divided for molecular analysis to assess the pattern of immune response and histopathological analysis. In another experiment, animals were monitored for 60 days for analysis of survival. Also, a test was carried out as previously described, but with no tumor cells instillation. Results: The rate of tumor implantation was 90% of the animals submitted to tumor inoculation. We obtained reduction of the average weights of bladder in groups BCG and rBCG-S1PT ((p<0.001). In both groups treated with immunotherapy, there was an increase of expression of interleukins related to Th1, which was more intense in the group treated with rBCG-S1PT (p<0.05). The analysis of survival showed a significant increase in the group of animals treated with rBCG-S1PT. The instillation of immunotherapeutic agents in animals without tumor did not demonstrate histological differences when compared to the control group. Conclusions: The establishment of the syngeneic orthotopic animal model was successful. The immunotherapy with rBCG-S1PT demonstrated more benefits than BCG in the treatment of bladder cancer in mice, reducing the bladder weight and increasing survival. The immune response obtained with the rBCG-S1PT expressed higher cytokines related to Th1. This new recombinant agent may promote better bladder tumor control than BCG imunotherapy in a clinical setting. No significant financial relationships to disclose.
A first-in-human phase I study to evaluate the pan-PI3K inhibitor GDC-0941 administered QD or BID in patients with advanced solid tumors
Authors: Wagner A. J. , Von Hoff D. H. , LoRusso P. M. , Tibes R. , Mazina K. E. , Ware J. A. , Yan Y. , Derynck M. K. , Demetri G. D. 
Published: August 2020

3501 Background: The PI3K-PTEN-AKT signaling pathway is deregulated in a wide variety of cancers. GDC-0941 is a potent and selective oral inhibitor of the class I PI3K with 3 nM IC50 for the p110-alpha subunit in vitro and 28 nM IC50 in a cell-based pAKT assay and demonstrates broad activity in breast, ovarian, lung, and prostate cancer models. Methods: A Phase I dose escalation study using a 3+3 design was initiated in patients (pts) with solid tumors. GDC-0941 was given on d1, followed by 1 wk washout to study single-dose PK and PD markers. GDC-0941 was then administered qd on a 3 wk on, 1 wk off, schedule. Steady-state PK and PD were evaluated after 1 wk of continuous dosing. A separate concurrent dose-escalation arm with bid dosing was initiated after the third qd cohort. Results: Nineteen pts have been enrolled in 5 successive dose-escalation cohorts in the qd arm with dose levels up to 80 mg daily. Seven pts were enrolled in 2 cohorts in the bid arm at total daily doses of 60 and 80 mg. The most frequently reported drug-related AEs were Grade 1/2 nausea, fatigue, diarrhea, peripheral edema, and dysgeusia; no drug related grade >3 events have been reported. PK data suggest dose-proportional increases in Cmax and AUC. Potential signs of anti-tumor activity have been observed with a soft tissue sarcoma pt on-study for >176 days with stable disease (30 mg qd), an ovarian cancer pt with an on-study 2.8-fold decrease in CA-125 response to normal levels (30 mg bid) and a pt with endometrial cancer with a decrease in tumor FDG-PET uptake (80 mg qd). Conclusions: GDC-0941 is generally well-tolerated with potential signs of anti-tumor activity. Preliminary PK data suggest dose-proportional increases in exposure over the dose levels evaluated. Dose-escalation on both the qd and bid schedules continues with updated data to be presented. [Table: see text]
A phase I dose-escalation study of the safety, pharmacokinetics (PK), and pharmacodynamics of XL765, a PI3K/TORC1/TORC2 inhibitor administered orally to patients (pts) with advanced solid tumors
Authors: LoRusso P. , Markman B. , Tabernero J. , Shazer R. , Nguyen L. , Heath E. , Patnaik A. , Papadopoulos K. 
Published: August 2020

3502 Background: XL765 is a potent and selective inhibitor of Class I PI3K isoforms, TORC1, and TORC2. XL765 has shown dose-dependent target modulation and tumor growth inhibition or shrinkage in multiple human xenografts. Methods: Pts receive XL765 bid or qd for 28-day cycles. PK and pharmacodynamic analyses are performed. Tumor response is assessed by RECIST every 8 weeks. Results: To date, 34 pts have been dosed with XL765; 26 pts on a bid regimen (15–120mg) and 8 pts on a qd regimen (70–100 mg). Maximum administered doses are 120 mg bid and 100 mg qd. Dose-limiting toxicities (DLTs) occurred at 120 mg bid and 60 mg bid and included elevated hepatic transaminases (2), anorexia/hypophosphatemia (1), rash (1), and nausea/vomiting (1). Grade > 2 increase in transaminases, including one possibly related serious adverse event of Grade 4, occurred in 3 of 7 pts at 120 mg bid. Non-specific neurological complaints (1) and rash (1) were the DLTs that occurred at 100 mg qd. The most common (> 10% of pts) related adverse events were elevated liver enzymes, nausea and diarrhea. XL765 exposure increased with increasing doses (15–120 mg bid). Median tmax was 1–3 h post-dose. Mean t1/2,z ranged from 3 to 9 h at steady-state. Repeat dosing (bid or qd) resulted in moderate to no drug accumulation. XL765 augmented food-induced increases in plasma insulin, but not glucose, in an exposure-dependent fashion. Robust pharmacodynamic modulation of PI3K pathway signaling in PBMCs, hair follicles, skin, and tumors was evident following administration of XL765. These effects were exposure-dependent for some biomarkers in PBMCs and hair. Five pts had durable stable disease (> 3 months): appendiceal cancer (15 mg bid) 8 cycles; RCC (15 mg bid) 4 cycles; NSCLC (30 mg bid) 4 cycles; mesothelioma (60 mg bid) 10 cycles; CRC (100 mg qd) 6 cycles. Conclusions: In this phase I study, XL765 has exhibited potent pharmacodynamic activity at generally well tolerated doses. PI3K pathway inhibition of ∼60–90% in hair and skin was seen at multiple tolerable doses. [Table: see text]