tbuckley/cabot-search huggingface dataset:
Abstract 3623: The CTLA-4 x OX40 bispecific antibody ATOR-1015 induces anti-tumor effects through tumor-directed immune activation
Authors: Niina Veitonmäki, Mia Thagesson, Doreen Werchau, Karin Hägerbrand, Kristine Smedenfors, Anne Månsson-Kvarnhammar, Anna Rosén, Maria Johansson, Christina Furebring, Per Norlén, Peter Ellmark
Journal: Cancer Research (2018)

Abstract ATOR-1015 is a CTLA-4 x OX40 bispecific immune activating antibody developed for tumor-directed immunotherapy. ATOR-1015 binds both targets simultaneously, promoting cell-cell interactions expected to enhance the immuno-stimulating effect of the compound. The mode of action of ATOR-1015 is thought to be a combination of regulatory T cell (Treg) depletion and effector T cell activation. It can be seen as a next generation CTLA-4 antibody with tumor-directed activity and augmented Treg depletion. The ability to induce ADCC of human Treg was investigated using an FcγR expressing reporter assay demonstrating superior effect of ATOR-1015 compared to the monospecific antibody counterparts. Further, ATOR-1015 has been shown to induce activation of T cells in the presence of CTLA-4 expressing cells, ability that is not observed when combining the monoclonal counterparts. Syngeneic tumor models in vivo using human transgenic mice cross-reacting with both targets demonstrate that ATOR-1015 reduces tumor growth and prolongs survival. Further, ATOR-1015 treatment demonstrates superior increase in the intratumoral CD8+ T cell/Treg ratio compared to the monospecific counterparts, without affecting systemic T cells. This tumor directed immune activation is demonstrated to be due to the tumor localization abilities of ATOR-1015. In conclusion, ATOR-1015 is a next generation CTLA-4 antibody with tumor directed activity with augmented T-reg depletion. It is currently in GLP manufacturing of clinical material and will start clinical trials in the second half of 2018. Citation Format: Niina Veitonmäki, Mia Thagesson, Doreen Werchau, Karin Hägerbrand, Kristine Smedenfors, Anne Månsson-Kvarnhammar, Anna Rosén, Maria Johansson, Christina Furebring, Per Norlén, Peter Ellmark. The CTLA-4 x OX40 bispecific antibody ATOR-1015 induces anti-tumor effects through tumor-directed immune activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3623.
Abstract 2304: In vivo E2F reporting reveals efficacious schedules of MEK1/2-CDK4/6 targeting and mTOR-S6 resistance mechanisms
Authors: Jessica Teh, Phil F. Cheng, Timothy J. Purwin, Neda Nikbakht, Prem Patel, Inna Chervoneva, Ines Keibler, HooKim Kim, Michael A. Davies, Lawrence N. Kwong, Mitch P. Levesque, Reinhard Dummer, Andrew E. Aplin
Journal: Cancer Research (2018)

Abstract Targeting cyclin dependent kinases 4 and 6 (CDK4/6) represents a viable therapeutic option in combination with BRAF inhibitor and/or MEK inhibitor in different genetic subsets of melanoma. However, continuous dosing of MEK inhibitor (MEKi) plus CDK4/6 inhibitor (CDK4/6i) elicits toxicities in patients. Utilizing an in vivo E2F reporter system, we analyzed the efficacy of MEKi plus CDK4/6i schedules in a quantitative and temporal manner. Continuous MEKi with intermittent CDK4/6i led to more complete responses as compared to either continuous CDK4/6i with intermittent MEKi or intermittent dosing of both drugs. Nevertheless, some tumors acquired resistance. Phospho-proteomic analysis of resistant tumors revealed increased phosphorylation of ribosomal S6 protein (RPS6). These data were supported by staining of patient biopsies from clinical trials, which also indicated that high phospho S6 levels may serve as a predictor of response to CDK4/6i plus targeted inhibitors. Enhanced phospho S6 provided a therapeutic window for the mTORC1/2 inhibitor, AZD2014, in MEKi plus CDK4/6i-resistant tumors. Mechanistically, aberrant regulation of NRAS was associated with resistance and sufficient to mediate resistance. This study highlights the use of an in vivo reporter model for optimization of schedules and supports targeting the mTORC1/2-S6 pathway as a salvage option to overcome MEKi plus CDK4/6i resistance. Citation Format: Jessica Teh, Phil F. Cheng, Timothy J. Purwin, Neda Nikbakht, Prem Patel, Inna Chervoneva, Ines Keibler, HooKim Kim, Michael A. Davies, Lawrence N. Kwong, Mitch P. Levesque, Reinhard Dummer, Andrew E. Aplin. In vivo E2F reporting reveals efficacious schedules of MEK1/2-CDK4/6 targeting and mTOR-S6 resistance mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2304.
Vitamin D Therapy in Individuals With Prehypertension or Hypertension
Authors: Pankaj Arora, Yanna Song, Jeffery Dusek, Gregory Plotnikoff, Marc S. Sabatine, Susan Cheng, Andre Valcour, Heather Swales, Beth Taylor, Erin Carney, Derek Guanaga, Joseph R. Young, Courtney Karol, Michael Torre, Atum Azzahir, Semerit M. Strachan, Dillon C. O’Neill, Myles Wolf, Frank Harrell, Christopher Newton-Cheh, Thomas J. Wang
Journal: Circulation (2014)

Background— A large body of epidemiological and experimental evidence suggests that vitamin D deficiency may promote hypertension. This raises the possibility that vitamin D supplementation could be a simple intervention to reduce blood pressure, but data from prospective, randomized trials are limited. Methods and Results— A double-blind, randomized, controlled trial was conducted at 4 sites in the United States. We enrolled 534 individuals 18 to 50 years of age with low vitamin D status (25-hydroxyvitamin D levels ≤25 ng/mL) and systolic blood pressure of 120 to 159 mm Hg. Participants were randomized to high-dose (4000 IU/d) versus low-dose (400 IU/d) oral vitamin D 3 for 6 months. The primary end point was change in mean 24-hour systolic blood pressure. Secondary end points included change in ambulatory diastolic blood pressure and clinic systolic and diastolic blood pressures. The median age was 38 years, and 62% of participants were men. Forty-six percent of participants were white, and 48% were black. The median 25-hydroxyvitamin D level at baseline was 15.3 ng/mL. Four-hundred fifty-five participants (85%) had at least 1 follow-up blood pressure measurement; 383 participants (72%) completed the full 6-month study. At the end of the study, there was no significant difference in the primary end point (change in mean 24-hour systolic blood pressure, −0.8 versus −1.6 mm Hg in the high-dose and low-dose arms; P =0.71) or in any of the secondary end points. Furthermore, there was no evidence of association between change in 25-hydroxyvitamin D and change in 24-hour systolic blood pressure at 6 months (Spearman correlation coefficient, −0.05, P =0.34). Results were consistent across prespecified subgroups. Conclusions— Vitamin D supplementation did not reduce blood pressure in individuals with prehypertension or stage I hypertension and vitamin D deficiency. Our findings suggest that the association between vitamin D status and elevated blood pressure noted in observational studies is not causal. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01240512.
Theory and Practice in Acute Venous Thrombosis
Authors: Stanfordwessler, Danieldeykin
Journal: Circulation (1958)

The purpose of this review has been to outline the basis for proposing, and the details for implementing, a rational and consistent plan of therapy for the management of acute venous thrombosis. We have interpreted the entity of venous thrombosis as representing a common, frequently systemic disease, clinically manifest by focal intravascular coagulation. Concerning this disease, the specific etiology is unknown, the diagnostic criteria are crude and unsatisfactory, and although the clinical course is usually benign and self limited it may be unpredictably recurrent and fatal. We have also inferred that the difficulties in statistically validating any specific therapeutic measure are, for the present, extremely great, and that this problem will not be significantly lessened until an accurate test for thrombosis is devised. To construct a workable frame of reference for the clinical management of venous thrombosis within the limits of our present knowledge, we have formulated the concept of the temporary t...
Safety and Efficacy of Fludrocortisone in the Treatment of Cerebral Salt Wasting in Patients With Tuberculous Meningitis
Authors: Usha K. Misra, Jayantee Kalita, Mritunjai Kumar
Journal: JAMA Neurology (2018)

Tuberculous meningitis is associated with high frequency of cerebral salt wasting. There is a paucity of objective information regarding the best method of treatment of this condition.To evaluate the efficacy and safety of fludrocortisone in the treatment of cerebral salt wasting in patients with tuberculous meningitis.This is a single-center, open-label, randomized clinical trial conducted from October 2015 to April 2017 in India. Patients were randomized in a 1:1 ratio to arms receiving saline only or saline plus fludrocortisone, in addition to a standard treatment of 4 antitubercular drugs, prednisolone, and aspirin. The 2 arms were matched for demographic, clinical, and magnetic resonance imaging findings. The patients were followed up for at least 6 months.Patients were randomized to a 0.9% solution of intravenous saline with 5 to 12 g per day of oral salt supplementation, with or without the addition of 0.1 to 0.4 mg of fludrocortisone per day.The primary end point was the time needed to correct serum sodium levels; secondary end points were in-hospital deaths, disability at 3 months, disability at 6 months, occurence of stroke, and serious adverse reactions.Ninety-three patients with suspected tuberculous meningitis were recruited; 12 did not meet the inclusion criteria, including 4 with alternate diagnoses. A total of 37 patients with cerebral salt wasting were eligible for the study. One refused to participate, and therefore 36 patients were included, with 18 randomized to each group. The median (range) age was 30 (20-46) years, and 19 were male (52.8%). Those receiving fludrocortisone regained normal serum sodium levels after 4 days, significantly earlier than those receiving saline only (15 days; P = .004). In an intention-to-treat analysis, hospital mortality, disability at 3 months, and disability at 6 months did not differ significantly, but fewer infarcts occurred in the deep border zone in the group receiving fludrocortisone (1 of 18 [6%]) vs those in the control arm (6 of 18 [33%]; P = .04). Fludrocortisone was associated with severe hypokalemia and hypertension in 2 patients each, and pulmonary edema occurred in 1 patient. These adverse reactions necessitated discontinuation of fludrocortisone in 2 patients.Fludrocortisone results in earlier normalization of serum sodium levels, but did not affect outcomes at 6 months. Fludrocortisone had to be withdrawn in 2 patients because of severe adverse effects. This study provides class II evidence on the role of fludrocortisone in treatment of hyponatremia associated with cerebral salt wasting in patients with tuberculous meningitis.Clinical Trials Registry of India (ctri.nic.in) Identifier: CTRI/2017/10/010255.
Abstract 1763: BiTEs vs CAR-Ts: Preclinical targeting of CD133+ brain tumor initiating cells using immunotherapy-based treatment strategies
Authors: Parvez Vora, Jarrett Adams, Mohini Singh, Chitra Venugopal, Nazanin Tatari, Chirayu Chokshi, Maleeha Qazi, Sabra Salim, Sujeivan Mahendram, David Bakhshinyan, Max London, Neil Savage, Minomi Subapanditha, Nicole McFarlane, James Pan, Jonathan Bramson, Sachdev Sidhu, Jason Moffat, Sheila Singh
Journal: Cancer Research (2018)

Abstract Glioblastoma (GBM) is a uniformly fatal primary brain tumor, characterized by extensive cellular heterogeneity. Numerous studies have implicated CD133+ brain tumor initiating cells (BTICs) as drivers of chemo- and radio-resistance in GBM. We have recently demonstrated that a CD133-driven gene signature is predictive of poor overall survival and targeting CD133+ treatment-refractory cells may be an effective strategy to block GBM recurrence. Bispecific T-Cell engaging antibodies (BiTEs) and Chimeric antigen receptors (CARs) present promising immunotherapeutic approaches that have not yet been validated for recurrent GBM. Using CellectSeq, a novel methodology that combines the use of phage-displayed synthetic antibody libraries and DNA sequencing, we developed the CD133-specific monoclonal antibody ‘RW03'. We constructed CD133-specific BiTEs that consist of two arms; one recognizes the tumor antigen (CD133) and the second is specific to the CD3 antigen that binds to human GBMs and PBMC-derived T cells, respectively. We observed BiTEs redirecting T cells to kill GBMs, with greater efficiency observed in CD133high GBMs, validating BiTE target specificity. Incubating T-cells with BiTEs and the CD133high GBMs resulted in increased expression of T cell activation markers. In parallel, we derived the single chain variable fragment (scFv) from RW03 we engineered a second-generation CAR T cell. CD133-specific CAR-T cells were cytotoxic to CD133+ GBMs. Co-culturing CD133 CAR-T cells with GBMs triggered T cell activation and proliferation. Treatment of GBM tumor-bearing mice with CD133-specific CAR-T cells yielded extended survival in mice and significant reductions in brain tumor burden. Furthermore, we uniquely adapted the existing chemoradiotherapy protocol for GBM patients for treatment of immunocompromised mice engrafted with human GBMs. Within this model, we have initiated treatment of recurrent GBM directed against CD133+ BTICs, to allow for a direct prospective comparison of toxicity and efficacy of BiTEs and CAR-T cell strategies. Citation Format: Parvez Vora, Jarrett Adams, Mohini Singh, Chitra Venugopal, Nazanin Tatari, Chirayu Chokshi, Maleeha Qazi, Sabra Salim, Sujeivan Mahendram, David Bakhshinyan, Max London, Neil Savage, Minomi Subapanditha, Nicole McFarlane, James Pan, Jonathan Bramson, Sachdev Sidhu, Jason Moffat, Sheila Singh. BiTEs vs CAR-Ts: Preclinical targeting of CD133+ brain tumor initiating cells using immunotherapy-based treatment strategies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1763.
Abstract 5614: Targeting the radiation-inducible neoantigen GRP78 as a novel strategy for non-small cell lung carcinoma treatment
Authors: Abhay Singh, Vaishali Kapoor, David Dadey, Dinesh Thotala, Dennis Hallahan
Journal: Cancer Research (2018)

Abstract Non-small cell lung cancer (NSCLC) ranks among the highest cancer-related mortalities worldwide. NSCLC immunotherapy has not been successful in the past. Although lung cancer is not typically believed to be an immunogenic malignancy, more and more evidence suggests that immune responses to lung cancer may be important. The objective of this research was to address a critical barrier and develop a new paradigm in the treatment of NSCLC. Development of anticancer antibodies is limited by the scarcity of antigens that are specifically overexpressed in lung cancer, resulting in too few molecular targets and small percentages of patients who can be treated with the therapeutic antibody. We established a platform technology to develop antibodies to radiation-inducible neoantigens. Several radiation-inducible antigens have been identified by our group. Glucose-regulated protein 78 (GRP78), a multifunctional protein folding chaperone and co-receptor that is highly expressed on the surface of NSCLC, holds significant promise as a cancer-specific target. Although the potential of targeting GRP78 has been demonstrated in prostate cancer, melanoma, and breast cancer, there are limited data on the impact of targeting cell surface-associated GRP78 in NSCLC. We show that GRP78 undergoes radiation-induced translocation to the surface of NSCLC cells. We developed several GRP78-targeting monoclonal antibodies. NSCLC-specific antibody binding is achieved for several days by anti-GRP78 monoclonal antibodies after irradiation. Optical imaging and immunohistochemical staining indicated that the GRP78-specific antibodies achieve specific binding to irradiated NSCLC in mouse models. The anti-GRP78 antibodies also have a direct cytotoxic effect on NSCLC cells. The combination of anti-GRP78 antibodies and radiation showed an additive effect. Overall, this study suggests that GRP78 is a promising therapeutic target for the treatment of lung cancer. We propose to harness the physiologic response of cancer to radiotherapy and evolve it for immunotherapy of lung cancer using specific targeting antibodies. Citation Format: Abhay Singh, Vaishali Kapoor, David Dadey, Dinesh Thotala, Dennis Hallahan. Targeting the radiation-inducible neoantigen GRP78 as a novel strategy for non-small cell lung carcinoma treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5614.
Breast Cancer Screening Using Tomosynthesis or Mammography: A Meta-analysis of Cancer Detection and Recall
Authors: M Luke Marinovich, Kylie E Hunter, Petra Macaskill, Nehmat Houssami
Journal: JNCI Journal of the National Cancer Institute (2018)

Tomosynthesis approximates a 3D mammogram of the breast, reducing parenchymal overlap that masks cancers or creates false "lesions" on 2D mammography, and potentially enabling more accurate detection of breast cancer. We compared breast cancer screening detection and recall in asymptomatic women for tomosynthesis vs 2D mammography. A systematic review and random effects meta-analysis were undertaken. Electronic databases (2009–July 2017) were searched for studies comparing tomosynthesis and 2D mammography in asymptomatic women who attended population breast cancer screening and reporting cancer detection rate (CDR) and recall rate. All statistical tests were two-sided. Seventeen studies (1 009 790 participants) were included from 413 citations. The pooled incremental CDR for tomosynthesis was 1.6 cancers per 1000 screens (95% confidence interval [CI] = 1.1 to 2.0, P < .001, I2 = 36.9%). Incremental CDR was statistically significantly higher for European/Scandinavian studies, all using a "paired" design where women had both tests (2.4 per 1000 screens, 95% CI = 1.9 to 2.9, P < .001, I2 = 0.0%) compared with US ("unpaired") studies (1.1 per 1000 screens, 95% CI = 0.8 to 1.5, P < .001, I2 = 0.0%; P < .001 between strata). The recall rate for tomosynthesis was statistically significantly lower than for 2D mammography (pooled absolute reduction = –2.2%, 95% CI = –3.0 to –1.4, P < .001, I2 = 98.2%). Stratified analyses showed a decrease in US studies (pooled difference in recall rate = –2.9%, 95% CI = –3.5 to –2.4, P < .001, I2 = 92.9%) but not European/Scandinavian studies (0.5% increase in recall, 95% CI = –0.1 to 1.2, P = .12, I2 = 93.5%; P < .001 between strata). Results were similar in sensitivity analyses excluding studies with overlapping cohorts. Tomosynthesis improves CDR and reduces recall; however, effects are dependent on screening setting, with greater improvement in CDR in European/Scandinavian studies (biennial screening) and reduction in recall in US studies with high baseline recall.
Abstract 3213: Evaluation of porphyrin biodistribution for use in photodynamic therapy of retinoblastoma in transgenic mice
Authors: Florent Poyer, Samuel Hugeut, Stéphanie Lemaitre, Olivier Madar, Carole D Thomas, Philippe Maillard, Marie-Paule Teulade-Fichou, Nathalie Cassoux, François Doz, Keyvan Rezai
Journal: Cancer Research (2018)

Abstract Background: Porphyrins are a group of heterocyclic macrocycle organic compounds. They have shown good efficiency in the photodynamic treatment of tumors in the last twenty years. The photodynamic therapy could be an alternative treatment for retinoblastoma using a photosensitizer with low dark toxicity and low mutagenic properties unlike the conventional chemotherapies. The objectives of this study were to develop a photosensitizer in our lab which is a diethylene glycol mannoconjugated tetraphenyl porphyrin (TPP, MW: 1413.6) and to determine the optimal interval time for photodynamic therapy using the concentration of TPP in eye and blood samples of mice. Materials and method: Transgenic mice developed bilateral retinoblastoma from the retina since 4 weeks of age to 16 weeks of age (tumors fill the ocular globe and the mice will be sacrificed for ethic purpose). The evaluation of the biodistribution of our TPP was realized to know the best drug-light interval to perform the photodynamic therapy. For this purpose, an intraperitoneal injection of 200 µl at 5.25 mg/ml in PEG 400/physiological serum (1:1, v/v) was performed on the LHbetaTag transgenic mice. At different time intervals (8h, 24h, 40h, 48h, and 72h) following injection, the mice were sacrificed and the eyes and blood were collected. TPP in eye samples were extracted in methanol and the level of TPP was measured by ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) analysis (0.5-100 ng/mL). The level of TTP in blood samples was quantified after protein precipitation by UPLC-MS/MS method (5.00-1000 ng/mL). Results: We observed a time dependency accumulation of TPP in eyes with observed Tmax=48 hours. TPP serum concentrations decreased by the same manner up to 48 h. The determination of drug-light interval allowed us to perform the light delivery when the TPP level is highest (48 h) in the ocular tumor tissue (retinoblastoma). Conclusions: Our TPP had a good in vitro photocytotoxicity at very low doses and showed a good efficacy in vivo with subcutaneous patient derived retinoblastoma xenografts in immunodeficient mice. The knowledge of Tmax and this interval is essential to realize the photodynamic therapy with the better efficiency, the final goal being to eradicate the retinoblastoma from the retina. Citation Format: Florent Poyer, Samuel Hugeut, Stéphanie Lemaitre, Olivier Madar, Carole D Thomas, Philippe Maillard, Marie-Paule Teulade-Fichou, Nathalie Cassoux, François Doz, Keyvan Rezai. Evaluation of porphyrin biodistribution for use in photodynamic therapy of retinoblastoma in transgenic mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3213.