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Targeted inhibition of the PD-L1-PD-1 pathway might be further amplified through combination of PD-1 or PD-L1 inhibitors with novel anti-TIGIT inhibitory immune checkpoint agents, such as tiragolumab. In the CITYSCAPE trial, we aimed to assess the preliminary efficacy and safety of tiragolumab plus atezolizumab (anti-PD-L1) therapy as first-line treatment for non-small-cell lung cancer (NSCLC).CITYSCAPE is a phase 2, randomised, double-blind, placebo-controlled trial. Patients with chemotherapy-naive, PD-L1-positive (defined as a tumour proportion score of ≥1% by 22C3 immunohistochemistry pharmDx assay; Dako, Agilent Technologies, Santa Clara, CA, USA) recurrent or metastatic NSCLC with measurable disease, Eastern Cooperative Oncology Group performance status of 0 or 1, and no EGFR or ALK alterations were enrolled from 41 clinics in Europe, Asia, and the USA. Patients were randomly assigned (1:1), via an interactive voice or web-based response system, to receive tiragolumab (600 mg) plus atezolizumab (1200 mg) or placebo plus atezolizumab intravenously once every 3 weeks. Investigators and patients were masked to treatment assignment. The co-primary endpoints were investigator-assessed objective response rate and progression-free survival as per Response Evaluation Criteria in Solid Tumors version 1.1 in the intention-to-treat population, analysed after approximately 80 progression-free survival events had been observed in the primary population. Safety was assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT03563716, and is ongoing.Patients were enrolled between Aug 10, 2018, and March 20, 2019. At data cutoff for the primary analysis (June 30, 2019), 135 of 275 patients assessed for eligibility were randomly assigned to receive tiragolumab plus atezolizumab (67 [50%]) or placebo plus atezolizumab (68 [50%]). In this primary analysis, after a median follow-up of 5·9 months (4·6-7·6, in the intention-to-treat population, 21 patients (31·3% [95% CI 19·5-43·2]) in the tiragolumab plus atezolizumab group versus 11 patients (16·2% [6·7-25·7]) in the placebo plus atezolizumab group had an objective response (p=0·031). Median progression-free survival was 5·4 months (95% CI 4·2-not estimable) in the tiragolumab plus atezolizumab group versus 3·6 months (2·7-4·4) in the placebo plus atezolizumab group (stratified hazard ratio 0·57 [95% CI 0·37-0·90], p=0·015). 14 (21%) patients receiving tiragolumab plus atezolizumab and 12 (18%) patients receiving placebo plus atezolizumab had serious treatment-related adverse events. The most frequently reported grade 3 or worse treatment-related adverse event was lipase increase (in six [9%] patients in the tiragolumab plus atezolizumab group vs two [3%] in the placebo plus atezolizumab group). Two treatment-related deaths (of pyrexia and infection) occurred in the tiragolumab plus atezolizumab group.Tiragolumab plus atezolizumab showed a clinically meaningful improvement in objective response rate and progression-free survival compared with placebo plus atezolizumab in patients with chemotherapy-naive, PD-L1-positive, recurrent or metastatic NSCLC. Tiragolumab plus atezolizumab was well tolerated, with a safety profile generally similar to that of atezolizumab alone. These findings demonstrate that tiragolumab plus atezolizumab is a promising immunotherapy combination for the treatment of previously untreated, locally advanced unresectable or metastatic NSCLC.F Hoffmann-La Roche and Genentech.

Tremendous innovation is underway among a rapidly expanding repertoire of promising personalized immune-based treatments. Therapeutic cancer vaccines (TCVs) are attractive systemic immunotherapies that activate and expand antigen-specific CD8(+) and CD4(+) T cells to enhance anti-tumor immunity. Our review highlights key issues impacting TCVs in clinical practice and reports on progress in development. We review the mechanism of action, immune-monitoring, dosing strategies, combinations, obstacles, and regulation of cancer vaccines. Most trials of personalized TCVs are ongoing and represent diverse platforms with predominantly early investigations of mRNA, DNA, or peptide-based targeting strategies against neoantigens in solid tumors, with many in combination immunotherapies. Multiple delivery systems, routes of administration, and dosing strategies are used. Intravenous or intramuscular administration is common, including delivery by lipid nanoparticles. Absorption and biodistribution impact antigen uptake, expression, and presentation, affecting the strength, speed, and duration of immune response. The emerging trials illustrate the complexity of developing this class of innovative immunotherapies. Methodical testing of the multiple potential factors influencing immune responses, as well as refined quantitative methodologies to facilitate optimal dosing strategies, could help resolve uncertainty of therapeutic approaches. To increase the likelihood of success in bringing these medicines to patients, several unique development challenges must be overcome.

Ipatasertib is a highly selective small-molecule pan-Akt inhibitor in clinical development. Ipatasertib is predominantly eliminated by the liver, and therefore the effect of hepatic impairment on ipatasertib pharmacokinetics (PK) was evaluated. In this Phase I open-label, parallel group study, the PK of ipatasertib was evaluated in subjects with hepatic impairment based on both, the Child-Pugh and the National Cancer Institute-Organ Dysfunction Working Group (NCI-ODWG) classification for hepatic impairment. A single dose of ipatasertib at 100 mg was administered and the PK was characterized in healthy subjects with normal hepatic function or mild, moderate and severe hepatic impairment. Based on Child-Pugh classification, subjects with moderate or severe hepatic impairment had an approximately 2- and 3-fold increase in systemic exposure (AUC0-∞ ) to ipatasertib, respectively, compared to subjects with normal hepatic function. Systemic exposure (AUC0-∞ ) to ipatasertib in subjects with mild hepatic impairment was comparable to that in subjects with normal hepatic function. In accordance with reduced clearance capacity, subjects with mild to severe hepatic impairment showed lower systemic exposure (AUC0-∞ ) of ipatasertib metabolite M1 (G-037720). Overall results were comparable between Child-Pugh and NCI-ODWG classification criteria. Based upon the results from this study, no dosage adjustment is required for ipatasertib when treating patients with mild hepatic impairment, whereas a dose reduction would be recommended for subjects with moderate or severe hepatic impairment. Based on real world data analysis, ∼2% of intended patient population is expected to need a modified dose due to moderate or severe hepatic impairment. This article is protected by copyright. All rights reserved.

BackgroundPlasmodium vivax malaria requires a 2-week course of primaquine (PQ) for radical cure. Evidence suggests that the hepatic isoenzyme cytochrome P450 2D6 (CYP2D6) is the key enzyme required to convert PQ into its active metabolite.MethodsCYP2D6 genotypes and phenotypes of 550 service personnel were determined, and the pharmacokinetics (PK) of a 30-mg oral dose of PQ was measured in 45 volunteers. Blood and urine samples were collected, with PQ and metabolites were measured using ultraperformance liquid chromatography with mass spectrometry.ResultsSeventy-six CYP2D6 genotypes were characterized for 530 service personnel. Of the 515 personnel for whom a single phenotype was predicted, 58% had a normal metabolizer (NM) phenotype, 35% had an intermediate metabolizer (IM) phenotype, 5% had a poor metabolizer (PM) phenotype, and 2% had an ultrametabolizer phenotype. The median PQ area under the concentration time curve from 0 to ∞ was lower for the NM phenotype as compared to the IM or PM phenotypes. The novel 5,6-ortho-quinone was detected in urine but not plasma from all personnel with the NM phenotype.ConclusionThe plasma PK profile suggests PQ metabolism is decreased in personnel with the IM or PM phenotypes as compared to those with the NM phenotype. The finding of 5,6-ortho-quinone, the stable surrogate for the unstable 5-hydroxyprimaquine metabolite, almost exclusively in personnel with the NM phenotype, compared with sporadic or no production in those with the IM or PM phenotypes, provides further evidence for the role of CYP2D6 in radical cure.Clinical Trials RegistrationNCT02960568.

Background: RO7297089 is a bispecific tetravalent antibody targeting BCMA (Genentech licensed from Affimed GMBH), which is highly expressed on MM cells and CD16a, which is expressed on innate immune cells including natural killer (NK) cells, macrophages, and monocyte subsets. Here we report findings from a Phase I dose-escalation study of RO7297089 in patients with RRMM (GO41582, Study registration NCT04434469). Methods: All patients had RRMM for which no established therapy is available, appropriate, or tolerated. Prior exposure to CAR-T cells, T-cell engaging bispecific antibodies, and therapies targeting BCMA was permitted. Patients received RO7297089 as weekly IV infusions in 14-day cycles with dose escalation guided by a model implementing the Bayesian continuous reassessment method with overdose control. In Arm A the first dose was given over a single-day infusion, and in Arm B the first dose was divided over two consecutive days. Dose limiting toxicities (DLT) were assessed from Cycle 1. Study objectives included safety, pharmacokinetics (PK), and biologic activity as assessed by the IMWG Uniform Response Criteria. Results: As of 30 April 2021, 21 patients received RO7297089 at 5 dose levels (60 mg [n=3], 180 mg [n=5], 360 mg [n=4], 1080 mg [n=6], and 1850 mg [n=3]). Median age was 63 years (range 41-76) and median number of prior lines of therapy was 8 (range 2-11). Patients received a median of 8 doses (range 2-42) of RO7297089; 5 patients had prior BCMA-targeted therapy. The most common AEs were anemia (n=11), infusion related reaction (IRR; n=10), back pain (n=5), ALT increased (n=4), and thrombocytopenia (n=4). Eleven (52%) patients had ≥1 treatment-related adverse event (AE) which included IRR (n=9), C-reactive protein increase (n=3), ALT increase (n=3), AST increase (n=2), and thrombocytopenia (n=2). Grade ≥ 3 AEs included anemia (n=9), and platelet count decreased (n=5). Related Grade ≥ 3 AEs were ALT increase and AST increase and lymphocyte count decreased (both n=1). No DLTs or dose-dependent toxicities were reported. Fifteen patients discontinued study treatment due to disease progression (n=12), clinical relapse (n=2), and symptomatic deterioration (n=1). Four deaths were reported in the AE follow-up period, all due to disease progression. Thirteen IRR events (1 Grade 1, 12 Grade 2) were observed in 10 patients (48%). IRR was most common in Cycle 1 (12 events in 10 patients) and was uncommon in subsequent cycles (1 patient). Symptoms of IRR occurring in >1 patient included fever, rigors/chills, and dyspnea. To mitigate IRRs, additional measures were implemented from the 180 mg dose level including steroid premedication and slow infusion for the first dose. Dividing the first dose over 2 days (Arm B) was also implemented from the 1080 mg dose level for improved convenience. Preliminary PK assessments demonstrated a more than dose proportional increase in the exposure of RO7297089 with increasing dose levels from 60-1080 mg, suggesting non-linear PK and target-mediated drug disposition, with a trend of approaching linear PK at doses higher than 1080 mg. The estimated half-life was supportive of weekly dosing. Preliminary observation showed 1/18 patients with treatment-induced anti-drug antibodies, which did not appear to impact PK. BCMA expression was detected in the bone marrow in all patients regardless of prior BCMA-targeted therapy. Levels of total soluble BCMA and soluble CD16a increased immediately after the first dose as expected suggesting engagement and stabilization of soluble factors by RO7297089. Of the 18 response-evaluable patients, 1 patient experienced a partial response (1080 mg cohort) per IMWG criteria. Ten patients had stable disease as their best response at dose levels of 60 mg (1/3 patients), 180 mg (2/5 patients), 360 mg (3/4 patients), 1080 mg (4/6 patients). One patient who started at the 60 mg dose and gradually escalated to the 1080 mg dose has been on treatment for 9.5 months with stable disease at the time of the clinical cut-off date. Conclusions: Treatment with RO7297089 was well-tolerated at the dose levels tested, although infusion reactions necessitated long infusion duration for the first dose. Modest activity has been observed to date with doses up to 1080 mg. There were no DLTs and a recommended phase 2 dose has not been identified. The latest clinical, biomarker, and PK data will be presented including data from higher dose level cohorts. Disclosures Plesner: AbbVie: Other: Advisor, Research Funding; CSL Behring: Other: Advisor; Genentech: Other: Advisor, Research Funding; Oncopeptides: Other: Advisor, Research Funding; Takeda: Research Funding; Celgene: Other: Advisor, Research Funding; Genmab: Research Funding; Janssen: Other: Advisor, Research Funding. Harrison: Celgene/ Juno/ BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Terumo BCT: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Haemalogix: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Eusa: Consultancy, Honoraria, Speakers Bureau. Quach: GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lee: BMS: Other: Advisor, Research Funding; Janssen: Other: Advisor; Amgen: Other: Advisor. Bryant: Sandoz: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Roche: Honoraria. Estell: Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees. Delforge: Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Twomey: Genentech: Current Employment. Choeurng: Genentech: Current Employment. Li: Genentech: Current Employment. Hendricks: Genentech: Current Employment. Sumiyoshi: Genentech: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Miller: Genentech: Current Employment. Choi: Genentech: Current Employment. Schjesvold: Schain: Honoraria; AbbVie: Honoraria; Adaptive Biotechnologies: Consultancy; Nordics Nanovector: Current holder of individual stocks in a privately-held company; Sanofi: Consultancy, Honoraria, Research Funding; Oncopeptides: Consultancy, Current holder of individual stocks in a privately-held company, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; GSK: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; SkyliteDX: Honoraria; Bayer: Consultancy; Celgene/BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria. OffLabel Disclosure: RO7297089 is a Bâ€'Cell maturation antigen (BCMA)-CD16a bispecific antibody intended for use if approved in patients with relapsed/refractory multiple myeloma

Background: The immunomodulatory receptor TIGIT (T-cell Immunoreceptor with Ig and ITIM domains) is a novel inhibitory immune checkpoint present on activated T cells and NK cells in multiple cancers. In preclinical models, co-inhibition of the TIGIT and PD-L1/PD-1 pathways improved anti-tumor activity compared to either agent alone. Tiragolumab (tira or MTIG7192A) is a humanized IgG1/kappa monoclonal antibody (mAb) that binds TIGIT to prevent its interaction with its ligand PVR (CD155). In this first-in-human dose-escalation study, we report the preliminary safety and anti-tumor activity of tira as a single agent and in combination with atezolizumab (atezo) in patients with advanced solid tumors. Methods: Enrolled patients, ECOG PS 0-1, had advanced tumors for whom standard therapy did not exist or was ineffective. Patients received escalating doses of tira alone IV Q3W alone (Phase Ia) or in combination with atezo 1200 mg IV Q3W (Phase Ib) to determine the maximum tolerated dose (MTD) and continued until disease progression, intolerable toxicity, or patient/investigator decision. Study objectives included evaluation of safety and tolerability, pharmacokinetics (PK), pharmacodynamics, and anti-tumor activity of tira alone or tira + atezo. Data cut-off date was April 2019. Results: 73 patients with multiple tumor types were treated in dose-escalation (24 in Phase Ia, 49 in Ib with tira + atezo). In Phase Ia and Phase Ib, median age was 60 and 54 years, ECOG 0 for 29% and 27% of patients, and those who received ≥ 3 prior therapies were 67% and 57%, respectively. No DLTs were observed. Across doses, treatment-related AEs occurred in 67% in Phase Ia and 59% in Phase Ib (Grade ≥ 3: 4% and 4%, respectively), and most common AEs were fatigue (38%) in Phase Ia and anemia (31%) in Phase Ib. Exposure of tira increased with increasing dose, and saturation of nonlinear PK occurred at tira doses ≥ 100 mg Q3W. Complete and sustained occupancy of peripheral TIGIT receptors was observed at tira doses ≥ 30 mg Q3W. In Phase Ia, there were no objective responses, but SD of > 4 months duration was observed (n=4). In Phase Ib, there were 3 responses, which all occurred in PD-L1 positive tumors (2 non-small cell lung cancer [NSCLC]: 1 CR, 1 PR; and 1 head/neck squamous cell carcinoma: PR) with two patients not receiving prior immunotherapy (CIT-naïve). Therefore, expansion cohorts were initiated in PD-L1-positive CIT-naïve indications in Phase Ib. In the metastatic NSCLC expansion cohort (n=14) ORR was 50%, with 1 CR and 6 PRs; DCR was 79%, and the safety profile was similar. Conclusions: Tira monotherapy or combined with atezo was well-tolerated and had an acceptable safety profile across all dose levels. Preliminary anti-tumor activity was observed in Phase Ib with tira + atezo in CIT-naïve PD-L1-positive tumors, including NSCLC, and enrollment is ongoing in these expansion cohorts. Citation Format: Johanna C. Bendell, Philippe Bedard, Yung-Jue Bang, Patricia LoRusso, Stephen Hodi, Michael Gordon, Sandra D'Angelo, Sandra D'Angelo, Jayesh Desai, Elena Garralda, Antoine Italiano, Myung-Ju Ahn, Andres Cervantes, Zev Wainberg, Emiliano Calvo, Marta Gil-Martin, Maria Martinez-Garcia, Rastilav Bahleda, Philippe Cassier, Jean-Pierre Delord, Amy Prawira, Ignacio Melero, Leisha Emens, Emanuela Romano, Karen Miller, Robert W. Hsieh, Cloris Xue, Kari Morrissey, Patrick Twomey, Kelly Gash, Namrata S. Patil, Jane Grogan, Raymond Meng, Byoung Cho, Tae Won Kim. Phase Ia/Ib dose-escalation study of the anti-TIGIT antibody tiragolumab as a single agent and in combination with atezolizumab in patients with advanced solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT302.

Background: Neoantigens arising from somatic mutations are attractive targets for cancer immunotherapy as they may be recognized as foreign by the immune system. RO7198457 is a systemically administered RNA-Lipoplex iNeST designed to stimulate T cell responses against neoantigens. A first-in-human Phase Ia study of RO7198457 was conducted in patients with locally advanced or metastatic solid tumors. Methods: RO7198457 is manufactured on a per-patient basis and contains up to 20 patient- specific neoantigens. Nine doses of RO7198457 were administered i.v. at weekly and bi-weekly intervals during the 12-week induction stage and every 24 weeks during the maintenance stage. Results: In total, 29 patients enrolled in cohorts with doses ranging from 25-100 μg. The most common tumor types were HR+/HER2+ breast, prostate, and ovarian cancer. The median number of prior therapies was 5 (range 1-17). 34% of patients received prior immunotherapy. Most patients had low PD-L1 expression (97% patients with Conclusion: RO7198457 can be manufactured for individual patients with clinically relevant turn-around times. RO7198457 has a manageable safety profile consistent with its mechanism of action, and induced strong neoantigen-specific immune responses in patients with low and intermediate mutational load tumors types. A Ph1b study in combination with atezolizumab and a randomized Ph2 study of RO7198457 in 1L melanoma patients with pembrolizumab have been initiated, and two randomized clinical trials are planned in resected lung and CRC. Citation Format: Fadi Braiteh, Patricia LoRusso, Ani Balmanoukian, Sam Klempner, D R. Camidge, Matthew Hellmann, Michael Gordon, Johanna Bendell, Lars Mueller, Rachel Sabado, Patrick Twomey, Leila Delamarre, Jack Huang, Mahesh Yadav, Jingbin Zhang, Patrick McDonald, Felicitas Müller, Evelyna Derhovanessian, Özlem Türeci, Ugur Sahin, Lillian Siu. A phase Ia study to evaluate RO7198457, an individualized Neoantigen Specific immunoTherapy (iNeST), in patients with locally advanced or metastatic solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT169.

Background: Neoantigens arising from somatic mutations are attractive targets for cancer immunotherapy as they may be recognized as foreign by the immune system. RO7198457, a systemically administered RNA-Lipoplex iNeST was designed to stimulate T cell responses against neoantigens. A first-in-human Phase Ib study of RO7198457, in combination with the aPD-L1 antibody atezolizumab is being conducted in patients with locally advanced or metastatic solid tumors. Methods: RO7198457 is manufactured on a per-patient basis and contains up to 20 tumor-specific neoepitopes. Nine doses of RO7198457 were administered i.v. in weekly and bi-weekly intervals during the 12-week induction stage and every 24 weeks during the maintenance stage. Atezolizumab 1200 mg was administered on Day 1 of each 21-day cycle. Results: In total, 132 patients enrolled in cohorts with doses ranging from 15-50 μg RO7198457 in combination with atezolizumab. Most common tumor types were NSCLC, TNBC, melanoma and CRC. The median number of prior therapies was 3 (range 1-11). 39% of patients received prior immunotherapy. Most patients had low levels of PD-L1 expression (93% patients with Citation Format: Juanita S. Lopez, Ross Camidge, Marco Iafolla, Sylvie Rottey, Martin Schuler, Matthew Hellmann, Ani Balmanoukian, Luc Dirix, Michael Gordon, Ryan Sullivan, Brian S. Henick, Charles Drake, Kit Wong, Patricia LoRusso, Patrick Ott, Lawrence Fong, Aglaia Schiza, Jeffery Yachnin, Christian Ottensmeier, Fadi Braiteh, Johanna Bendell, Rom Leidner, George Fisher, Guy Jerusalem, Laura Molenaar-Kuijsten, Marcus Schmidt, Scott A. Laurie, Raid Aljumaily, Achim Rittmeyer, Eelke Gort, Ignacio Melero, Lars Mueller, Rachel Sabado, Patrick Twomey, Jack Huang, Manesh Yadav, Jingbin Zhang, Felicitas Mueller, Evelyna Derhovanessian, Ugur Sahin, Özlem Türeci, Thomas Powles. A phase Ib study to evaluate RO7198457, an individualized Neoantigen Specific immunoTherapy (iNeST), in combination with atezolizumab in patients with locally advanced or metastatic solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT301.

A recent paper1 in this journal describes an experimental demonstration of the conservation of total momentum before, during, and after an elastic collision between two bodies. The experiment also appears to show that total kinetic energy is conserved in the process, including during the collision. There is a danger that this may give rise to some misconception given that, in any collision that takes place over a finite time, some kinetic energy must transfer to potential energy—albeit temporarily in the case of an elastic collision. Indeed, when a collision is observed in the c.m. frame, all kinetic energy is lost momentarily. The sequence of simple experiments described below, which can be performed using standard equipment available in undergraduate laboratories, was developed so that undergraduate students could study a collision process in some detail. It was designed to enable students to gain insight into a range of important ideas in elementary analytical dynamics, including conservation of momentum, energy transfer in inelastic collisions, and coefficient of restitution. An extension of the experiment also gives insight into wave propagation in elastic media.

A simple undergraduate experiment designed to study cooling purely by radiation and cooling by a combination of convection and radiation is described. Results indicate that the contribution from radiative cooling in normal laboratory experiments is more significant than students often realize, even in the case of forced cooling.

Blood transfusion has been associated with infection; however, the collinearity of injury severity has not been clearly addressed to show a direct relationship. Using more rigorous analysis, we aimed to untangle the effect of injury severity from transfusion leading to sepsis. We hypothesized that blood transfusion independently increases infection in massively transfused versus nontransfused patients with matched Injury Severity Scores (ISSs). We performed a matched cohort study measuring infection rates in trauma patients receiving massive transfusion. Control subjects were contemporaneous patients with matched ISS receiving no blood. Infection was defined as intraperitoneal or intrathoracic abscesses, pneumonia, urinary tract infection, or bacteremia. Multivariate logistic and univariate analysis was completed. Infection rate was 61 per cent in 44 transfused patients versus 20 per cent in 44 control subjects ( P = 0.001). Odds of infection were eightfold greater in transfused patients (OR, 7.97; 95% CI, 2.3 to 27.5; P < 0.001) independent of ISS, Glasgow Coma Scale, mechanism, and age. Infection was most associated with transfusion of packed red blood cells (PRBCs), although transfusion of other blood products had strong collinearity with PRBCs. Transfused patients had eight times the risk of infection independent of ISS; this appears to be the result of PRBC transfusion. Modifying the ratio of components in transfusion protocols favoring plasma may cause less infection after injury

Quinidine gluconate, the only U.S. Food and Drug Administration-approved treatment for life-threatening malaria in the United States, has a problematic safety profile and is often unavailable in hospitals.To assess the safety and clinical benefit of intravenous artesunate as an alternative to quinidine.Retrospective case series.U.S. hospitals.102 patients aged 1 to 72 years (90% adults; 61% men) with severe and complicated malaria. Patients received 4 weight-based doses of intravenous artesunate (2.4 mg/kg) under a treatment protocol implemented by the Centers for Disease Control and Prevention between January 2007 and December 2010. At baseline, 35% had evidence of cerebral malaria, and 17% had severe hepatic impairment. Eligibility required the presence of microscopically confirmed malaria, need for intravenous treatment, and an impediment to quinidine.Clinical and laboratory data from each patient's hospital records were abstracted retrospectively, including information from baseline through a maximum 7-day follow-up, and presented before a physician committee to evaluate safety and clinical benefit outcomes.7 patients died (mortality rate, 6.9%). The most frequent adverse events were anemia (65%) and elevated hepatic enzyme levels (49%). All deaths and most adverse events were attributed to the severity of malaria. Patients' symptoms generally improved or resolved within 3 days, and the median time to discharge from the intensive care unit was 4 days, even for patients with severe liver disease or cerebral malaria. More than 100 concomitant medications were used, with no documented drug-drug interactions.Potential late-presenting safety issues might occur outside the 7-day follow-up.Artesunate was a safe and clinically beneficial alternative to quinidine.

Resume Au cours des 30 dernieres annees, les progres sensibles des techniques de la nutrition enterale, de l'acces veineux, et des melanges pour nutrition enterale et parenterale ont permis de fournir un soutien nutritionnel a presque tous les malades. Malgre l'abondante litterature medicale et l'usage repandu de la nutrition artificielle, de nombreux aspects du soutien nutritionnel restent controverses. Pour cette raison, les directions des National Institutes of Health, American Society for Parenteral and Enteral Nutrition, et American Society for Clinical Nutrition ont reuni un comite consultatif pour effectuer une revue critique de la litterature medicale actuelle en matiere d'evaluation de l'utilisation clinique du support nutritionnel ; l'objectif a ete d'evaluer la masse precise de nos connaissances et d'identifier les questions qui meritent de plus amples investigations. Le panel a ete divise en cinq groupes pour evaluer les domaines suivants : evolution de l'etat nutritionnel, prise en charge nutritionnelle des patients atteints de maladies gastrointestinales, au cours des affections cachectisantes, chez les patients en phase critique et nutrition perioperatoire. Les observations de chaque groupe sont resumees dans ce rapport. Ce document n'est pas cense etablir des directives pratiques en matiere de soutien nutritionnel. L'utilisation d'une nutrition artificielle exige une integration prudente des donnees provenant d'essais cliniques pertinents, une connaissance approfondie de la maladie ou du type d'agression consideree, une competence clinique en matiere de nutrition, et une contribution de la part du patient et de sa famille.

In the last 30 years, marked advances in enteral feeding techniques, venous access, and enteral and parenteral nutrient formulations have made it possible to provide nutrition support to almost all patients. Despite the abundant medical literature and widespread use of nutritional therapy, many areas of nutrition support remain controversial. Therefore, the leadership at the National Institutes of Health, The American Society for Parenteral and Enteral Nutrition, and The American Society for Clinical Nutrition convened an advisory committee to perform a critical review of the current medical literature evaluating the clinical use of nutrition support; the goal was to assess our current body of knowledge and to identify the issues that deserve further investigation. The panel was divided into five groups to evaluate the following areas: nutrition assessment, nutrition support in patients with gastrointestinal diseases, nutrition support in wasting diseases, nutrition support in critically ill patients, and perioperative nutrition support. The findings from each group are summarized in this report. This document is not meant to establish practice guidelines for nutrition support. The use of nutritional therapy requires a careful integration of data from pertinent clinical trials, clinical expertise in the illness or injury being treated, clinical expertise in nutritional therapy, and input from the patient and his/her family. (Journal of Parenteral and Enteral Nutrition 21:133-156, 1997).

In the last 30 years, marked advances in enteral feeding techniques, venous access, and enteral and parenteral nutrient formulations have made it possible to provide nutrition support to almost all patients. Despite the abundant medical literature and widespread use of nutritional therapy, many areas of nutrition support remain controversial. Therefore, the leadership at the National Institutes of Health, The American Society for Parenteral and Enteral Nutrition, and The American Society for Clinical Nutrition convened an advisory committee to perform a critical review of the current medical literature evaluating the clinical use of nutrition support; the goal was to assess our current body of knowledge and to identify the issues that deserve further investigation. The panel was divided into five groups to evaluate the following areas: nutrition assessment, nutrition support in patients with gastrointestinal diseases, nutrition support in wasting diseases, nutrition support in critically ill patients, and perioperative nutrition support. The findings from each group are summarized in this report. This document is not meant to establish practice guidelines for nutrition support. The use of nutritional therapy requires a careful integration of data from pertinent clinical trials, clinical expertise in the illness or injury being treated, clinical expertise in nutritional therapy, and input from the patient and his/her family.

The new Class I anti-arrhythmic agent 2,2,5,5-tetramethyl-3-pyrroline-1-carboxamide derivative, is currently being evaluated in clinical trials in patients with a high risk for cardiac arrhythmias. In this study we show that this antiarrhythmic drug can be chemically converted to the nitroxide free radical analog. Further, using an in vivo Electron Paramagnetic Resonance (EPR) spectroscopy model by detecting free radicals in the distal portion of the tail of an anesthetized mouse, we demonstrate that the drug is oxidized to the corresponding nitroxide. In vitro studies using Chinese hamster V79 cells suggest that the oxidation products of the drug, namely, the hydroxylamine and the nitroxide protect against oxidative damage induced by hydrogen peroxide (H2O2). Taken together, our results suggest that, in addition to the antiarrhythmic effects of the parent drug, sufficient levels of nitroxides may accumulate from the parent drug in vivo to provide antioxidant defense to cardiac tissue that may be subject to ischemia and oxidation-driven injury.

Purpose: The insulin-like growth factor system has recently been shown to have important mitogenic effects in the prostate. The system consists of 2 ligands: insulin-like growth factor types 1 and 2, which are potent mitogens for prostate cell growth, and 6 insulin-like growth factor binding proteins that modify the activity of these growth factors. Recently, changes in serum levels of insulin-like growth factor binding proteins 2 and 3 have been identified in prostate cancer patients but in vivo studies of these changes have not been previously reported.Materials and Methods: We performed immunohistochemical staining for insulin-like growth factor binding proteins 2 and 3 in areas of benign disease, prostatic intraepithelial neoplasia, and cancer from specimens obtained from 24 patients who underwent prostatectomy to determine changes in the quantity of these proteins with progression from the benign through the premalignant and into the malignant states. Quantification of the differences noted i...

Macrophages play a major role in inflammatory processes and have been associated with poor prognosis in a variety of cancers, including breast cancer. Previously, we investigated the relationship of a subset of tumor-associated macrophages (PCNA(+) TAMs) with clinicopathologic characteristics of breast cancer. We reported that high PCNA(+) TAM counts were associated with hormone receptor (HR)-negative, high-grade tumors and early recurrence. To further understand the significance of elevated PCNA(+) TAMs and the functionality of TAMs, we examined the expression of S100A8/S100A9 with the antibody Mac387. The heterodimeric S100A8/S100A9 complex plays a role in inflammation and is increased in several cancer types.We performed immunohistochemistry using the Mac387 antibody on 367 invasive human breast cancer cases. Results were compared to previous PCNA(+) TAM counts and were correlated with patient outcomes adjusting for HR status and histologic grade.Like PCNA(+) TAMs, high Mac387 counts were associated with HR negativity, high tumor grade, younger age, and decreased recurrence-free survival. Mac387, however, appears to identify both a subset of macrophages and a subset of tumor cells. The concordance between Mac387 and PCNA(+) TAM counts was low and cases that had both high Mac387 and high PCNA(+) TAMs counts had a stronger association with early recurrence.The presence of high numbers of PCNA(+) TAMs and Mac387-positive cells in breast cancers with poor outcomes may implicate a subset of TAMs in breast cancer pathogenesis, and may ultimately serve to develop potential cellular targets for therapeutic interventions.

African American and Hispanic women develop more triple negative breast cancer at younger ages than Caucasian women. The frequently observed association between race and socioeconomic status (SES) has confounded our understanding of the outcomes disparities seen in these groups. Given the association between inflammatory cells and high-grade, triple negative tumors, we sought to investigate whether differences in the presence of these cells varies by race. We evaluated breast tumor specimens for the presence PCNA+ tumor-associated macrophages (TAMs) in consecutive cases from a county hospital serving primarily un- or under-insured patients. All patients in this cohort had elevated PCNA + TAM levels. Higher PCNA + TAM counts were associated with hormone receptor (HR) negative tumors and non-Caucasian ethnicity. Hispanic women specifically had significantly higher PCNA + TAM counts than Caucasian patients and shorter disease-free survival. These findings implicate immune function in the development of aggressive breast cancer and suggest a possible link between SES and the inflammatory response.

Blood transfusion has been associated with infection; however, the collinearity of injury severity has not been clearly addressed to show a direct relationship. Using more rigorous analysis, we aimed to untangle the effect of injury severity from transfusion leading to sepsis. We hypothesized that blood transfusion independently increases infection in massively transfused versus nontransfused patients with matched Injury Severity Scores (ISSs). We performed a matched cohort study measuring infection rates in trauma patients receiving massive transfusion. Control subjects were contemporaneous patients with matched ISS receiving no blood. Infection was defined as intraperitoneal or intrathoracic abscesses, pneumonia, urinary tract infection, or bacteremia. Multivariate logistic and univariate analysis was completed. Infection rate was 61 per cent in 44 transfused patients versus 20 per cent in 44 control subjects (P = 0.001). Odds of infection were eightfold greater in transfused patients (OR, 7.97; 95% CI, 2.3 to 27.5; P0.001) independent of ISS, Glasgow Coma Scale, mechanism, and age. Infection was most associated with transfusion of packed red blood cells (PRBCs), although transfusion of other blood products had strong collinearity with PRBCs. Transfused patients had eight times the risk of infection independent of ISS; this appears to be the result of PRBC transfusion. Modifying the ratio of components in transfusion protocols favoring plasma may cause less infection after injury.

The effects of certain antibiotics on the colony forming activity of human bone marrow cells in semisolid methylcellulose medium in vitro and on murine BM cells in spleen colony forming units (cfu-s) in vivo were evaluated. Amikacin, gentamicin, piperacillin, co-trimoxazole and pentamidine had little or no effect on human bone marrow progenitor cell function; amphotericin B, aztreonam, ceftazidime and imipenem caused significant suppression of human colony forming unit-erythroid (cfu-e), burst forming unit-erythroid (bfu-e) and colony forming unit-granulocyte macrophage (cfu-gm) at both peak and trough serum concentrations. At molar equivalent concentrations ceftazidime, cefotaxime and cefoperazone caused significant decreases in human cfu-e, bfu-e and cfu-gm in vitro (P less than 0.01) and murine cfu-s in vivo (P less than 0.05); cefoxitin, cefuroxime, ceftizoxime and ceftriaxone did not suppress human bone marrow progenitor cell activity. Gentamicin, piperacillin and ceftriaxone had no effect on murine cfu-s formation. Further studies to evaluate the effect of these antibiotics on human bone marrow in vivo are suggested.

This chapter outlines the core concepts of human rights-based approaches (HRBAs) and explores the evolution of human rights-based approaches to development including the United Nations (UN) commitment to integrate human rights into all its work, national development plans, the role of socio-economic rights in development problem analysis, impact assessment, and key challenges to undertaking human rights-based development. The chapter also highlights the issue of measurement of human rights change as a critical factor in development planning, implementation, and evaluation towards ensuring accountability for both process and impact.

THE ‘‘VOLUME/QUALITY’’ CONTROVERSY smolders on. Are there surgical procedures whose complexity, resource demands, or other factors require their concentration in certain high-volume hospitals? Does restricting some operations to a few ‘‘centers of excellence’’ lead to better outcomes? Today’s centralized data collection by government and other agencies generates plenty of numbers, but how should we interpret them? 1 This report by Stukenborg and colleagues is one in a series from this group comparing different scoring systems retrospectively applied to administrative data. This time, the target procedures were resective surgery for lung cancer, and the sole outcome variable is mortality. In their sample of more than 14,000 patients, there were 519 deaths scattered among 330 hospitals in a 3-year period, an average well below 1 death per hospital per year. The distribution of hospital deaths for this 3.6% of the patients, adjusted for risk, is proposed as a measure of ‘‘quality of care’’ for the hospitals, which is then correlated with their lung cancer operative volume. The authors’ extensive statistical analysis compares 3 models of measuring risk-adjusted, in-hospital mortality for lung cancer operations. They show that adjusting estimates of risk using only comorbidities found at admission (and not adding other comorbidities developed or detected later to the prediction model) reduces the apparent differences sometimes found between low-volume and high-volume hospitals. Using the authors’ favored analytic technique, the direction of the difference inches toward including the possibility that ‘‘volume matters little,’’ although this is never explicitly said by the authors. But, by any method of analysis considered here, hospital volume is a minor contributor to variation in mortality. Apart from the small size of any volume-mortality effect, there’s another problem with using studies such as this to guide policy: Administrative data are a poor basis for measuring clinical outcomes. 2 It is said that ‘‘The King’s census is only as good as the village watchman’s count.’’ The primary data analyzed here were gathered by coders

IN 1989 when Fleischmann and Pons claimed to have produced room temperature fusion, the ensuing flashes of discussion and reports of attempts at confirmation were transacted largely by fax. When comet Shoemaker-Levy 9 hit Jupiter, the first images of the event were disseminated instantly on the Internet. The exciting claim by Princeton mathematician Andrew Wiles to have proved Fermat's 350-year-old Last Theorem is now being scrutinized and fleshed out in fermat@e-math.ams.org. Medical students of today no longer have folders filled with torn-out magazine articles and file card cross-references. They are fluent with MEDLINE, CD-ROMs, and databases with automatic E-mail updates on topics of their choice. What then is the future of paper journals, such as Archives of Surgery? Scholarly journals in and out of medicine serve several functions, including dissemination, discrimination (ie, editing), summarization, and archiving. DISSEMINATION AND RETRIEVAL For material that is not time sensitive, paper journals, even those

Introduction: The conventional view that admission lactate levels predict outcome in trauma patients stems from simple comparisons of mean blood levels between groups and small sample sizes. To better address this question, we performed more rigorous statistical analyses of lactate in a larger patient sample. Methods: We prospectively collected data on admission lactate and outcomes in 5,995 patients admitted to an urban, university-based trauma center. The ability of admission lactate to predict mortality was assessed by logistic regression, calculation of positive predictive values (PPV), and measurement of areas under receiver operating characteristic (ROC) curves. Results: Differences between survivors and nonsurvivors in means of most proposed prognosticators was again demonstrated. However, the large overlap in these variables between survivors and nonsurvivors prevented clinically useful predictions. The overall PPV of elevated lactate was only 5.4%. Even in severely injured patients (Injury Severity Score >20; mortality 23%), elevated admission lactate level was a poor predictor of outcome. ROC analyses found no useful sensitivity threshold overall or after stratification by age, sex, Glasgow Coma Scale score, revised trauma score, or mechanism of injury. Conclusions: This large retrospective examination of admission lactate levels failed to show useful predictive accuracy for hospital death. Serum lactate levels need not be obtained routinely but can be reserved for patients who will be admitted to the intensive care unit and/or require an emergency operation.

Between the years 1973-1977, 152 male patients from 28 participating Veterans Hospitals with histologically proven nonresectable cancer of the pancreas were randomized in a two-arm study. The treated group was to receive combination chemotherapy with 5-FU and CCNU, and the controls were to receive no chemotherapy. Both groups were comparable with respect to age, amount of weight loss, extent of histologically proved metastases, and operation performed. In the treatment group, drug therapy was begun between 10 and 60 days postoperatively. Intravenous 5-FU, 9 mg/kg, was administered on five consecutive days, and CCNU, 70 mg/m2, was given orally on the first day of each course. In the absence of toxicity, the course was repeated every six weeks for life; 146 drug courses were given. The incidence of toxicity was not great. One or more toxic reactions were reported for one-third of the drug courses administered, but for the most part, these were mild. The most frequent toxic reaction was vomiting in 17% of the courses, and hematologic toxicity-primarily leukopenia-in 15% of the drug courses. There was no evidence of a beneficial effect on survival from drug treatment in the group as a whole or in any subgroup analyzed. The median survival of the control group was 3.9 months, and of the drug-treated group, 3.0 months.

Defects in cellular immunity have been documented in a variety of neoplasms of both lymphoid and nonlymphoid origin. Cellular immune function was studied pre-operatively in 47 patients with untreated but apparently resectable sarcomas of bone or soft tissue by measuring in vitro lymphocyte response to the mitogen PHA. This quantitative assay of lymphocyte function was used to compare patients with various subtypes of soft-tissue sarcoma (fibro, lipo, myo, and undifferentiated) to patients with osteosarcoma and to a group of over 250 age-matched normal controls. The percentage of low lymphocyte response in 32 soft-tissue sarcoma patients (19%) did not differ significantly from that in controls (16%). By contrast, 80% of 15 osteosarcoma patients had depressed lymphocyte reactivity, a highly significant difference compared both with age-matched controls (P < 0.01 by chi square) and with soft-tissue sarcoma patients (P < 0.05). This depression of lymphocyte function peculiar to osteosarcoma has important implications for understanding the pathogenesis of these tumors, for clarifying host interactions with viral agents, and for rational planning of immunotherapy.

To evaluate the claim that delayed cutaneous hypersensitivity skin testing is useful in nutritional assessment of hospitalized patients, we reviewed the English language literature of the last 12 years. Although several hundred publications discussed delayed cutaneous hypersensitivity testing and nutritional status, only 15 provided new, objective data correlating these variables in hospitalized adults. Of these, only three provided age-matched control groups to control for antigen variability, lack of prior exposure, and other technical problems. The majority of reports took no account of diseases (cancer, immune disease, infection) or therapies (radiation, drugs, surgery) known to affect skin test response. In the reports specifying different degrees of malnutrition, the most important group, those with less than obvious malnutrition, were not abnormal by skin testing. Ten reports described serial skin testing during nutritional intervention. Non reported serially tested controls without nutritional intervention, important since serial testing alone can augment skin test response. Nonnutritional intercurrent therapy which might affect skin tests was seldom mentioned. In the few reports specifying that nutritional repletion was even achieved, repleted patients were not separated from unrepleted in subsequent analyses. No report examined skin testing for its predictive accuracy, cost/benefit ratio, or influence on outcome. Because of these problems in experimental design, the frequent lack of appropriate controls, and the low specificity of abnormal delayed cutaneous hypersensitivity responses, we conclude that the utility of skin testing in nutritional assessment remains unproved.

The technic of Schilling, Joel, and Shurley [2] has been adapted to the study of oxygen tension, carbon dioxide tensions, and hydrogen ion concentration in wound fluid. The gas tensions have been shown to be characteristic of those present at the advancing edge of the granulation tissue. Oxygen tensions were very low in the early phases of healing and rose as healing progressed. Carbon dioxide tensions were low five days after wounding but rose thereafter, probably because of increased production of carbon dioxide by the healing tissue. The low hydrogen ion concentration primarily reflects the high carbon dioxide tensions of wound fluid. The significance of these data is discussed.

A system is described which enables the Universal Time of occurance of certain events to be recorded. Hourly synchronization of the system by means of standard radio VLF timing signals eliminates the need for expensive clocks.