Network analysis of the genomic basis of the placebo effect

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Abstract

The placebo effect is a phenomenon in which patients who are given an inactive treatment (e.g., inert pill) show a perceived or actual improvement in a medical condition. Placebo effects in clinical trials have been investigated for many years especially because placebo treatments often serve as the control arm of randomized clinical trial designs. Recent observations suggest that placebo effects may be modified by genetics. This observation has given rise to the term “placebome,” which refers to a group of genome-related mediators that affect an individual’s response to placebo treatments. In this study, we conduct a network analysis of the placebome and identify a placebome module in the comprehensive human interactome using a seed-connector algorithm. The placebome module is significantly enriched with neurotransmitter signaling pathways and brain-specific proteins. We validate the placebome module using a large cohort of the Women’s Genome Health Study (WGHS) trial and demonstrate that the placebome module is significantly enriched with genes whose SNPs modify the outcome in the placebo arm of the trial. To gain insights into placebo effects in different diseases and drug treatments, we use a network proximity measure to examine the closeness of the placebome module to different disease modules and drug target modules. The results demonstrate that the network proximity of the placebome module to disease modules in the interactome significantly correlates with the strength of the placebo effect in the corresponding diseases. The proximity of the placebome module to molecular pathways affected by certain drug classes indicates the existence of placebo-drug interactions. This study is helpful for understanding the molecular mechanisms mediating the placebo response, and sets the stage for minimizing its effects in clinical trials and for developing therapeutic strategies that intentionally engage it.

Authors

Rui-Sheng Wang, Kathryn T. Hall, Franco Giulianini, Dani Passow, Ted J. Kaptchuk, Joseph Loscalzo

First-in-human trial of multikinase VEGF inhibitor regorafenib and anti-EGFR antibody cetuximab in advanced cancer patients

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Abstract

BACKGROUND. The combination of multikinase VEGF inhibitor regorafenib and anti-EGFR antibody cetuximab overcomes intrinsic and acquired resistance in both EGFR-sensitive and EGFR-resistant preclinical models of colorectal cancer (CRC).

METHODS. Utilizing a standard 3+3 design, a phase I study was designed to determine safety, maximum tolerated dose (MTD), and dose-limiting toxicities (DLTs) of the regorafenib plus cetuximab combination among patients with advanced cancer including CRC. Comprehensive genomic profiling was performed on the exceptional responder.

RESULTS. Among the 27 patients enrolled the median age was 54 years. None of 19 patients treated at dose level 1 (cetuximab i.v. 200 mg/m² followed by 150 mg/m² weekly + regorafenib 80 mg daily) experienced a DLT, and 2 of 5 patients treated at dose level 2 (cetuximab i.v. 200 mg/m² followed by 150 mg/m² weekly + regorafenib 120 mg daily) experienced a DLT (grade 3 thrombocytopenia [n = 1] and grade 3 intra-abdominal bleed [n = 1]). Most common adverse events were grade 1 or 2 rash (20 patients). Of 24 evaluable patients, 11 (46%) patients had clinical benefit (stable disease > 6 cycles or partial response [PR]) (CRC n = 8, one patient each with head and neck cancer, carcinoma of unknown primary, and glioblastoma). A CRC patient, who progressed on anti-EGFR and regorafenib, achieved a PR (46% decrease per RECIST v1.1) lasting 15 months. Genomic profiling of an exceptional responder with response for over 27 cycles revealed hypermutated genotype with microsatellite instability (MSI).

CONCLUSION. Regorafenib 80 mg daily plus cetuximab 200 mg/m² loading dose, followed by 150 mg/m² every week is the MTD/recommended phase II dose. The combination demonstrated early signals of activity in wild-type CRC, including 1 exceptional responder with MSI high.

TRIAL REGISTRATION. clinicaltrials.gov NCT02095054

FUNDING. The University of Texas MD Anderson Cancer Center is supported by the NIH Cancer Center Support Grant CA016672. This work was supported in part by the Cancer Prevention Research Institute of Texas grant RP110584 and National Center for Advancing Translational Sciences grant UL1 TR000371 (Center for Clinical and Translational Sciences).

Authors

Vivek Subbiah, Muhammad Rizwan Khawaja, David S. Hong, Behrang Amini, Jiang Yungfang, Hui Liu, Adrienne Johnson, Alexa B. Schrock, Siraj M. Ali, James X. Sun, David Fabrizio, Sarina Piha-Paul, Siqing Fu, Apostolia M. Tsimberidou, Aung Naing, Filip Janku, Daniel D. Karp, Michael Overman, Cathy Eng, Scott Kopetz, Funda Meric-Bernstam, Gerald S. Falchook

Twelve-year survival and immune correlates in dendritic cell–vaccinated melanoma patients

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Abstract

Background. Reports on long-term (≥10 years) effects of cancer vaccines are missing. Therefore, in 2002, we initiated a phase I/II trial in cutaneous melanoma patients to further explore the immunogenicity of our DC vaccine and to establish its long-term toxicity and clinical benefit after a planned 10-year followup.

Methods. Monocyte-derived DCs matured by TNFα, IL-1β, IL-6, and PGE₂ and then loaded with 4 HLA class I and 6 class II–restricted tumor peptides were injected intradermally in high doses over 2 years. We performed serial immunomonitoring in all 53 evaluable patients.

Results. Vaccine-specific immune responses including high-affinity, IFNγ-producing CD4⁺ and lytic polyfunctional CD8⁺ T cells were de novo induced or boosted in most patients. Exposure of mature DCs to trimeric soluble CD40 ligand, unexpectedly, did not further enhance such immune responses, while keyhole limpet hemocyanin (KLH) pulsing to provide unspecific CD4⁺ help promoted CD8⁺ T cell responses — notably, their longevity. An unexpected 19% of nonresectable metastatic melanoma patients are still alive after 11 years, a survival rate similar to that observed in ipilimumab-treated patients and achieved without any major (>grade 2) toxicity. Survival correlated significantly with the development of intense vaccine injection site reactions, and with blood eosinophilia after the first series of vaccinations, suggesting that prolonged survival was a consequence of DC vaccination.

Conclusions. Long-term survival in advanced melanoma patients undergoing DC vaccination is similar to ipilimumab-treated patients and occurs upon induction of tumor-specific T cells, blood eosinophilia, and strong vaccine injection site reactions occurring after the initial vaccinations.

TRIAL REGISTRATION. ClinicalTrials.gov NCT00053391.

FUNDING. European Community, Sixth Framework Programme (Cancerimmunotherapy LSHC-CT-2006-518234; DC-THERA LSHB-CT-2004-512074), and German Research Foundation (CRC 643, C1, Z2).

Authors

Stefanie Gross, Michael Erdmann, Ina Haendle, Steve Voland, Thomas Berger, Erwin Schultz, Erwin Strasser, Peter Dankerl, Rolf Janka, Stefan Schliep, Lucie Heinzerling, Karl Sotlar, Pierre Coulie, Gerold Schuler, Beatrice Schuler-Thurner

Randomized, placebo-controlled window trial of EGFR, Src, or combined blockade in head and neck cancer

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Abstract

BACKGROUND. EGFR and Src family kinases are upregulated in head and neck squamous cell carcinoma (HNSCC). EGFR interacts with Src to activate STAT3 signaling, and dual EGFR-Src targeting is synergistic in HNSCC preclinical models. pSrc overexpression predicted resistance to the EGFR inhibitor, erlotinib, in a prior window trial. We conducted a 4-arm window trial to identify biomarkers associated with response to EGFR and/or Src inhibition.

METHODS. Patients with operable stage II–IVa HNSCC were randomized to 7–21 days of neoadjuvant erlotinib, the Src inhibitor dasatinib, the combination of both, or placebo. Paired tumor specimens were collected before and after treatment. Pharmacodynamic expression of EGFR and Src pathway components was evaluated by IHC of tissue microarrays and reverse-phase protein array of tissue lysates. Candidate biomarkers were assessed for correlation with change in tumor size.

RESULTS. From April 2009 to December 2012, 58 patients were randomized and 55 were treated. There was a significant decrease in tumor size in both erlotinib arms (P = 0.0014); however, no effect was seen with dasatinib alone (P = 0.24). High baseline pMAPK expression was associated with response to erlotinib (P = 0.03). High baseline pSTAT3 was associated with resistance to dasatinib (P = 0.099).

CONCLUSIONS. Brief exposure to erlotinib significantly decreased tumor size in operable HNSCC, with no additive effect from dasatinib. Baseline pMAPK expression warrants further study as a response biomarker for anti-EGFR therapy. Basal expression of pSTAT3 may be independent of Src, explain therapeutic resistance, and preclude development of dasatinib in biomarker-unselected cohorts.

TRIAL REGISTRATION. NCT00779389.

FUNDING. National Cancer Institute, American Cancer Society, Pennsylvania Department of Health, V Foundation for Cancer Research, Bristol-Myers Squibb, and Astellas Pharma.

Authors

Julie E. Bauman, Umamaheswar Duvvuri, William E. Gooding, Tanya J. Rath, Neil D. Gross, John Song, Antonio Jimeno, Wendell G. Yarbrough, Faye M. Johnson, Lin Wang, Simion Chiosea, Malabika Sen, Jason Kass, Jonas T. Johnson, Robert L. Ferris, Seungwon Kim, Fred R. Hirsch, Kimberly Ellison, John T. Flaherty, Gordon B. Mills, Jennifer R. Grandis

Leukemia cell proliferation and death in chronic lymphocytic leukemia patients on therapy with the BTK inhibitor ibrutinib

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Abstract

BACKGROUND. Ibrutinib is an effective targeted therapy for patients with chronic lymphocytic leukemia (CLL) that inhibits Bruton’s tyrosine kinase (BTK), a kinase involved in B cell receptor signaling.

METHODS. We used stable isotopic labeling with deuterated water (²H₂O) to measure directly the effects of ibrutinib on leukemia cell proliferation and death in 30 patients with CLL.

RESULTS. The measured average CLL cell proliferation (“birth”) rate before ibrutinib therapy was 0.39% of the clone per day (range 0.17%–1.04%); this decreased to 0.05% per day (range 0%–0.36%) with treatment. Death rates of blood CLL cells increased from 0.18% per day (average, range 0%–0.7%) prior to treatment to 1.5% per day (range 0%–3.0%) during ibrutinib therapy, and they were even higher in tissue compartments.

CONCLUSIONS. This study provides the first direct in vivo measurements to our knowledge of ibrutinib’s antileukemia actions, demonstrating profound and immediate inhibition of CLL cell proliferation and promotion of high rates of CLL cell death.

TRIAL REGISTRATION. This trial was registered at clinicaltrials.gov (NCT01752426).

FUNDING. This study was supported by a Cancer Center Support Grant (National Cancer Institute grant P30 CA016672), an NIH grant (CA081554) from the National Cancer Institute, MD Anderson’s Moon Shots Program in CLL, and Pharmacyclics, an AbbVie company.

Authors

Jan A. Burger, Kelvin W. Li, Michael J. Keating, Mariela Sivina, Ahmed M. Amer, Naveen Garg, Alessandra Ferrajoli, Xuelin Huang, Hagop Kantarjian, William G. Wierda, Susan O’Brien, Marc K. Hellerstein, Scott M. Turner, Claire L. Emson, Shih-Shih Chen, Xiao-Jie Yan, Dominik Wodarz, Nicholas Chiorazzi

Protection against Plasmodium falciparum malaria by PfSPZ Vaccine

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Abstract

BACKGROUND: A radiation-attenuated Plasmodium falciparum (Pf) sporozoite (SPZ) malaria vaccine, PfSPZ Vaccine, protected 6 of 6 subjects (100%) against homologous Pf (same strain as in the vaccine) controlled human malaria infection (CHMI) 3 weeks after 5 doses administered intravenously. The next step was to assess protective efficacy against heterologous Pf (different from Pf in the vaccine), after fewer doses, and at 24 weeks.

METHODS: The trial assessed tolerability, safety, immunogenicity, and protective efficacy of direct venous inoculation (DVI) of 3 or 5 doses of PfSPZ Vaccine in non-immune subjects.

RESULTS: Three weeks after final immunization, 5 doses of 2.7 × 10⁵ PfSPZ protected 12 of 13 recipients (92.3% [95% CI: 48.0, 99.8]) against homologous CHMI and 4 of 5 (80.0% [10.4, 99.5]) against heterologous CHMI; 3 doses of 4.5 × 10⁵ PfSPZ protected 13 of 15 (86.7% [35.9, 98.3]) against homologous CHMI. Twenty-four weeks after final immunization, the 5-dose regimen protected 7 of 10 (70.0% [17.3, 93.3]) against homologous and 1 of 10 (10.0% [–35.8, 45.6]) against heterologous CHMI; the 3-dose regimen protected 8 of 14 (57.1% [21.5, 76.6]) against homologous CHMI. All 22 controls developed Pf parasitemia. PfSPZ Vaccine was well tolerated, safe, and easy to administer. No antibody or T cell responses correlated with protection.

CONCLUSIONS: We have demonstrated for the first time to our knowledge that PfSPZ Vaccine can protect against a 3-week heterologous CHMI in a limited group of malaria-naive adult subjects. A 3-dose regimen protected against both 3-week and 24-week homologous CHMI (87% and 57%, respectively) in this population. These results provide a foundation for developing an optimized immunization regimen for preventing malaria.

TRIAL REGISTRATION: ClinicalTrials.gov NCT02215707.

FUNDING: Support was provided through the US Army Medical Research and Development Command, Military Infectious Diseases Research Program, and the Naval Medical Research Center’s Advanced Medical Development Program.

Authors

Judith E. Epstein, Kristopher M. Paolino, Thomas L. Richie, Martha Sedegah, Alexandra Singer, Adam J. Ruben, Sumana Chakravarty, April Stafford, Richard C. Ruck, Abraham G. Eappen, Tao Li, Peter F. Billingsley, Anita Manoj, Joana C. Silva, Kara Moser, Robin Nielsen, Donna Tosh, Susan Cicatelli, Harini Ganeshan, Jessica Case, Debbie Padilla, Silas Davidson, Lindsey Garver, Elizabeth Saverino, Tooba Murshedkar, Anusha Gunasekera, Patrick S. Twomey, Sharina Reyes, James E. Moon, Eric R. James, Natasha KC, Minglin Li, Esteban Abot, Arnel Belmonte, Kevin Hauns, Maria Belmonte, Jun Huang, Carlos Vasquez, Shon Remich, Mary Carrington, Yonas Abebe, Amy Tillman, Bradley Hickey, Jason Regules, Eileen Villasante, B. Kim Lee Sim, Stephen L. Hoffman

Chorioretinal thinning in chronic kidney disease links to inflammation and endothelial dysfunction

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Abstract

BACKGROUND. Chronic kidney disease (CKD) is strongly associated with cardiovascular disease and there is an established association between vasculopathy affecting the kidney and eye. Optical coherence tomography (OCT) is a novel, rapid method for high-definition imaging of the retina and choroid. Its use in patients at high cardiovascular disease risk remains unexplored.

METHODS. We used the new SPECTRALIS OCT machine to examine retinal and retinal nerve fiber layer (RNFL) thickness, macular volume, and choroidal thickness in a prospective cross-sectional study in 150 subjects: 50 patients with hypertension (defined as a documented clinic BP greater than or equal to 140/90 mmHg (prior to starting any treatment) with no underlying cause identified); 50 with CKD (estimated glomerular filtration rate (eGFR) 8–125 ml/min/1.73 m²); and 50 matched healthy controls. We excluded those with diabetes. The same, masked ophthalmologist carried out each study. Plasma IL-6, TNF-α , asymmetric dimethylarginine (ADMA), and endothelin-1 (ET-1), as measures of inflammation and endothelial function, were also assessed.

RESULTS. Retinal thickness, macular volume, and choroidal thickness were all reduced in CKD compared with hypertensive and healthy subjects (for retinal thickness and macular volume P < 0.0001 for CKD vs. healthy and for CKD vs. hypertensive subjects; for choroidal thickness P < 0.001 for CKD vs. healthy and for CKD vs. hypertensive subjects). RNFL thickness did not differ between groups. Interestingly, a thinner choroid was associated with a lower eGFR (r = 0.35, P <0.0001) and, in CKD, with proteinuria (r = –0.58, P < 0.001) as well as increased circulating C-reactive protein (r = –0.57, P = 0.0002), IL-6 (r = –0.40, P < 0.01), ADMA (r = –0.37, P = 0.02), and ET-1 (r = –0.44, P < 0.01). Finally, choroidal thinning was associated with renal histological inflammation and arterial stiffness. In a model of hypertension, choroidal thinning was seen only in the presence of renal injury.

CONCLUSIONS. Chorioretinal thinning in CKD is associated with lower eGFR and greater proteinuria, but not BP. Larger studies, in more targeted groups of patients, are now needed to clarify whether these eye changes reflect the natural history of CKD. Similarly, the associations with arterial stiffness, inflammation, and endothelial dysfunction warrant further examination.

TRIAL REGISTRATION. Registration number at www.clinicalTrials.gov: NCT02132741.

SOURCE OF FUNDING. TR was supported by a bursary from the Erasmus Medical Centre, Rotterdam. JJMHvB was supported by a bursary from the Utrecht University. JRC is supported by a Rowling Scholarship. SB was supported by a Wellcome Trust funded clinical research fellowship from the Scottish Translational Medicine and Therapeutics Initiative, and by a Rowling Scholarship, at the time of this work. ND is supported by a British Heart Foundation Intermediate Clinical Research Fellowship (FS/13/30/29994).

Authors

Craig Balmforth, Job J.M.H. van Bragt, Titia Ruijs, James R. Cameron, Robert Kimmitt, Rebecca Moorhouse, Alicja Czopek, May Khei Hu, Peter J. Gallacher, James W. Dear, Shyamanga Borooah, Iain M. MacIntyre, Tom M.C. Pearson, Laura Willox, Dinesh Talwar, Muriel Tafflet, Christophe Roubeix, Florian Sennlaub, Siddharthan Chandran, Baljean Dhillon, David J. Webb, Neeraj Dhaun