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1. Intratumoral oncolytic virus V937 plus ipilimumab in patients with advanced melanoma: the phase 1b MITCI study

Author

Gregory A Daniels, Sigrun Hallmeyer, Mark Grose, Jon Richards, Mark Faries, Brendan D Curti, Kim A Margolin, Yiwei Zhang, Lynn Feun, Anlong Li, John R Hyngstrom, and Robert H I Andtbacka

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Background Intratumoral administration of V937, a bioselected, genetically unmodified coxsackievirus A21, has previously demonstrated antitumor activity in patients with advanced melanoma as monotherapy and in combination with the programmed cell death 1 (PD-1) antibody pembrolizumab. We report results from an open-label, single-arm, phase 1b study (NCT02307149) evaluating V937 plus the cytotoxic T-lymphocyte antigen 4 inhibitor ipilimumab in patients with advanced melanoma.Methods Adult patients (aged ≥18 years) with histologically confirmed metastatic or unresectable stage IIIB/C or IV melanoma received intratumoral V937 on days 1, 3, 5, 8, and 22 and every 3 weeks (Q3W) thereafter for up to 19 sets of injections plus intravenous ipilimumab 3 mg/kg Q3W administered for four doses starting on day 22. Imaging was performed at screening, on days 43 and 106 and every 6 weeks thereafter; response was assessed by immune-related response criteria per investigator assessment. Primary endpoints were safety in all treated patients and objective response rate (ORR) in all treated patients and in patients with disease that progressed on prior anti-PD-1 therapy.Results Fifty patients were enrolled and treated. ORR was 30% (95% CI 18% to 45%) among all treated patients, 47% (95% CI 23% to 72%) among patients who had not received prior anti-PD-1 therapy, and 21% (95% CI 9% to 39%) among patients who had experienced disease progression on prior anti-PD-1 therapy. Tumor regression occurred in injected and non-injected lesions. Median immune-related progression-free survival was 6.2 months (95% CI 3.5 to 9.0 months), and median overall survival was 45.1 months (95% CI 28.3 months to not reached). The most common treatment-related adverse events (AEs) were pruritus (n=25, 50%), fatigue (n=22, 44%), and diarrhea (n=16, 32%). There were no V937-related dose-limiting toxicities and no treatment-related grade 5 AEs. Treatment-related grade 3 or 4 AEs, all of which were considered related to ipilimumab, occurred in 14% of patients (most commonly dehydration, diarrhea, and hepatotoxicity in 4% each).Conclusions Responses associated with intratumoral V937 plus ipilimumab were robust, including in the subgroup of patients who had experienced disease progression on prior anti-PD-1 therapy. Toxicities were manageable and consistent with those of the individual monotherapies.

Published
2022
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2. Engaging Remote Aboriginal Communities in COVID-19 Public Health Messaging via Crowdsourcing

Author

Miriam Glennie, Michelle Dowden, Mark Grose, Meg Scolyer, Alessandra Superina, and Karen Gardner

Subjects
crowdsourcing, remote Aboriginal communities, health communication, COVID-19, social media, Indigenous language, Public aspects of medicine, RA1-1270
Abstract

Health comunication is a critical component of pandemic mitigation, but mainstream prevention messaging often lacks social, cultural and linguistic relevance to vulnerable populations. This community case study presents a novel, highly participatory pandemic prevention communication campaign that engaged individuals in remote Aboriginal communities of the Northern Territory of Australia directly in prevention messaging via crowdsourcing, and distributed videos to remote area post-codes via targeted Facebook advertising. Facebook metrics, administrative campaign data and national statistics are used to assess campaign reach and engagement. The case study discusses lessons learned from the campaign, including how seeking unscripted COVID-19 prevention video messaging can support community ownership of pandemic messaging, rapid content generation, and a high level of Facebook user engagement. It also discusses the effectiveness of targeting remote area post-codes via Facebook advertising both to reach the target audience, and to support quality improvement assessments to inform health communication decision-making in a low resource setting.

Published
2022
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4. Data from Phase I Trial of an ICAM-1-Targeted Immunotherapeutic-Coxsackievirus A21 (CVA21) as an Oncolytic Agent Against Non Muscle-Invasive Bladder Cancer

Author

Hardev S. Pandha, Darren Shafren, Hugh Mostafid, Richard Vile, Bernard Fox, Izhar Bagwan, Mark Grose, Gough Au, Bronwyn Davies, Kevin J. Harrington, Alan A. Melcher, Sarbjinder S. Sandhu, Mick Denyer, Guy R. Simpson, Carmen Ballesteros-Merino, Mehreen Arif, David Mansfield, and Nicola E. Annels

Abstract

Purpose:The CANON [CAVATAK in NON–muscle-invasive bladder cancer (NMIBC)] study evaluated a novel ICAM-1–targeted immunotherapeutic-coxsackievirus A21 as a novel oncolytic agent against bladder cancer.Patients and Methods:Fifteen patients enrolled in this “window of opportunity” phase I study, exposing primary bladder cancers to CAVATAK prior to surgery. The first 9 patients received intravesical administration of monotherapy CAVATAK; in the second stage, 6 patients received CAVATAK with a subtherapeutic dose of mitomycin C, known to enhance expression of ICAM-1 on bladder cancer cells. The primary endpoint was to determine patient safety and maximum tolerated dose (MTD). Secondary endpoints were evidence of viral replication, induction of inflammatory cytokines, antitumor activity, and viral-induced changes in resected tissue.Results:Clinical activity of CAVATAK was demonstrated by induction of tumor inflammation and hemorrhage following either single or multiple administrations of CAVATAK in multiple patients, and a complete resolution of tumor in 1 patient. Whether used alone or in combination with mitomycin C, CAVATAK caused marked inflammatory changes within NMIBC tissue biopsies by upregulating IFN-inducible genes, including both immune checkpoint inhibitory genes (PD-L1 and LAG3) and Th1-associated chemokines, as well as the induction of the innate activator RIG-I, compared with bladder cancer tissue from untreated patients. No significant toxicities were reported in any patient, from either virus or combination therapy.Conclusions:The acceptable safety profile of CAVATAK, proof of viral targeting, replication, and tumor cell death together with the virus-mediated increases in “immunological heat” within the tumor microenvironment all indicate that CAVATAK may be potentially considered as a novel therapeutic for NMIBC.

Published
2023
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5. Supplementary Data from Phase I Trial of an ICAM-1-Targeted Immunotherapeutic-Coxsackievirus A21 (CVA21) as an Oncolytic Agent Against Non Muscle-Invasive Bladder Cancer

Author

Hardev S. Pandha, Darren Shafren, Hugh Mostafid, Richard Vile, Bernard Fox, Izhar Bagwan, Mark Grose, Gough Au, Bronwyn Davies, Kevin J. Harrington, Alan A. Melcher, Sarbjinder S. Sandhu, Mick Denyer, Guy R. Simpson, Carmen Ballesteros-Merino, Mehreen Arif, David Mansfield, and Nicola E. Annels

Abstract

Supplementary data - revised

Published
2023
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6. A phase 1b single-arm trial of intratumoral oncolytic virus V937 in combination with pembrolizumab in patients with advanced melanoma: results from the CAPRA study

Author

Ann W. Silk, Steven J. O’Day, Howard L. Kaufman, Jennifer Bryan, Jacqueline T. Norrell, Casey Imbergamo, Daniella Portal, Edwin Zambrano-Acosta, Marisa Palmeri, Seymour Fein, Cai Wu, Leslie Guerreiro, Daniel Medina, Praveen K. Bommareddy, Andrew Zloza, Bernard A. Fox, Carmen Ballesteros-Merino, Yixin Ren, Darren Shafren, Mark Grose, Joshua A. Vieth, and Janice M. Mehnert

Subjects
Cancer Research, Oncology, Immunology, Immunology and Allergy
Abstract

Background CAPRA (NCT02565992) evaluated Coxsackievirus A21 (V937) + pembrolizumab for metastatic/unresectable stage IIIB–IV melanoma. Methods Patients received intratumoral V937 on days 1, 3, 5, and 8 (then every 3 weeks [Q3W]) and intravenous pembrolizumab 2 mg/kg Q3W from day 8. Primary endpoint was safety. Results Median time from first dose to data cutoff was 32.0 months. No dose-limiting toxicities occurred; 14% (5/36) of patients experienced grade 3‒5 treatment-related adverse events. Objective response rate was 47% (complete response, 22%). Among 17 responders, 14 (82%) had responses ≥ 6 months. Among 8 patients previously treated with immunotherapy, 3 responded (1 complete, 2 partial). Responses were associated with increased serum CXCL10 and CCL22, suggesting viral replication contributes to antitumor immunity. For responders versus nonresponders, there was no difference in baseline tumor PD-L1 expression, ICAM1 expression, or CD3+ infiltrates. Surprisingly, the baseline cell density of CD3+CD8− T cells in the tumor microenvironment was significantly lower in responders compared with nonresponders (P = 0.0179). Conclusions These findings suggest responses to this combination may be seen even in patients without a typical “immune-active” microenvironment. Trial registration number NCT02565992.

Published
2022

7. Intratumoral oncolytic virus V937 plus ipilimumab in patients with advanced melanoma: the phase 1b MITCI study

Author

Brendan D Curti, Jon Richards, John R Hyngstrom, Gregory A Daniels, Mark Faries, Lynn Feun, Kim A Margolin, Sigrun Hallmeyer, Mark Grose, Yiwei Zhang, Anlong Li, and Robert H I Andtbacka

Subjects
Adult, Pharmacology, Cancer Research, Adolescent, Immunology, Ipilimumab, Progression-Free Survival, Oncolytic Viruses, Oncology, Disease Progression, Humans, Molecular Medicine, Immunology and Allergy, Melanoma
Abstract

BackgroundIntratumoral administration of V937, a bioselected, genetically unmodified coxsackievirus A21, has previously demonstrated antitumor activity in patients with advanced melanoma as monotherapy and in combination with the programmed cell death 1 (PD-1) antibody pembrolizumab. We report results from an open-label, single-arm, phase 1b study (NCT02307149) evaluating V937 plus the cytotoxic T-lymphocyte antigen 4 inhibitor ipilimumab in patients with advanced melanoma.MethodsAdult patients (aged ≥18 years) with histologically confirmed metastatic or unresectable stage IIIB/C or IV melanoma received intratumoral V937 on days 1, 3, 5, 8, and 22 and every 3 weeks (Q3W) thereafter for up to 19 sets of injections plus intravenous ipilimumab 3 mg/kg Q3W administered for four doses starting on day 22. Imaging was performed at screening, on days 43 and 106 and every 6 weeks thereafter; response was assessed by immune-related response criteria per investigator assessment. Primary endpoints were safety in all treated patients and objective response rate (ORR) in all treated patients and in patients with disease that progressed on prior anti-PD-1 therapy.ResultsFifty patients were enrolled and treated. ORR was 30% (95% CI 18% to 45%) among all treated patients, 47% (95% CI 23% to 72%) among patients who had not received prior anti-PD-1 therapy, and 21% (95% CI 9% to 39%) among patients who had experienced disease progression on prior anti-PD-1 therapy. Tumor regression occurred in injected and non-injected lesions. Median immune-related progression-free survival was 6.2 months (95% CI 3.5 to 9.0 months), and median overall survival was 45.1 months (95% CI 28.3 months to not reached). The most common treatment-related adverse events (AEs) were pruritus (n=25, 50%), fatigue (n=22, 44%), and diarrhea (n=16, 32%). There were no V937-related dose-limiting toxicities and no treatment-related grade 5 AEs. Treatment-related grade 3 or 4 AEs, all of which were considered related to ipilimumab, occurred in 14% of patients (most commonly dehydration, diarrhea, and hepatotoxicity in 4% each).ConclusionsResponses associated with intratumoral V937 plus ipilimumab were robust, including in the subgroup of patients who had experienced disease progression on prior anti-PD-1 therapy. Toxicities were manageable and consistent with those of the individual monotherapies.

Published
2022
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8. Clinical Responses of Oncolytic Coxsackievirus A21 (V937) in Patients With Unresectable Melanoma

Author

Eric D. Whitman, Meihua Wang, Howard L. Kaufman, Praveen K. Bommareddy, Lynn E. Spitler, Cai Wu, Karl Zhou, Robert H.I. Andtbacka, Gregory A. Daniels, Brendan D. Curti, Mark Grose, Sigrun Hallmeyer, and Jose Lutzky

Subjects
Oncology, Adult, Aged, 80 and over, Cancer Research, medicine.medical_specialty, business.industry, Melanoma, Coxsackievirus A21, Coxsackievirus Infections, Middle Aged, medicine.disease, Oncolytic virus, Oncolytic Viruses, Internal medicine, Medicine, Humans, Stage IIIC, In patient, Female, business, Aged
Abstract

PURPOSEWe evaluated the activity of intratumoral Coxsackievirus A21 (V937) in 57 patients with unresectable stage IIIC or IV melanoma.PATIENTS AND METHODSIn this multicenter, open-label, phase II study, patients received up to a total V937 dose of 3 × 108TCID50(50% tissue culture infectious dose) in a maximum 4.0-mL volume by intratumoral injection. Ten sets of V937 injections were administered between days 1 and 127 ( NCT01227551 ). Patients who had stable disease or were responding could continue treatment in an extension study ( NCT01636882 ). Response and progression status were based on contrast-enhanced computed tomography, magnetic resonance imaging, or caliper measurement and were categorized using immune-related Response Evaluation Criteria in Solid Tumors (irRECIST). Other evaluations included monitoring of adverse events and serum levels of V937 and anti-V937 antibody titers. The primary efficacy end point was 6-month progression-free survival (PFS) rate per irRECIST.RESULTSThe primary efficacy end point, 6-month PFS rate per irRECIST, was 38.6% (95% CI, 26.0 to 52.4). Durable response rate (partial or complete response for ≥ 6 months) was 21.1% per irRECIST. Best overall response rate (complete plus partial response) was 38.6% (unconfirmed) and 28.1% (confirmed) per irRECIST. Regression of melanoma was observed in noninjected lesions. Based on Kaplan-Meier estimation, 12-month PFS was 32.9% (95% CI, 19.5 to 46.9) per irRECIST and 12-month overall survival was 75.4% (95% CI, 62.1 to 84.7). No treatment-related grade ≥ 3 adverse events occurred. Viral RNA was detected in serum within 30 minutes of administration. Neutralizing antibody titers increased to > 1:16 in all patients after day 22, without effect on clinical or immunologic response.CONCLUSIONV937 was well tolerated and warrants further investigation for treatment of patients with unresectable melanoma. Studies of combination approaches with V937 and immune checkpoint inhibitors are ongoing.

Published
2021

9. Abstract CT139: Intratumoral oncolytic virus V937 in combination with pembrolizumab (pembro) in patients (pts) with advanced melanoma: Updated results from the phase 1b CAPRA study

Author

Ann W. Silk, Bernard A. Fox, Jacqueline Norrell, Praveen K. Bommareddy, Jennifer L. Bryan, Daniella E Portal, Janice M. Mehnert, Seymour Fein, Joshua A. Vieth, Casey Imbergamo, Leslie Guerreiro, Cai Wu, Edwin Zambrano-Acosta, Steven J. O'Day, Andrew Zloza, Carmen Ballesteros-Merino, Marisa Palmeri, Howard L. Kaufman, Mark Grose, Daniel J. Medina, and Darren R. Shafren

Subjects
Oncology, Autoimmune encephalitis, Cancer Research, medicine.medical_specialty, Septic shock, business.industry, Melanoma, Coxsackievirus A21, Cancer, Pembrolizumab, medicine.disease, Oncolytic virus, medicine.anatomical_structure, Internal medicine, medicine, business, Lymph node
Abstract

Background: Coxsackievirus A21 (V937) is an RNA oncolytic virus targeting ICAM-1 receptors. Pharmacodynamic effects of oncolytic viruses in the tumor microenvironment (TME), including increased CD8+ T cells and PD-L1 expression, support their use in combination with checkpoint inhibitors. We present updated clinical and correlative data from the multicenter phase 1b CAPRA study (NCT02565992) of V937 + pembro in pts with advanced melanoma. Methods: Eligible pts had metastatic/unresectable stage IIIB-IV melanoma and ≥1 cutaneous/subcutaneous tumor or lymph node amenable to V937 intratumoral injection. Pts received V937 on days 1, 3, 5, and 8; then Q3W for up to 19 injections (maximum dose, 3 × 108 50% TCID50). Pts received IV pembro 2 mg/kg Q3W on day 8, continuing for up to 2 y. Primary endpoints were incidence of AEs, serious AEs (SAEs), and dose-limiting toxicities (DLTs). Secondary endpoints were ORR, duration of response (DOR), PFS, and OS. Biomarkers were an exploratory endpoint. Results: 36 pts were enrolled (mean age, 68.5 y; 75% male; 22% had prior immunotherapy). As of 4 Nov 2019, median (range) time from first dose to data cutoff was 32.0 (10.7−45.3) mo. No DLTs occurred. Grade 3-5 treatment-related AEs occurred in 5 (14%) pts. 3 (8%) pts had treatment-related SAEs (autoimmune encephalitis and septic shock in 1 pt, keratoacanthoma, autoimmune hepatitis); 1 died from septic shock. Efficacy results included ORR of 47% (CR, 22%; PR, 25%; Table 1). In comparing responders vs nonresponders, baseline tumor samples showed no difference in PD-L1 expression and lower CD3+CD8- infiltrate in responders. Conclusions: V937 + pembro had manageable safety and promising efficacy in pts with advanced melanoma. Response was not associated with an inflamed TME at baseline, indicating that V937 may induce an immune responsive TME. The combination is being studied in the neoadjuvant setting in pts with stage III melanoma (KEYMAKER-U02). Table 1.Efficacy OutcomesV937 + Pembro (N = 36)ORR,a % (95% CI)b47 (30-65)- CR22 (10-39)- PR25 (12-42)DOR,c median (range), moNR (1.4+ to 22.0+)PFS,c,d median (95% CI), mo11.9 (3.4-NR)12-mo PFS,c % (95% CI)45 (28-60)OS,c median (95% CI), mo30.9 (20.3-40.5)12-mo OS,c % (95% CI)85 (68-94)+ indicates no PD by the time of last disease assessment. NR, not reached.aBest overall response with confirmation based on investigator assessment per immune-related response criteria; imaging was performed Q6W.bBased on the exact method for binomial data.cKaplan-Meier estimate.dBased on investigator assessment per immune-related response criteria. Citation Format: Ann W. Silk, Steven J. O'Day, Howard L. Kaufman, Jennifer Bryan, Jacqueline T. Norrell, Casey Imbergamo, Daniella Portal, Edwin Zambrano-Acosta, Marisa Palmeri, Seymour Fein, Cai Wu, Leslie Guerreiro, Daniel Medina, Praveen K. Bommareddy, Andrew Zloza, Bernard A. Fox, Carmen Ballesteros-Merino, Darren Shafren, Mark Grose, Joshua A. Vieth, Janice M. Mehnert. Intratumoral oncolytic virus V937 in combination with pembrolizumab (pembro) in patients (pts) with advanced melanoma: Updated results from the phase 1b CAPRA study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT139.

Published
2021
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10. Phase I Trial of an ICAM-1-Targeted Immunotherapeutic-Coxsackievirus A21 (CVA21) as an Oncolytic Agent Against Non Muscle-Invasive Bladder Cancer

Author

Nicola E. Annels, Richard G. Vile, Mehreen Arif, M. Denyer, Darren R. Shafren, Izhar Bagwan, Carmen Ballesteros-Merino, Bernard A. Fox, Bronwyn Davies, Guy Simpson, Hardev Pandha, Gough G. Au, David Mansfield, Kevin J. Harrington, Mark Grose, Sarbjinder S Sandhu, Hugh Mostafid, and Alan Melcher

Subjects
0301 basic medicine, Oncology, Male, Cancer Research, medicine.medical_specialty, Combination therapy, Maximum Tolerated Dose, Coxsackievirus A21, Proinflammatory cytokine, 03 medical and health sciences, 0302 clinical medicine, Immune system, Internal medicine, medicine, Clinical endpoint, Tumor Microenvironment, Humans, Molecular Targeted Therapy, Aged, Aged, 80 and over, Oncolytic Virotherapy, Bladder cancer, business.industry, Middle Aged, medicine.disease, Intercellular Adhesion Molecule-1, Oncolytic virus, Clinical trial, Oncolytic Viruses, 030104 developmental biology, Administration, Intravesical, Urinary Bladder Neoplasms, 030220 oncology & carcinogenesis, Feasibility Studies, Female, Immunotherapy, business
Abstract

Purpose: The CANON [CAVATAK in NON–muscle-invasive bladder cancer (NMIBC)] study evaluated a novel ICAM-1–targeted immunotherapeutic-coxsackievirus A21 as a novel oncolytic agent against bladder cancer. Patients and Methods: Fifteen patients enrolled in this “window of opportunity” phase I study, exposing primary bladder cancers to CAVATAK prior to surgery. The first 9 patients received intravesical administration of monotherapy CAVATAK; in the second stage, 6 patients received CAVATAK with a subtherapeutic dose of mitomycin C, known to enhance expression of ICAM-1 on bladder cancer cells. The primary endpoint was to determine patient safety and maximum tolerated dose (MTD). Secondary endpoints were evidence of viral replication, induction of inflammatory cytokines, antitumor activity, and viral-induced changes in resected tissue. Results: Clinical activity of CAVATAK was demonstrated by induction of tumor inflammation and hemorrhage following either single or multiple administrations of CAVATAK in multiple patients, and a complete resolution of tumor in 1 patient. Whether used alone or in combination with mitomycin C, CAVATAK caused marked inflammatory changes within NMIBC tissue biopsies by upregulating IFN-inducible genes, including both immune checkpoint inhibitory genes (PD-L1 and LAG3) and Th1-associated chemokines, as well as the induction of the innate activator RIG-I, compared with bladder cancer tissue from untreated patients. No significant toxicities were reported in any patient, from either virus or combination therapy. Conclusions: The acceptable safety profile of CAVATAK, proof of viral targeting, replication, and tumor cell death together with the virus-mediated increases in “immunological heat” within the tumor microenvironment all indicate that CAVATAK may be potentially considered as a novel therapeutic for NMIBC.

Published
2018

11. 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part two

Author

Casey Ager, Matthew Reilley, Courtney Nicholas, Todd Bartkowiak, Ashvin Jaiswal, Michael Curran, Tina C. Albershardt, Anshika Bajaj, Jacob F. Archer, Rebecca S. Reeves, Lisa Y. Ngo, Peter Berglund, Jan ter Meulen, Caroline Denis, Hormas Ghadially, Thomas Arnoux, Fabien Chanuc, Nicolas Fuseri, Robert W. Wilkinson, Nicolai Wagtmann, Yannis Morel, Pascale Andre, Michael B. Atkins, Matteo S. Carlino, Antoni Ribas, John A. Thompson, Toni K. Choueiri, F. Stephen Hodi, Wen-Jen Hwu, David F. McDermott, Victoria Atkinson, Jonathan S. Cebon, Bernie Fitzharris, Michael B. Jameson, Catriona McNeil, Andrew G. Hill, Eric Mangin, Malidi Ahamadi, Marianne van Vugt, Mariëlle van Zutphen, Nageatte Ibrahim, Georgina V. Long, Robyn Gartrell, Zoe Blake, Ines Simoes, Yichun Fu, Takuro Saito, Yingzhi Qian, Yan Lu, Yvonne M. Saenger, Sadna Budhu, Olivier De Henau, Roberta Zappasodi, Kyle Schlunegger, Bruce Freimark, Jeff Hutchins, Christopher A. Barker, Jedd D. Wolchok, Taha Merghoub, Elena Burova, Omaira Allbritton, Peter Hong, Jie Dai, Jerry Pei, Matt Liu, Joel Kantrowitz, Venus Lai, William Poueymirou, Douglas MacDonald, Ella Ioffe, Markus Mohrs, William Olson, Gavin Thurston, Cristian Capasso, Federica Frascaro, Sara Carpi, Siri Tähtinen, Sara Feola, Manlio Fusciello, Karita Peltonen, Beatriz Martins, Madeleine Sjöberg, Sari Pesonen, Tuuli Ranki, Lukasz Kyruk, Erkko Ylösmäki, Vincenzo Cerullo, Fabio Cerignoli, Biao Xi, Garret Guenther, Naichen Yu, Lincoln Muir, Leyna Zhao, Yama Abassi, Víctor Cervera-Carrascón, Mikko Siurala, João Santos, Riikka Havunen, Suvi Parviainen, Akseli Hemminki, Angus Dalgleish, Satvinder Mudan, Mark DeBenedette, Ana Plachco, Alicia Gamble, Elizabeth W. Grogan, John Krisko, Irina Tcherepanova, Charles Nicolette, Pooja Dhupkar, Ling Yu, Eugenie S. Kleinerman, Nancy Gordon, Italia Grenga, Lauren Lepone, Sofia Gameiro, Karin M. Knudson, Massimo Fantini, Kwong Tsang, James Hodge, Renee Donahue, Jeffrey Schlom, Elizabeth Evans, Holm Bussler, Crystal Mallow, Christine Reilly, Sebold Torno, Maria Scrivens, Cathie Foster, Alan Howell, Leslie Balch, Alyssa Knapp, John E. Leonard, Mark Paris, Terry Fisher, Siwen Hu-Lieskovan, Ernest Smith, Maurice Zauderer, William Fogler, Marilyn Franklin, Matt Thayer, Dan Saims, John L. Magnani, Jian Gong, Michael Gray, George Fromm, Suresh de Silva, Louise Giffin, Xin Xu, Jason Rose, Taylor H. Schreiber, Sofia R. Gameiro, Paul E. Clavijo, Clint T. Allen, James W. Hodge, Kwong Y. Tsang, Jane Grogan, Nicholas Manieri, Eugene Chiang, Patrick Caplazi, Mahesh Yadav, Patrick Hagner, Hsiling Chiu, Michelle Waldman, Anke Klippel, Anjan Thakurta, Michael Pourdehnad, Anita Gandhi, Ian Henrich, Laura Quick, Rob Young, Margaret Chou, Andrew Hotson, Stephen Willingham, Po Ho, Carmen Choy, Ginna Laport, Ian McCaffery, Richard Miller, Kimberly A. Tipton, Kenneth R. Wong, Victoria Singson, Chihunt Wong, Chanty Chan, Yuanhiu Huang, Shouchun Liu, Jennifer H. Richardson, W. Michael Kavanaugh, James West, Bryan A. Irving, Ritika Jaini, Matthew Loya, Charis Eng, Melissa L. Johnson, Alex A. Adjei, Mateusz Opyrchal, Suresh Ramalingam, Pasi A. Janne, George Dominguez, Dmitry Gabrilovich, Laura de Leon, Jeannette Hasapidis, Scott J. Diede, Peter Ordentlich, Scott Cruickshank, Michael L. Meyers, Matthew D. Hellmann, Pawel Kalinski, Amer Zureikat, Robert Edwards, Ravi Muthuswamy, Nataša Obermajer, Julie Urban, Lisa H. Butterfield, William Gooding, Herbert Zeh, David Bartlett, Olga Zubkova, Larissa Agapova, Marina Kapralova, Liudmila Krasovskaia, Armen Ovsepyan, Maxim Lykov, Artem Eremeev, Vladimir Bokovanov, Olga Grigoryeva, Andrey Karpov, Sergey Ruchko, Alexandr Shuster, Danny N. Khalil, Luis Felipe Campesato, Yanyun Li, Adam S. Lazorchak, Troy D. Patterson, Yueyun Ding, Pottayil Sasikumar, Naremaddepalli Sudarshan, Nagaraj Gowda, Raghuveer Ramachandra, Dodheri Samiulla, Sanjeev Giri, Rajesh Eswarappa, Murali Ramachandra, David Tuck, Timothy Wyant, Jasmin Leshem, Xiu-fen Liu, Tapan Bera, Masaki Terabe, Birgit Bossenmaier, Gerhard Niederfellner, Yoram Reiter, Ira Pastan, Leiming Xia, Yang Xia, Yangyang Hu, Yi Wang, Yangyi Bao, Fu Dai, Shiang Huang, Elaine Hurt, Robert E. Hollingsworth, Lawrence G. Lum, Alfred E. Chang, Max S. Wicha, Qiao Li, Thomas Mace, Neil Makhijani, Erin Talbert, Gregory Young, Denis Guttridge, Darwin Conwell, Gregory B. Lesinski, Rodney JM Macedo Gonzales, Austin P. Huffman, Ximi K. Wang, Ran Reshef, Andy MacKinnon, Jason Chen, Matt Gross, Gisele Marguier, Peter Shwonek, Natalija Sotirovska, Susanne Steggerda, Francesco Parlati, Amani Makkouk, Mark K. Bennett, Ethan Emberley, Tony Huang, Weiqun Li, Silinda Neou, Alison Pan, Jing Zhang, Winter Zhang, Netonia Marshall, Thomas U. Marron, Judith Agudo, Brian Brown, Joshua Brody, Christopher McQuinn, Matthew Farren, Hannah Komar, Reena Shakya, Thomas Ludwug, Y. Maurice Morillon, Scott A. Hammond, John W. Greiner, Pulak R. Nath, Anthony L. Schwartz, Dragan Maric, David D. Roberts, Aung Naing, Kyriakos P. Papadopoulos, Karen A. Autio, Deborah J. Wong, Manish Patel, Gerald Falchook, Shubham Pant, Patrick A. Ott, Melinda Whiteside, Amita Patnaik, John Mumm, Filip Janku, Ivan Chan, Todd Bauer, Rivka Colen, Peter VanVlasselaer, Gail L. Brown, Nizar M. Tannir, Martin Oft, Jeffrey Infante, Evan Lipson, Ajay Gopal, Sattva S. Neelapu, Philippe Armand, Stephen Spurgeon, John P. Leonard, Rachel E. Sanborn, Ignacio Melero, Thomas F. Gajewski, Matthew Maurer, Serena Perna, Andres A. Gutierrez, Raphael Clynes, Priyam Mitra, Satyendra Suryawanshi, Douglas Gladstone, Margaret K. Callahan, James Crooks, Sheila Brown, Audrey Gauthier, Marc Hillairet de Boisferon, Andrew MacDonald, Laura Rosa Brunet, William T. Rothwell, Peter Bell, James M. Wilson, Fumi Sato-Kaneko, Shiyin Yao, Shannon S. Zhang, Dennis A. Carson, Cristina Guiducci, Robert L. Coffman, Kazutaka Kitaura, Takaji Matsutani, Ryuji Suzuki, Tomoko Hayashi, Ezra E. W. Cohen, David Schaer, Yanxia Li, Julie Dobkin, Michael Amatulli, Gerald Hall, Thompson Doman, Jason Manro, Frank Charles Dorsey, Lillian Sams, Rikke Holmgaard, Krishnadatt Persaud, Dale Ludwig, David Surguladze, John S. Kauh, Ruslan Novosiadly, Michael Kalos, Kyla Driscoll, Hardev Pandha, Christy Ralph, Kevin Harrington, Brendan Curti, Wallace Akerley, Sumati Gupta, Alan Melcher, David Mansfield, David R. Kaufman, Emmett Schmidt, Mark Grose, Bronwyn Davies, Roberta Karpathy, Darren Shafren, Katerina Shamalov, Cyrille Cohen, Naveen Sharma, James Allison, Tala Shekarian, Sandrine Valsesia-Wittmann, Christophe Caux, Aurelien Marabelle, Brian M. Slomovitz, Kathleen M. Moore, Hagop Youssoufian, Marshall Posner, Poonam Tewary, Alan D. Brooks, Ya-Ming Xu, Kithsiri Wijeratne, Leslie A. A. Gunatilaka, Thomas J. Sayers, John P. Vasilakos, Tesha Alston, Simon Dovedi, James Elvecrog, Iwen Grigsby, Ronald Herbst, Karen Johnson, Craig Moeckly, Stefanie Mullins, Kristen Siebenaler, Julius SternJohn, Ashenafi Tilahun, Mark A. Tomai, Katharina Vogel, Eveline E. 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Leong, Leonard Sung, Ken Metchette, Shailaja Kasibhatla, Anne Marie Pferdekamper, Lianxing Zheng, Charles Cho, Yan Feng, Jeffery M. McKenna, John Tallarico, Steven Bender, Chudi Ndubaku, Sarah M. McWhirter, Elena Gonzalez Gugel, Charles J. M. Bell, Adiel Munk, Luciana Muniz, Nina Bhardwaj, Fei Zhao, Kathy Evans, Christine Xiao, Alisha Holtzhausen, Brent A. Hanks, Nathalie Scholler, Catherine Yin, Pien Van der Meijs, Andrew M. Prantner, Cecile M. Krejsa, Leia Smith, Brian Johnson, Daniel Branstetter, Paul L. Stein, Juan C. Jaen, Joanne BL Tan, Ada Chen, Timothy Park, Jay P. Powers, Holly Sexton, Guifen Xu, Steve W. Young, Ulrike Schindler, Wentao Deng, David John Klinke, Hannah M. Komar, Gregory Serpa, Omar Elnaggar, Philip Hart, Carl Schmidt, Mary Dillhoff, Ming Jin, Michael C. Ostrowski, Madhuri Koti, Katrina Au, Nichole Peterson, Peter Truesdell, Gillian Reid-Schachter, Charles Graham, Andrew Craig, Julie-Ann Francis, Beatrix Kotlan, Timea Balatoni, Emil Farkas, Laszlo Toth, Mihaly Ujhelyi, Akos Savolt, Zoltan Doleschall, Szabolcs Horvath, Klara Eles, Judit Olasz, Orsolya Csuka, Miklos Kasler, Gabriella Liszkay, Eytan Barnea, Collin Blakely, Patrick Flynn, Reid Goodman, Raphael Bueno, David Sugarbaker, David Jablons, V. Courtney Broaddus, Brian West, Paul R. Kunk, Joseph M. Obeid, Kevin Winters, Patcharin Pramoonjago, Edward B. Stelow, Todd W. Bauer, Osama E. Rahma, Adam Lamble, Yoko Kosaka, Fei Huang, Kate A. Saser, Homer Adams, Christina E. Tognon, Ted Laderas, Shannon McWeeney, Marc Loriaux, Jeffery W. Tyner, Brian J. Druker, Evan F. Lind, Zhuqing Liu, Shanhong Lu, Lawrence P. Kane, Gulidanna Shayan, Julia Femel, Ryan Lane, Jamie Booth, Amanda W. Lund, Anthony Rodriguez, Victor H. Engelhard, Alessandra Metelli, Bill X. Wu, Caroline W. Fugle, Rachidi Saleh, Shaoli Sun, Jennifer Wu, Bei Liu, Zihai Li, Zachary S. Morris, Emily I. Guy, Clinton Heinze, Jasdeep Kler, Monica M. Gressett, Lauryn R. Werner, Stephen D. Gillies, Alan J. Korman, Hans Loibner, Jacquelyn A. Hank, Alexander L. Rakhmilevich, Paul M. Harari, Paul M. Sondel, Erica Huelsmann, Joseph Broucek, Dorothee Brech, Tobias Straub, Martin Irmler, Johannes Beckers, Florian Buettner, Elke Schaeffeler, Matthias Schwab, Elfriede Noessner, Alison Wolfreys, Andre Da Costa, John Silva, Andrea Crosby, Ludovicus Staelens, Graham Craggs, Annick Cauvin, Sean Mason, Alison M. Paterson, Andrew C. Lake, Caroline M. Armet, Rachel W. O’Connor, Jonathan A. Hill, Emmanuel Normant, Ammar Adam, Detlev M. Biniszkiewicz, Scott C. Chappel, Vito J. Palombella, Pamela M. Holland, Annette Becker, Manmohan R. Leleti, Eric Newcomb, Joanne B. L. Tan, Suthee Rapisuwon, Arash Radfar, Kellie Gardner, Geoffrey Gibney, Michael Atkins, Keith R. Rennier, Robert Crowder, Ping Wang, Russell K. Pachynski, Rosa M. Santana Carrero, Sarai Rivas, Figen Beceren-Braun, Scott Anthony, Kimberly S. Schluns, Deepali Sawant, Maria Chikina, Hiroshi Yano, Creg Workman, Elise Salerno, Ileana Mauldin, Donna Deacon, Sofia Shea, Joel Pinczewski, Thomas Gajewski, Stefani Spranger, Brendan Horton, Akiko Suzuki, Pamela Leland, Bharat H. Joshi, Raj K. Puri, Randy F. Sweis, Riyue Bao, Jason Luke, Marie-Nicole Theodoraki, Frances-Mary Mogundo, Haejung Won, Dayson Moreira, Chan Gao, Xingli Zhao, Priyanka Duttagupta, Jeremy Jones, Massimo D’Apuzzo, and Sumanta Pal

Subjects
0301 basic medicine, Pharmacology, Cancer Research, medicine.medical_specialty, business.industry, medicine.medical_treatment, Immunology, Cancer, Immunotherapy, medicine.disease, 3. Good health, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, Family medicine, Molecular Medicine, Immunology and Allergy, Medicine, business
Abstract

O1 IL-15 primes an mTOR-regulated gene-expression program to prolong anti-tumor capacity of human natural killer cells #### Andreas Lundqvist1, Vincent van Hoef1, Xiaonan Zhang1, Erik Wennerberg2, Julie Lorent1, Kristina Witt1, Laia Masvidal Sanz1, Shuo Liang1, Shannon Murray3, Ola Larsson1

Published
2016
Full Text
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12. 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part one

Author

Andreas Lundqvist, Vincent van Hoef, Xiaonan Zhang, Erik Wennerberg, Julie Lorent, Kristina Witt, Laia Masvidal Sanz, Shuo Liang, Shannon Murray, Ola Larsson, Rolf Kiessling, Yumeng Mao, John-William Sidhom, Catherine A. Bessell, Jonathan Havel, Jonathan Schneck, Timothy A. Chan, Eliot Sachsenmeier, David Woods, Anders Berglund, Rupal Ramakrishnan, Andressa Sodre, Jeffrey Weber, Roberta Zappasodi, Yanyun Li, Jingjing Qi, Philip Wong, Cynthia Sirard, Michael Postow, Walter Newman, Henry Koon, Vamsidhar Velcheti, Margaret K. Callahan, Jedd D. Wolchok, Taha Merghoub, Lawrence G. Lum, Minsig Choi, Archana Thakur, Abhinav Deol, Gregory Dyson, Anthony Shields, Cara Haymaker, Marc Uemura, Ravi Murthy, Marihella James, Daqing Wang, Julie Brevard, Catherine Monaghan, Suzanne Swann, James Geib, Mark Cornfeld, Srinivas Chunduru, Sudhir Agrawal, Cassian Yee, Jennifer Wargo, Sapna P. Patel, Rodabe Amaria, Hussein Tawbi, Isabella Glitza, Scott Woodman, Wen-Jen Hwu, Michael A. Davies, Patrick Hwu, Willem W. Overwijk, Chantale Bernatchez, Adi Diab, Erminia Massarelli, Neil H. Segal, Vincent Ribrag, Ignacio Melero, Tara C. Gangadhar, Walter Urba, Dirk Schadendorf, Robert L. Ferris, Roch Houot, Franck Morschhauser, Theodore Logan, Jason J. Luke, William Sharfman, Fabrice Barlesi, Patrick A. Ott, Laura Mansi, Shivaani Kummar, Gilles Salles, Cecilia Carpio, Roland Meier, Suba Krishnan, Dan McDonald, Matthew Maurer, Xuemin Gu, Jaclyn Neely, Satyendra Suryawanshi, Ronald Levy, Nikhil Khushalani, Jennifer Wu, Jinyu Zhang, Fahmin Basher, Mark Rubinstein, Mark Bucsek, Guanxi Qiao, Cameron MacDonald, Bonnie Hylander, Elizabeth Repasky, Shilpak Chatterjee, Anusara Daenthanasanmak, Paramita Chakraborty, Kyle Toth, Megan Meek, Elizabeth Garrett-Mayer, Michael Nishimura, Chrystal Paulos, Craig Beeson, Xuezhong Yu, Shikhar Mehrotra, Fei Zhao, Kathy Evans, Christine Xiao, Alisha Holtzhausen, Brent A. Hanks, Nicole Scharping, Ashley V. Menk, Rebecca Moreci, Ryan Whetstone, Rebekah Dadey, Simon Watkins, Robert Ferris, Greg M. Delgoffe, Jonathan Peled, Sean Devlin, Anna Staffas, Melissa Lumish, Kori Porosnicu Rodriguez, Katya Ahr, Miguel Perales, Sergio Giralt, Ying Taur, Eric Pamer, Marcel R. M. van den Brink, Robert Jenq, Nicola Annels, Hardev Pandha, Guy Simpson, Hugh Mostafid, Kevin Harrington, Alan Melcher, Mark Grose, Bronwyn Davies, Gough Au, Roberta Karpathy, Darren Shafren, Jacob Ricca, Dmitriy Zamarin, Luciana Batista, Florence Marliot, Angela Vasaturo, Sabrina Carpentier, Cécile Poggionovo, Véronique Frayssinet, Jacques Fieschi, Marc Van den Eynde, Franck Pagès, Jérôme Galon, Fabienne Hermitte, Sean G. Smith, Khue Nguyen, Sruthi Ravindranathan, Bhanu Koppolu, David Zaharoff, Gustavo Schvartsman, Roland Bassett, Jennifer L. McQuade, Lauren E. Haydu, Douglas Kline, Xiufen Chen, Dominick Fosco, Justin Kline, Abigail Overacre, Maria Chikina, Erin Brunazzi, Gulidanna Shayan, William Horne, Jay Kolls, Tullia C. Bruno, Creg Workman, Dario Vignali, Prasad S. Adusumilli, Ephraim A Ansa-Addo, Zihai Li, Andrew Gerry, Joseph P. Sanderson, Karen Howe, Roslin Docta, Qian Gao, Eleanor A. L. Bagg, Nicholas Tribble, Miguel Maroto, Gareth Betts, Natalie Bath, Luca Melchiori, Daniel E. Lowther, Indu Ramachandran, Gabor Kari, Samik Basu, Gwendolyn Binder-Scholl, Karen Chagin, Lini Pandite, Tom Holdich, Rafael Amado, Hua Zhang, John Glod, Donna Bernstein, Bent Jakobsen, Crystal Mackall, Ryan Wong, Jonathan D. Silk, Katherine Adams, Garth Hamilton, Alan D. Bennett, Sara Brett, Junping Jing, Adriano Quattrini, Manoj Saini, Guy Wiedermann, Joanna Brewer, MyLinh Duong, An Lu, Peter Chang, Aruna Mahendravada, Nicholas Shinners, Kevin Slawin, David M. Spencer, Aaron E. Foster, J. Henri Bayle, Cristina Bergamaschi, Sinnie Sin Man Ng, Bethany Nagy, Shawn Jensen, Xintao Hu, Candido Alicea, Bernard Fox, Barbara Felber, George Pavlakis, Jessica Chacon, Tori Yamamoto, Thomas Garrabrant, Luis Cortina, Daniel J. Powell, Marco Donia, Julie Westerlin Kjeldsen, Rikke Andersen, Marie Christine Wulff Westergaard, Valentina Bianchi, Mateusz Legut, Meriem Attaf, Garry Dolton, Barbara Szomolay, Sascha Ott, Rikke Lyngaa, Sine Reker Hadrup, Andrew Kelvin Sewell, Inge Marie Svane, Aaron Fan, Takumi Kumai, Esteban Celis, Ian Frank, Amanda Stramer, Michelle A. Blaskovich, Seth Wardell, Maria Fardis, James Bender, Michael T. Lotze, Stephanie L. Goff, Nikolaos Zacharakis, Yasmine Assadipour, Todd D. Prickett, Jared J. Gartner, Robert Somerville, Mary Black, Hui Xu, Harshini Chinnasamy, Isaac Kriley, Lily Lu, John Wunderlich, Paul F. Robbins, Steven Rosenberg, Steven A. Feldman, Kasia Trebska-McGowan, Parisa Malekzadeh, Eden Payabyab, Richard Sherry, Aishwarya Gokuldass, Charlene Kopits, Brian Rabinovich, Daniel S. Green, Olena Kamenyeva, Kathryn C. Zoon, Christina M. Annunziata, Joanne Hammill, Christopher Helsen, Craig Aarts, Jonathan Bramson, Yui Harada, Yoshikazu Yonemitsu, Kenneth Mwawasi, Galina Denisova, Rajanish Giri, Benjamin Jin, Tracy Campbell, Lindsey M. Draper, Sanja Stevanovic, Zhiya Yu, Bianca Weissbrich, Nicholas P. Restifo, Cornelia L. Trimble, Christian S. Hinrichs, Kwong Tsang, Massimo Fantini, James W. Hodge, Rika Fujii, Ingrid Fernando, Caroline Jochems, Christopher Heery, James Gulley, Patrick Soon-Shiong, Jeffrey Schlom, Weiqing Jing, Jill Gershan, Grace Blitzer, James Weber, Laura McOlash, Bryon D. Johnson, Simin Kiany, Huang Gangxiong, Eugenie S. Kleinerman, Michael Klichinsky, Marco Ruella, Olga Shestova, Saad Kenderian, Miriam Kim, John Scholler, Carl H. June, Saar Gill, Duane Moogk, Shi Zhong, Ivan Liadi, William Rittase, Victoria Fang, Janna Dougherty, Arianne Perez-Garcia, Iman Osman, Cheng Zhu, Navin Varadarajan, Alan Frey, Michelle Krogsgaard, Daniel Landi, Kristen Fousek, Malini Mukherjee, Ankita Shree, Sujith Joseph, Kevin Bielamowicz, Tiara Byrd, Nabil Ahmed, Meenakshi Hegde, Sylvia Lee, David Byrd, John Thompson, Shailender Bhatia, Scott Tykodi, Judy Delismon, Liz Chu, Siddiq Abdul-Alim, Arpy Ohanian, Anna Marie DeVito, Stanley Riddell, Kim Margolin, Isabelle Magalhaes, Jonas Mattsson, Michael Uhlin, Satoshi Nemoto, Patricio Pérez Villarroel, Ryosuke Nakagawa, James J. Mule, Adam W. Mailloux, Melinda Mata, Phuong Nguyen, Claudia Gerken, Christopher DeRenzo, Stephen Gottschalk, Mélissa Mathieu, Sandy Pelletier, John Stagg, Simon Turcotte, Nicholas Minutolo, Prannda Sharma, Andrew Tsourkas, Nadine Mockel-Tenbrinck, Daniela Mauer, Katharina Drechsel, Carola Barth, Katharina Freese, Ulrike Kolrep, Silke Schult, Mario Assenmacher, Andrew Kaiser, John Mullinax, MacLean Hall, Julie Le, Krithika Kodumudi, Erica Royster, Allison Richards, Ricardo Gonzalez, Amod Sarnaik, Shari Pilon-Thomas, Morten Nielsen, Anders Krarup-Hansen, Dorrit Hovgaard, Michael Mørk Petersen, Anand Chainsukh Loya, Niels Junker, Charlotte Rivas, Robin Parihar, Cliona M. Rooney, Haiying Qin, Sang Nguyen, Paul Su, Chad Burk, Brynn Duncan, Bong-Hyun Kim, M. Eric Kohler, Terry Fry, Arjun A. Rao, Noam Teyssier, Jacob Pfeil, Nikolaos Sgourakis, Sofie Salama, David Haussler, Sarah A. 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Landis, Sally Koegler, Brooke Hirsch, Roberto Gianani, Jeffrey Kim, Ming-Xiao He, Bingqing Zhang, Nan Su, Yuling Luo, Xiao-Jun Ma, Emily Park, Dae Won Kim, Domenico Copploa, Nishi Kothari, Young doo Chang, Richard Kim, Namyong Kim, Melvin Lye, Ee Wan, Hanna A. Knaus, Sofia Berglund, Hubert Hackl, Judith E. Karp, Ivana Gojo, Leo Luznik, Henoch S. Hong, Sven D. Koch, Birgit Scheel, Ulrike Gnad-Vogt, Karl-Josef Kallen, Volker Wiegand, Linus Backert, Oliver Kohlbacher, Ingmar Hoerr, Mariola Fotin-Mleczek, James M. Billingsley, Yoshinobu Koguchi, Valerie Conrad, William Miller, Iliana Gonzalez, Tomasz Poplonski, Tanisha Meeuwsen, Ana Howells-Ferreira, Rogan Rattray, Mary Campbell, Carlo Bifulco, Keith Bahjat, Brendan Curti, E-K Vetsika, G. Kallergi, Despoina Aggouraki, Z. Lyristi, P. Katsarlinos, Filippos Koinis, V. Georgoulias, Athanasios Kotsakis, Nathan T. Martin, Famke Aeffner, Logan Cerkovnik, Luke Pratte, Rebecca Kim, Joseph Krueger, Amaia Martínez-Usatorre, Camilla Jandus, Alena Donda, Laura Carretero-Iglesia, Daniel E. Speiser, Dietmar Zehn, Nathalie Rufer, Pedro Romero, Anshuman Panda, Janice Mehnert, Kim M. Hirshfield, Greg Riedlinger, Sherri Damare, Tracie Saunders, Levi Sokol, Mark Stein, Elizabeth Poplin, Lorna Rodriguez-Rodriguez, Ann Silk, Nancy Chan, Melissa Frankel, Michael Kane, Jyoti Malhotra, Joseph Aisner, Howard L. Kaufman, Siraj Ali, Jeffrey Ross, Eileen White, Gyan Bhanot, Shridar Ganesan, Anne Monette, Derek Bergeron, Amira Ben Amor, Liliane Meunier, Christine Caron, Antigoni Morou, Daniel Kaufmann, Moishe Liberman, Igor Jurisica, Anne-Marie Mes-Masson, Kamel Hamzaoui, Rejean Lapointe, Ann Mongan, Yuan-Chieh Ku, Warren Tom, Yongming Sun, Alex Pankov, Tim Looney, Janice Au-Young, Fiona Hyland, Jeff Conroy, Carl Morrison, Sean Glenn, Blake Burgher, He Ji, Mark Gardner, Angela R. Omilian, Wiam Bshara, Omilian Angela, Joseph M. Obeid, Gulsun Erdag, Mark E. Smolkin, Donna H. Deacon, James W. Patterson, Lieping Chen, Timothy N. Bullock, Craig L. Slingluff, John T. Loffredo, Raja Vuyyuru, Sophie Beyer, Vanessa M. Spires, Maxine Fox, Jon M. Ehrmann, Katrina A. Taylor, Alan J. Korman, Robert F. Graziano, David Page, Katherine Sanchez, Maritza Martel, Mariana Petaccia De Macedo, Yong Qin, Alex Reuben, Christine Spencer, Michele Guindani, Adriana Racolta, Brian Kelly, Tobin Jones, Nathan Polaske, Noah Theiss, Mark Robida, Jeffrey Meridew, Iva Habensus, Liping Zhang, Lidija Pestic-Dragovich, Lei Tang, Ryan J. Sullivan, Thomas Olencki, Thomas Hutson, Joanna Roder, Shauna Blackmon, Heinrich Roder, John Stewart, Asim Amin, Marc S. Ernstoff, Joseph I. Clark, Michael B. Atkins, Jeffrey Sosman, David F. McDermott, Harriet Kluger, Ruth Halaban, Mario Snzol, Senait Asmellash, Arni Steingrimsson, Chichung Wang, Kristin Roman, Amanda Clement, Sean Downing, Clifford Hoyt, Nathalie Harder, Guenter Schmidt, Ralf Schoenmeyer, Nicolas Brieu, Mehmet Yigitsoy, Gabriele Madonna, Gerardo Botti, Antonio Grimaldi, Paolo A. Ascierto, Ralf Huss, Maria Athelogou, Harald Hessel, Alexander Buchner, Christian Stief, Gerd Binnig, Thomas Kirchner, Shankar Sellappan, Sheeno Thyparambil, Sarit Schwartz, Fabiola Cecchi, Andrew Nguyen, Charles Vaske, Todd Hembrough, Jan Spacek, Michal Vocka, Eva Zavadova, Helena Skalova, Pavel Dundr, Lubos Petruzelka, Nicole Francis, Rau T. Tilman, Arndt Hartmann, Irena Netikova, Julia Stump, Amanda Tufman, Frank Berger, Michael Neuberger, Rudolf Hatz, Michael Lindner, Rachel E. Sanborn, John Handy, Rudolf M. Huber, Hauke Winter, Simone Reu, Cheng Sun, Weihua Xiao, Zhigang Tian, Kshitij Arora, Niyati Desai, Anupriya Kulkarni, Mihir Rajurkar, Miguel Rivera, Vikram Deshpande, David Ting, Katy Tsai, Adi Nosrati, Simone Goldinger, Omid Hamid, Alain Algazi, Paul Tumeh, Jimmy Hwang, Jacqueline Liu, Lawrence Chen, Reinhard Dummer, Michael Rosenblum, Adil Daud, Tsu-Shuen Tsao, Julia Ashworth-Sharpe, Donald Johnson, Srabani Bhaumik, Christopher Bieniarz, Joseph Couto, Michael Farrell, Mahsa Ghaffari, Antony Hubbard, Jerome Kosmeder, Cleo Lee, Erin Marner, Diana Uribe, Hongjun Zhang, Jian Zhang, Wenjun Zhang, Yifei Zhu, Larry Morrison, Takahiro Tsujikawa, Rohan N. Borkar, Vahid Azimi, Sushil Kumar, Guillaume Thibault, Motomi Mori, Edward El Rassi, Daniel R. Clayburgh, Molly F. Kulesz-Martin, Paul W. Flint, Lisa M. Coussens, Lisa Villabona, Giuseppe V. Masucci, Gary Geiss, Brian Birditt, Qian Mei, Alan Huang, Maribeth A. Eagan, Eduardo Ignacio, Nathan Elliott, Dwayne Dunaway, Jaemyeong Jung, Chris Merritt, Isaac Sprague, Philippa Webster, Yan Liang, Jessica Wenthe, Gunilla Enblad, Hannah Karlsson, Magnus Essand, Barbara Savoldo, Gianpietro Dotti, Martin Höglund, Malcolm K. Brenner, Hans Hagberg, Angelica Loskog, Matthew J. Bernett, Gregory L. Moore, Michael Hedvat, Christine Bonzon, Seung Chu, Rumana Rashid, Kendra N. Avery, Umesh Muchhal, John Desjarlais, Matthew Kraman, Katarzyna Kmiecik, Natalie Allen, Mustapha Faroudi, Carlo Zimarino, Mateusz Wydro, Jacqueline Doody, Sreesha P. Srinivasa, Nagaraja Govindappa, Praveen Reddy, Aparajita Dubey, Sankar Periyasamy, Madhukara Adekandi, Chaitali Dey, Mary Joy, Pieter Fokko van Loo, Henrike Veninga, Setareh Shamsili, Mark Throsby, Harry Dolstra, Lex Bakker, Ajjai Alva, Juergen Gschwendt, Yohann Loriot, Joaquim Bellmunt, Dai Feng, Christian Poehlein, Thomas Powles, Emmanuel S. Antonarakis, Charles G. Drake, Haiyan Wu, Johann De Bono, Rajat Bannerji, John Byrd, Gareth Gregory, Stephen Opat, Jake Shortt, Andrew J. Yee, Noopur Raje, Seth Thompson, Arun Balakumaran, Shaji Kumar, Brian I. Rini, Toni K. Choueiri, Mariangela Mariani, Laurence Albiges, John B. Haanen, James Larkin, Manuela Schmidinger, Domenico Magazzù, Alessandra di Pietro, Robert J. Motzer, Troels Holz Borch, Per Kongsted, Magnus Pedersen, Özcan Met, Karim Boudadi, Hao Wang, James Vasselli, Jan E. Baughman, Jon Wigginton, Rehab Abdallah, Ashley Ross, Jiwon Park, Steven Grossenbacher, Jesus I. Luna, Sita Withers, William Culp, Mingyi Chen, Arta Monjazeb, Michael S. Kent, Smita Chandran, David Danforth, James Yang, Christopher Klebanoff, Stephanie Goff, Biman Paria, Arvind Sabesan, Abhishek Srivastava, Udai Kammula, Jon Richards, Mark Faries, Robert H. I. Andtbacka, Luis A. Diaz, Dung T. Le, Takayuki Yoshino, Thierry André, Johanna Bendell, Minori Koshiji, Yayan Zhang, S Peter Kang, Bao Lam, Dirk Jäger, Todd M. Bauer, Judy S. Wang, Jean K. Lee, Gulam A. Manji, Ragini Kudchadkar, John S. Kauh, Shande Tang, Naomi Laing, Gerald Falchook, Edward B. Garon, Balazs Halmos, Hui Rina, Natasha Leighl, Sung Sook Lee, William Walsh, Konstanin Dragnev, Bilal Piperdi, Luis Paz-Ares Rodriguez, Nabeegha Shinwari, Ziewn Wei, Mary L Maas, Michael Deeds, Adam Armstrong, Tim Peterson, Sue Steinmetz, Thomas Herzog, Floor J. Backes, Larry Copeland, Maria Del Pilar Estevez Diz, Thomas W. Hare, Warner Huh, Byoung-Gie Kim, Kathleen M. Moore, Ana Oaknin, William Small, Krishnansu S. Tewari, Bradley J. Monk, Ashish M. Kamat, Kijoeng Nam, Maria De Santis, Robert Dreicer, Noah M. Hahn, Rodolfo Perini, Arlene Siefker-Radtke, Guru Sonpavde, Ronald de Wit, J. Alfred Witjes, Stephen Keefe, Dean Bajorin, Philippe Armand, John Kuruvilla, Craig Moskowitz, Mehdi Hamadani, Pier Luigi Zinzani, Sabine Chlosta, Nancy Bartlett, Rachel Sabado, Yvonne Saenger, Loging William, Michael Joseph Donovan, Erlinda Sacris, John Mandeli, Andres M. Salazar, John Powderly, Joshua Brody, John Nemunaitis, Leisha Emens, Amita Patnaik, Ian McCaffery, Richard Miller, Ginna Laport, Andrew L. Coveler, David C. Smith, Juneko E. Grilley-Olson, Sanjay Goel, Shyra J. Gardai, Che-Leung Law, Gary Means, Thomas Manley, Kristen A. Marrone, Gary Rosner, Valsamo Anagnostou, Joanne Riemer, Jessica Wakefield, Cynthia Zanhow, Stephen Baylin, Barbara Gitlitz, Julie Brahmer, Sabina Signoretti, Wenting Li, Charles Schloss, Jean-Marie Michot, Wei Ding, Beth Christian, Patricia Marinello, Margaret Shipp, Yana G. Najjar, null Lin, Lisa H. Butterfield, Ahmad A. Tarhini, Diwakar Davar, Hassane Zarour, Elizabeth Rush, Cindy Sander, Siqing Fu, Todd Bauer, Chris Molineaux, Mark K. Bennett, Keith W. Orford, Kyriakos P. Papadopoulos, Sukhmani K. Padda, Sumit A. Shah, A Dimitrios Colevas, Sujata Narayanan, George A. Fisher, Dana Supan, Heather A. Wakelee, Rhonda Aoki, Mark D. Pegram, Victor M. Villalobos, Jie Liu, Chris H. Takimoto, Mark Chao, Jens-Peter Volkmer, Ravindra Majeti, Irving L. Weissman, Branimir I. Sikic, Wendy Yu, Alison Conlin, Janet Ruzich, Stacy Lewis, Anupama Acheson, Kathleen Kemmer, Kelly Perlewitz, Nicole M. Moxon, Staci Mellinger, Heather McArthur, Trine Juhler-Nøttrup, Jayesh Desai, Ben Markman, Shahneen Sandhu, Hui Gan, Michael L. Friedlander, Ben Tran, Tarek Meniawy, Joanne Lundy, Duncan Colyer, Malaka Ameratunga, Christie Norris, Jason Yang, Kang Li, Lai Wang, Lusong Luo, Zhen Qin, Song Mu, Xuemei Tan, James Song, Michael Millward, Matthew H. G. Katz, Todd W. Bauer, Gauri R. Varadhachary, Nicolas Acquavella, Nipun Merchant, Gina Petroni, Osama E. Rahma, Mei Chen, Yang Song, Markus Puhlmann, Arun Khattri, Ryan Brisson, Christopher Harvey, Jatin Shah, Maria Victoria Mateos, Morio Matsumoto, Hilary Blacklock, Albert Oriol Rocafiguera, Hartmut Goldschmidt, Shinsuke Iida, Dina Ben Yehuda, Enrique Ocio, Paula Rodríguez-Otero, Sundar Jagannath, Sagar Lonial, Uma Kher, Jesus San-Miguel, Moacyr Ribeiro de Oliveira, Habte Yimer, Robert Rifkin, Fredrik Schjesvold, Razi Ghori, Anna Spreafico, Victor Lee, Roger K. C. Ngan, Ka Fai To, Myung Ju Ahn, Quan Sing Ng, Jin-Ching Lin, Ramona F. Swaby, Christine Gause, Sanatan Saraf, Anthony T. C. Chan, Elaine Lam, Nizar M. Tannir, Funda Meric-Bernstam, Matt Gross, Andy MacKinnon, Sam Whiting, Martin Voss, Evan Y. Yu, Mark R. Albertini, Erik A. Ranheim, Jacquelyn A. Hank, Cindy Zuleger, Thomas McFarland, Jennifer Collins, Erin Clements, Sharon Weber, Tracey Weigel, Heather Neuman, Greg Hartig, David Mahvi, MaryBeth Henry, Jacek Gan, Richard Yang, Lakeesha Carmichael, KyungMann Kim, Stephen D. Gillies, Paul M. Sondel, Vivek Subbiah, Lori Noffsinger, Kyle Hendricks, Marnix Bosch, Jay M. Lee, Mi-Heon Lee, Jonathan W. Goldman, Felicita E. Baratelli, Dorthe Schaue, Gerald Wang, Frances Rosen, Jane Yanagawa, Tonya C. Walser, Ying Q. Lin, Sharon Adams, Franco M. Marincola, Paul C. Tumeh, Fereidoun Abtin, Robert Suh, Karen Reckamp, William D. Wallace, Gang Zeng, David A. Elashoff, Sherven Sharma, Steven M. Dubinett, Anna C. Pavlick, Brian Gastman, Brent Hanks, Tibor Keler, Tom Davis, Laura A. Vitale, Elad Sharon, Chihiro Morishima, Martin Cheever, Christopher R. Heery, Joseph W. Kim, Elizabeth Lamping, Jennifer Marte, Sheri McMahon, Lisa Cordes, Farhad Fakhrejahani, Ravi Madan, Rachel Salazar, Maggie Zhang, Christoph Helwig, James L Gulley, Roger Li, John Amrhein, Zvi Cohen, Monique Champagne, Ashish Kamat, M. Angela Aznar, Sara Labiano, Angel Diaz-Lagares, Manel Esteller, Juan Sandoval, Susannah D. Barbee, David I. Bellovin, John C. Timmer, Nebiyu Wondyfraw, Susan Johnson, Johanna Park, Amanda Chen, Mikayel Mkrtichyan, Amir S. Razai, Kyle S. Jones, Chelsie Y. Hata, Denise Gonzalez, Quinn Deveraux, Brendan P. Eckelman, Luis Borges, Rukmini Bhardwaj, Raj K. Puri, Akiko Suzuki, Pamela Leland, Bharat H. Joshi, Todd Bartkowiak, Ashvin Jaiswal, Casey Ager, Midan Ai, Pratha Budhani, Renee Chin, David Hong, Michael Curran, William D. Hastings, Maria Pinzon-Ortiz, Masato Murakami, Jason R. Dobson, David Quinn, Joel P. Wagner, Xianhui Rong, Pamela Shaw, Ernesta Dammassa, Wei Guan, Glenn Dranoff, Alexander Cao, Ross B. Fulton, Steven Leonardo, Kathryn Fraser, Takashi O. Kangas, Nadine Ottoson, Nandita Bose, Richard D. Huhn, Jeremy Graff, Jamie Lowe, Keith Gorden, Mark Uhlik, Thomas O’Neill, Jenifer Widger, Andrea Crocker, Li-Zhen He, Jeffrey Weidlick, Karuna Sundarapandiyan, Venky Ramakrishna, James Storey, Lawrence J. Thomas, Joel Goldstein, Henry C. Marsh, Jamison Grailer, Julia Gilden, Pete Stecha, Denise Garvin, Jim Hartnett, Frank Fan, Mei Cong, Zhi-jie Jey Cheng, Marlon J. Hinner, Rachida-Siham Bel Aiba, Corinna Schlosser, Thomas Jaquin, Andrea Allersdorfer, Sven Berger, Alexander Wiedenmann, Gabriele Matschiner, Julia Schüler, Ulrich Moebius, Christine Rothe, Olwill A. Shane, Brendan Horton, Stefani Spranger, Dayson Moreira, Tomasz Adamus, Xingli Zhao, Piotr Swiderski, Sumanta Pal, Marcin Kortylewski, Alyssa Kosmides, Kevin Necochea, Kathleen M. Mahoney, Sachet A. Shukla, Nikolaos Patsoukis, Apoorvi Chaudhri, Hung Pham, Ping Hua, Xia Bu, Baogong Zhu, Nir Hacohen, Catherine J. Wu, Edward Fritsch, Vassiliki A. Boussiotis, Gordon J. Freeman, Amy E. Moran, Fanny Polesso, Lisa Lukaesko, Emelie Rådestad, Lars Egevad, Berit Sundberg, Lars Henningsohn, Victor Levitsky, William Rafelson, John L. Reagan, Loren Fast, Pottayil Sasikumar, Naremaddepalli Sudarshan, Raghuveer Ramachandra, Nagesh Gowda, Dodheri Samiulla, Talapaneni Chandrasekhar, Sreenivas Adurthi, Jiju Mani, Rashmi Nair, Amit Dhudashia, Nagaraj Gowda, Murali Ramachandra, Alexander Sankin, Benjamin Gartrell, Kerwin Cumberbatch, Hongying Huang, Joshua Stern, Mark Schoenberg, Xingxing Zang, Ryan Swanson, Michael Kornacker, Lawrence Evans, Erika Rickel, Martin Wolfson, Sandrine Valsesia-Wittmann, Tala Shekarian, François Simard, Rodrigo Nailo, Aurélie Dutour, Anne-Catherine Jallas, Christophe Caux, and Aurélien Marabelle

Subjects
Pharmacology, 0303 health sciences, Cancer Research, Side effect, business.industry, medicine.drug_class, Immunology, Phases of clinical research, Monoclonal antibody, Phase i study, Clinical trial, 03 medical and health sciences, 0302 clinical medicine, Oncology, Pharmacokinetics, 030220 oncology & carcinogenesis, Molecular Medicine, Immunology and Allergy, Medicine, In patient, Programmed death 1, business, 030304 developmental biology
Published
2016
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13. Phase Ib KEYNOTE-200: A study of an intravenously delivered oncolytic virus, coxsackievirus A21 in combination with pembrolizumab in advanced NSCLC and bladder cancer patients

Author

Hardev Pandha, Rachel E. Sanborn, M.R. Zibelman, R. Jennens, Charles M. Rudin, Timothy D. Clay, Gavin M. Wright, Christy Ralph, Steven J. O'Day, Emmett V. Schmidt, Sumati Gupta, Mark Grose, Brendan D. Curti, Wallace Akerley, Darren R. Shafren, David Campbell, Jonathan E. Rosenberg, A.G. Hill, David E. Gerber, and D. Day

Subjects
0301 basic medicine, Bladder cancer, business.industry, Coxsackievirus A21, Hematology, Pembrolizumab, medicine.disease, Oncolytic virus, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, Cancer research, medicine, business
Published
2018
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14. Abstract CT026: Phase 1b study of intratumoral Coxsackievirus A21 ( <u>C</u> V <u>A</u> 21) and systemic <u>p</u> emb <u>r</u> olizumab in <u>a</u> dvanced melanoma patients: Interim results of the CAPRA clinical trial

Author

Howard L. Kaufman, Daniel J. Medina, Jennifer L. Bryan, Janice M. Mehnert, Nashat Y. Gabrail, Mark Grose, Darren R. Shafren, Jacqueline Norrell, Andrew Zloza, Praveen K. Bommareddy, and Ann W. Silk

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Combination therapy, business.industry, Melanoma, Coxsackievirus A21, Pembrolizumab, medicine.disease, Surgery, Clinical trial, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Tolerability, 030220 oncology & carcinogenesis, Internal medicine, Clinical endpoint, Medicine, business, Adverse effect
Abstract

Background: Coxsackievirus A21 (CVA21) is a novel bio-selected oncolytic, immunotherapeutic agent. Intratumoral (i.t.) CVA21 injection can induce selective tumor-cell infection, immune-cell infiltration, IFN-γ response gene up-regulation, increased PD-L1 expression, tumor cell lysis and systemic anti-tumor immune responses. Preclinical studies in an immune-competent mouse model of melanoma have revealed that combinations of i.t. CVA21 and anti-PD-1 blockade mediate significantly greater antitumor activity compared to use of either agent alone. A clinical trial evaluating combination CVA21 and pembrolizumab in patients with melanoma was initiated and preliminary data on a pre-established futility endpoint are presented here. Materials and Methods: This is a single-arm, multi-institutional open-label phase Ib clinical trial of i.t. CVA21 and i.v. pembrolizumab for treated or untreated unresectable Stage IIIC-IVM1c melanoma. Subjects with injectable disease receive up to 3 x 108 TCID50 CVA21 i.t. on Days 1, 3, 5, 8, and then every 3 weeks for up to 19 injections. Subjects also receive pembrolizumab (2mg/kg) i.v. every 3 weeks starting on Day 8. The primary endpoint is safety/tolerability by incidence of dose-limiting toxicity. Secondary endpoints include best ORR by immune-related response criteria, progression-free survival, overall survival, quality of life, changes in melanoma-specific T cells, PD-L1 expression and Th1/Th2 gene expression profiles. The protocol included a futility analysis after the first 12 patients. Results: To date, 14 subjects have started on protocol therapy. Overall, the adverse events have been low-grade constitutional symptoms related to CVA21 and expected pembrolizumab-related side effects. No DLT’s have been reported. Currently, 11 patients are evaluable for investigator response assessment, not including 2 subjects who have not yet reached their first assessment and 1 subject who left the study early due to an unrelated adverse event. Among the evaluable subjects, the ORR was 73% (8/11). The DCR (CR+PR+SD) is currently 91% (10/11). In subjects with stage IVM1c disease, the ORR and the DCR is 100% (5/5). The study has met its primary statistical futility endpoint of achieving ≥2 confirmed objective responses (CR or PR) in the first 12 patients enrolled. Currently, the median time to response is 1.6 months. One of the 8 responders displayed early pseudo-progression and later developed a partial response. Conclusions: At a pre-specified futility analysis, combination CVA21 and pembrolizumab appears to be well-tolerated. Early tumor monitoring has identified encouraging reductions in a number of injected and non-injected lesions. Based on these initial results, the sample size has now been expanded to enroll up to 50 patients. Combination therapy of CVA21 and pembrolizumab may represent a new approach for the treatment of patients with injectable advanced melanoma. Citation Format: Ann W. Silk, Howard Kaufman, Nashat Gabrail, Janice Mehnert, Jennifer Bryan, Jacqueline Norrell, Daniel Medina, Praveen Bommareddy, Darren Shafren, Mark Grose, Andrew Zloza. Phase 1b study of intratumoral Coxsackievirus A21 (CVA21) and systemic pembrolizumab in advanced melanoma patients: Interim results of the CAPRA clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT026. doi:10.1158/1538-7445.AM2017-CT026

Published
2017
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15. Abstract CT114: The MITCI (Phase 1b) study: A novel immunotherapy combination of intralesional Coxsackievirus A21 and systemic ipilimumab in advanced melanoma patients with or without previous immune checkpoint therapy treatment

Author

Jon M. Richards, Mark Grose, Mark B. Faries, Robert H.I. Andtbacka, Brendan D. Curti, Darren R. Shafren, Greg Daniels, and Sigrun Hallmeyer

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, medicine.medical_treatment, Coxsackievirus A21, Population, Phases of clinical research, Ipilimumab, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Clinical endpoint, Medicine, education, education.field_of_study, business.industry, Melanoma, Immunotherapy, medicine.disease, Immune checkpoint, 030104 developmental biology, 030220 oncology & carcinogenesis, Immunology, business, medicine.drug
Abstract

Background: CAVATAKTM is a novel bio-selected oncolytic and immunotherapeutic strain of Coxsackievirus A21 (CVA21). In a phase 2 study, intratumoral (i.t.) CVA21 injection of advanced melanoma lesions resulted in increases in tumor immune-cell infiltration, up-regulation of γ-INF response and immune-checkpoint genes, including CD122 which may be a potential prognostic marker for enhanced anti-tumor activity by anti-CTLA-4 blockade strategies. Intratumoral replication of CAVATAK may act as a strong “immune-sequestration signal” to circulating activated T-cells following CTLA-4 blockade. We present the preliminary data of the open-label, Phase Ib MITCI (Melanoma Intra-Tumoral Cavatak and Ipilimumab) study of novel immunotherapy combination Coxsackievirus A21 and ipilimumab in patients (pts) with advanced melanoma. Methods: The Phase Ib MITCI study (NCT02307149) is investigating the efficacy and safety of i.t. CVA21 and i.v. ipilimumab in up to 50 pts with treated or untreated unresectable Stage IIIC-IVM1c melanoma. Pts received up to 3 x 108 TCID50 CVA21 i.t. on study days 1, 3, 5, 8 and 22, and then q3w for a further 6 series of injections. Ipilimumab (3 mg/kg) q3w was given as 4 i.v. infusions starting at Day 22. The first response assessment (irWHO) occurred at study Day 106. The primary endpoint was to assess safety of CVA21 in combination with ipilimumab treatment. Results: At present no DLT’s have been reported in the 23 pts currently enrolled. Combination treatment has been generally well-tolerated with surprisingly only one Gr 3 or higher treatment-related AE being ipilimumab-related fatigue. The study met its primary statistical futility endpoint of achieving ≥ 4 confirmed objective responses (CR or PR) in the first 12 pts enrolled. Currently, of the first 18 pts eligible for investigator response assessment, the confirmed ORR for the ITT population is 50.0% (9/18), with the ORR for immune checkpoint-naïve pts being 60% (6/10) and previous immune checkpoint therapy pts being 38% (3/8). Of note, is the encouraging ORR of 57.1% (4/7 pts) in pts with stage IVm1c disease. The DCR (CR+PR+SD) on the ITT population is currently 78% (14/18) of which 66% of patients have been administered prior systemic therapy(s) with DCR of 100% (7/7) in pts with stage IVm1c disease. All responses were observed by 3.5 mths with complete tumor responses being observed in individual injected and non-injected lesions. Preliminary immune monitoring has indicated that CVA21 + ipilimumab increases the % of activated CD8 and CD4 T-cells with effector and memory phenotypes in the peripheral blood. The greatest increases in activated T cells in the peripheral blood occurred after the third ipilimumab dose. Conclusions: Treatment of pts with CVA21 and ipilimumab has demonstrated durable response with minimal toxicity. The combination immunotherapy treatment has displayed anti-tumor activity in local, visceral and non-visceral lesions. The preliminary ORR rate for the ITT population of 50.0% is higher than published rates for either agent used alone (CVA21: ~28% and ipilimumab :~15-20%) in advanced melanoma patients. Finally, responses are observed in pts with PD following immune checkpoint inhibitor therapy, suggesting the additive therapeutic benefit of CVA21 with ipilimumab. Citation Format: Brendan Curti, Jon Richards, Sigrun Hallmeyer, Mark Faries, Robert Andtbacka, Greg Daniels, Mark Grose, Darren R. Shafren. The MITCI (Phase 1b) study: A novel immunotherapy combination of intralesional Coxsackievirus A21 and systemic ipilimumab in advanced melanoma patients with or without previous immune checkpoint therapy treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT114. doi:10.1158/1538-7445.AM2017-CT114

Published
2017
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16. Abstract CT115: Phase 1b KEYNOTE 200 (STORM study): A study of an intravenously delivered oncolytic virus, Coxsackievirus A21 in combination with pembrolizumab in advanced cancer patients

Author

Hardev Pandha, Jonathan E. Rosenberg, Kevin J. Harrington, Alan Melcher, Rachael E. Sandborn, C Ralph, Sumati Gupta, David Ross Kaufman, Darren R. Shafren, Emmett V. Schmidt, Wallace Akerley, Mark Grose, and Charles M. Rudin

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Bladder cancer, business.industry, Melanoma, Coxsackievirus A21, Pembrolizumab, medicine.disease, Oncolytic virus, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, Cohort, Blocking antibody, Immunology, medicine, Systemic administration, business
Abstract

Background: Coxsackievirus A21 (CVA21, CAVATAK) is a naturally occurring ICAM-1 targeted oncolytic immunotherapeutic virus. Pembrolizumab is a human programmed death receptor-1 (PD-1) blocking antibody that has yielded significant solid tumor responses via reversal of tumor induced T-cell suppression. Tumor infection by CVA21 can increase levels of immune-checkpoint molecules, immune-cell infiltration and enhancement of systemic antitumor immune response. Preclinical studies in immune-competent mouse models of NSCLC and melanoma confirmed that combinations of IV CVA21 + anti-PD-1 mAbs mediated significantly greater antitumor activity compared to use of either agent alone. The combination of CVA21+pembrolizumab may translate to a potential benefit in the clinic. Interim data are presented on the Phase Ib study assessing safety and efficacy of IV CVA21 alone (Part A) and in combination with pembrolizumab (Part B) in advanced cancer pts. Methods: The Phase I STORM: Systemic Treatment Of Resistant Malignancies: NCT02043665 (KEYNOTE-200): Primary objectives are to assess dose-limiting toxicities (DLT) of CVA21 alone and in combination with pembrolizumab. Secondary objectives are to assess ORR by irRECIST 1.1 criteria, PFS, and OS. Treatment: Part A: Pts were infused with CVA21 in 100 mL saline in Cohort 1 (n = 3), at a dose of 1 x 108 TCID50, in Cohort 2 (n = 3) at a dose of 3 x 108 TCID50 and in Cohort 3 (n = 10) at a dose of 1 x 109 TCID50 on study days 1,3,5,22 and Q3W for 6 additional infusions. Part B: Pts are infused with CVA21 in 100 mL saline + pembrolizumab. In Cohort 1 (n = 3), CVA21 is administered at a dose of 1 x 108 TCID50, in Cohort 2 (n = 3) at a dose of 3 x 108 TCID50 and in Cohort 3 (n = ~80) at a dose of 1 x 109 TCID50 on study days 1,3,5,8,29,and Q3W for 6 additional infusions. Pembrolizumab is given in all cohorts at 200 mg IV Q3W from Day 8 for up to 2 years. Treatment with CVA21 + pembrolizumab will continue until confirmed CR or PD (whichever comes first) per irRECIST 1.1 or DLT. Results: Part A: Enrolment is complete. IV delivery of CVA21 to all patients in Part A was generally well tolerated, with no Grade 3 or 4 product-related AE’s with a median of 6 CVA21 infusions per patient. CVA21 tumor targeting in patients with melanoma, NSCLC and bladder cancer patients in Cohort 3 was confirmed by detection of CVA21 viral RNA in tumor biopsies at study Day 8 and viral replication by IHC in melanoma tumor biopsies. Of the 13 patients from Cohorts 1-3 eligible for investigator best overall response assessment, 1 PR, 8 SD and 4 PD were observed. Part B: The combination of intravenous CVA21 and pembrolizumab has been generally well-tolerated. At present one gr 3 CVA21-related hyponatremia with no DLT for the combination of CVA21 and pembrolizumab being observed. Enrolment in Cohorts 1 and 2 is complete with that of Cohort 3 currently underway. All patients in Part B have displayed active host-antiviral immune responses by developing detectable anti-CVA21 neutralizing antibodies by study Day 22. Conclusions: Intravenous delivery of CVA21 is able to target metastatic tumor deposits with the potential to up-regulate PD-L1 expression during the viral replication process. Systemic administration of CVA21 alone or in combination with pembrolizumab has been generally well-tolerated with at present no DLT’s. Citation Format: Hardev Pandha, Kevin Harrington, Cristy Ralph, Alan Melcher, Sumati Gupta, Wallace Akerley, Rachael E. Sandborn, Charles Rudin, Jonathan Rosenberg, David Kaufman, Emmett Schmidt, Mark Grose, Darren R. Shafren. Phase 1b KEYNOTE 200 (STORM study): A study of an intravenously delivered oncolytic virus, Coxsackievirus A21 in combination with pembrolizumab in advanced cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT115. doi:10.1158/1538-7445.AM2017-CT115

Published
2017
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17. Activity of a novel immunotherapy combination of intralesional Coxsackievirus A21 and systemic ipilimumab in advanced melanoma patients previously treated with anti-PD1 blockade therapy

Author

Jon M. Richards, Mark B. Faries, Robert H.I. Andtbacka, Darren R. Shafren, Gregory A. Daniels, Brendan D. Curti, Mark Grose, and Sigrun Hallmeyer

Subjects
0301 basic medicine, Cancer Research, business.industry, medicine.medical_treatment, Melanoma, Coxsackievirus A21, Ipilimumab, Immunotherapy, medicine.disease, Blockade, Oncolytic virus, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, medicine, Cancer research, business, Infiltration (medical), Advanced melanoma, medicine.drug
Abstract

3014 Background: CAVATAK is a novel bio-selected oncolytic and immunotherapeutic strain of Coxsackievirus A21 (CVA21) that when injected into melanoma lesions can increase immune-cell infiltration, up-regulation of γ-INF response and immune-checkpoint genes, including CD122, which may be a potential marker for enhanced anti-tumor activity by anti-CTLA-4 blockade. Intratumoral replication of CVA21 may act as a strong “immune-sequestration signal” to circulating activated T-cells following CTLA-4 blockade. A large unmet need exists for active therapies in melanoma patients (pts) following treatment (tx) with anti-PD1 therapies. We present in a Phase 1 study, the clinical activity of a CVA21/ ipilimumab (ipi) combination following anti–PD1 therapy in advanced melanoma pts. Methods: The Phase Ib MITCI study (NCT02307149) investigated the efficacy and safety of i.t. CVA21 and i.v. ipi in 26 pts with unresectable Stage IIIB/C-IVM1c melanoma with 13 pts previously treated with anti-PD1 therapies. Pts received up to 3 x 108 TCID50CVA21 i.t. on study days 1, 3, 5, 8 and 22, and then q3w for a further 6 series of injections. Ipi (3 mg/kg) q3w was given as 4 i.v. infusions starting at Day 22. Results: Analysis of the prior anti–PD1 treated pts (n=13) revealed that the combination tx was generally well-tolerated with one case of Gr 3 ipi-related liver toxicity observed. Of the tx population, 54% (7/13) had received prior ipi tx in addition to anti-PD1, 85% (11/13) of pts were stage IV M1b/c, with the median time between the last anti-PD1 and first CVA21 and ipi doses being 5.7 and 8.7 weeks, respectively. The mean number of prior systemic therapies including anti-PD1 tx was 2.6. For all pts completing at least the first investigator response assessment (irWHO criteria at Day 106) we observed a confirmed BORR of 38.0% (3/8) and a DCR (CR+PR+SD) of 88% (7/8). Conclusions: Intratumoral CVA21 + ipilimumab treatment in anti–PD1 treated pts has displayed promising clinical activity together with low adverse toxicity and as such this regimen may represent a valuable tx option for pts that have been administered previous lines of immune checkpoint therapy. Clinical trial information: NCT02307149.

Published
2017
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18. Keynote-200 phase 1b: A novel combination study of intravenously delivered coxsackievirus A21 and pembrolizumab in advanced cancer patients

Author

Rachel E. Sanborn, Charles M. Rudin, Christy Ralph, Mark Grose, Kevin J. Harrington, Brendan D. Curti, David Ross Kaufman, Sumati Gupta, Darren R. Shafren, Wallace Akerley, Jonathan E. Rosenberg, Emmett V. Schmidt, and Hardev Pandha

Subjects
0301 basic medicine, Cancer Research, business.industry, Coxsackievirus A21, Pembrolizumab, Advanced cancer, Virus, Oncolytic virus, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, Cancer research, Medicine, business, Programmed death
Abstract

TPS3108 Background: Coxsackievirus A21 (CVA21, CAVATAK) is a naturally occurring ICAM-1 targeted oncolytic immunotherapeutic virus. Pembrolizumab is a human programmed death receptor-1 (PD-1) blocking antibody that has yielded significant solid tumor responses via reversal of tumor induced T-cell suppression. Intravenous (i.v.) CVA21 mono-therapy is generally well tolerated, with low toxicity and can successfully target tumors in patients with melanoma, NSCLC and bladder cancer as confirmed by detection of CVA21 viral RNA in post-treatment tumor biopsies (Pandha et al., 2016). Intratumoral CVA21 replication has the potential to up-regulate numerous key immune checkpoint molecules, including PD-L1 (Andtbacka et al., 2016).The combination of i.v. CVA21+pembrolizumab may translate to a potential enhanced benefit in the clinic. Methods: The Phase Ib KEYNOTE-200 (NCT02043665) Treatment: Primary objectives are to assess dose-limiting toxicities (DLT) of CVA21 in combination with pembrolizumab. Secondary objectives are to assess ORR by irRECIST 1.1 criteria, PFS, and OS. Patients (pts) are infused with CVA21 in 100 mL saline + pembrolizumab. In Cohort 1 (n = 3), CVA21 is administered at a dose of 1 x 108 TCID50, in Cohort 2 (n = 3) at a dose of 3 x 108 TCID50 and in Cohort 3 (n = ~80) at a dose of 1 x 109 TCID50 on study days 1,3,5,8,29,and Q3W for 6 additional infusions. Pembrolizumab is given in all cohorts at 200 mg IV Q3W from Day 8 for up to 2 years. Treatment (tx) with CVA21 + pembrolizumab will continue until confirmed CR or PD (whichever comes first) per irRECIST 1.1 or DLT.To date the combination of intravenous CVA21 and pembrolizumab has been generally well-tolerated. At present one gr 3 CVA21-related hyponatremia with no DLT for the combination of CVA21 and pembrolizumab being observed. Enrolment in Cohorts 1 and 2 is complete with tx of pts in Cohort 3 currently underway. Key eligibility: Pts with advanced disease considered appropriate tx with CVA21 + pembrolizumab, lesion(s) accessible for core biopsy, ECOG PS 0-1, no active cerebral metastases, no autoimmunity/immunosuppression. Clinical trial information: NCT02043665.

Published
2017
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19. Phase I/II CANON study: oncolytic immunotherapy for the treatment of non-muscle invasive bladder (NMIBC) cancer using intravesical coxsackievirus A21

Author

Gough G. Au, Hugh Mostafid, Sarbjinder S Sandhu, Darren R. Shafren, Mark Grose, Roberta Karpathy, Hardev Pandha, Mehreen Arif, Nicola E. Annels, David Mansfield, K.J. Harrington, and Alan Melcher

Subjects
0301 basic medicine, business.industry, medicine.medical_treatment, Coxsackievirus A21, Cancer, Hematology, Immunotherapy, medicine.disease, Oncolytic virus, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Phase i ii, Oncology, 030220 oncology & carcinogenesis, Immunology, medicine, Cancer research, Non muscle invasive, business
Published
2016
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20. Intravenous coxsackievirus A21 in combination with pembrolizumab in advanced cancer patients: phase Ib KEYNOTE 200 study

Author

Alan Melcher, David Ross Kaufman, Emmett V. Schmidt, Roberta Karpathy, Christy Ralph, Hardev Pandha, Darren R. Shafren, Mark Grose, and K.J. Harrington

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, business.industry, Coxsackievirus A21, Hematology, Pembrolizumab, Advanced cancer, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, Immunology, Medicine, business
Published
2016
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21. Phase Ib study of intratumoral oncolytic coxsackievirus A21 (CVA21) and pembrolizumab in subjects with advanced melanoma

Author

A. Zloza, K. Spencer, Mark Grose, Janice M. Mehnert, J. Wang, A. Silk, D. Moore, Darren R. Shafren, M. Kane, and Howard L. Kaufman

Subjects
business.industry, Coxsackievirus A21, Hematology, Pembrolizumab, 030204 cardiovascular system & hematology, Virology, Oncolytic virus, 03 medical and health sciences, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, Cancer research, Medicine, business, Advanced melanoma
Published
2016
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22. The MITCI (phase 1b) study: a novel immunotherapy combination of coxsackievirus A21 and ipilimumab in patients with advanced melanoma

Author

Jon M. Richards, Brendan D. Curti, Mark Grose, Robert H.I. Andtbacka, Darren R. Shafren, Roberta Karpathy, and Mark B. Faries

Subjects
Oncology, medicine.medical_specialty, business.industry, medicine.medical_treatment, Coxsackievirus A21, Ipilimumab, Hematology, Immunotherapy, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, medicine, In patient, business, medicine.drug, Advanced melanoma
Published
2016
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23. Abstract CT053: Intratumoral coxsackievirus A21 increases immune-cell infiltrates and upregulates immune-checkpoint molecules in the tumor microenvironment of advanced melanoma patients: phase II CALM extension study

Author

Mark Grose, Zipei Peng, Carlo Bifulco, Robert H.I. Andtbacka, Darren R. Shafren, Brendan D. Curti, Christopher Paustian, Sigrun Hallmeyer, and Bernard Fox

Subjects
0301 basic medicine, Cancer Research, Tumor microenvironment, business.industry, medicine.medical_treatment, Melanoma, Coxsackievirus A21, Cancer, Ipilimumab, Immunotherapy, medicine.disease, Oncolytic virus, 03 medical and health sciences, 030104 developmental biology, Immune system, Oncology, Immunology, medicine, business, medicine.drug
Abstract

Background: CAVATAK, an oncolytic immunotherapy, is a bio-selected oncolytic strain of Coxsackievirus A21 (CVA21). Following intratumoral (IT) injection, CVA21 preferentially infects ICAM-1 expressing tumor cells, resulting in viral replication, cell lysis, and a systemic anti-tumor immune response. The Phase II CALM study investigated the efficacy and safety of IT CVA21 in pts with advanced melanoma with durable responses being observed in both injected and non-injected melanoma metastases, suggesting the generation of significant host anti-tumor responses. Pre-clinical studies in an immune-competent mouse model of melanoma revealed that combinations of intratumoral CAVATAK and anti-PD-1 or anti-CTLA-4 mAbs mediated significantly greater antitumor activity and compared to use of either agent alone. Here we report on an extension study aimed at understanding the impact of CVA21 on immune cell infiltrates and immune checkpoint molecules within treated lesions of advanced melanoma patients. Methods: In the CALM extension study a cohort of 13 advanced melanoma patients received up to 3 × 108 TCID50 CVA21 IT on study days 1,3,5 and 8 and then every three weeks for a further 6 injections. Sequential tumor biopsies of injected lesions (study days 1 and 8) were monitored for evidence of viral-induced changes immune cell infiltrates (Multi-spectral imaging) and immune checkpoint molecules (NanoString® PanCancer Immune profiling panel). Serial serum samples were monitored for viral loads, anti-CVA21 neutralizing antibody (nAb) and levels of immune-inflammatory cytokines. Results: Intratumoral CVA21 administration in a number of cases induced significant increases in immune cell infiltrates within the tumor microenvironment, in particular CD8+ cells (p = 0.044) and increased expression of PD-L1+ cells (p = 0.041) as assessed by multi-spectral imaging. Analysis of a number of pre- and post-treatment biopsy samples by NanoString® digital RNA counting identified notable increases in the levels of immune checkpoint molecules including PD-1, PD-L1, CTLA-4, TIM-3 and LAG-3 and sizable up-regulation of a number of immune modulation elements, including Th1-gene shifts, with increases in interferon-induced genes. Of particular interest was the reconstitution of immune cell infiltrates in a number of CVA21 treated lesions from patients failing previous immune-checkpoint blockade or other immunotherapies. Conclusions: Intratumoral administration of CVA21 can notably influence the dynamics of the tumor micro-environment as evidenced by increases in both immune cell infiltrates and levels of immune-checkpoint genes. Such CVA21 induced immune-changes appear to be beneficial in combination immunotherapy, with preliminary overall response rates in a Phase 1b study CVA21 and anti-CTLA-4 blockade (ipilimumab) in advanced melanoma patients being higher than published response rates for either agent used alone. The use of CVA21 to reconstitute immune cell infiltrates in lesions resistant to immune-checkpoint blockade prior to re-commencing such treatment is an exciting novel therapeutic option. Citation Format: Robert Andtbacka, Brendan Curti, Sigrun Hallmeyer, Zipei Peng, Christopher Paustian, Carlo Bifulco, Bernard Fox, Mark Grose, Darren R. Shafren. Intratumoral coxsackievirus A21 increases immune-cell infiltrates and upregulates immune-checkpoint molecules in the tumor microenvironment of advanced melanoma patients: phase II CALM extension study. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT053.

Published
2016
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24. Phase I STORM study (KEYNOTE 200): Intravenous delivery of a novel oncolytic immunotherapy agent, Coxsackievirus A21 in combination with pembrolizumab in advanced cancer patients

Author

Roberta Karpathy, Christy Ralph, Darren R. Shafren, Bronwyn Davies, Kevin J. Harrington, Alan Melcher, David Mansfield, Mark Grose, and Hardev Pandha

Subjects
Cancer Research, business.industry, viruses, medicine.medical_treatment, Coxsackievirus A21, food and beverages, Pembrolizumab, Immunotherapy, biochemical phenomena, metabolism, and nutrition, Advanced cancer, Virus, Oncolytic virus, 03 medical and health sciences, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, medicine, Cancer research, business, 030215 immunology
Abstract

TPS3108Background: Coxsackievirus A21 (CVA21, CAVATAK) is a naturally occurring ICAM-1 targeted oncolytic immunotherapeutic virus. Tumor infection by CVA21 can increase levels immune-checkpoint mol...

Published
2016
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25. Dynamics of tumor response in advanced melanoma patients treated with Coxsackievirus A21

Author

Gregory A. Daniels, Eric D. Whitman, Brendan D. Curti, Darren R. Shafren, Mark Grose, Bernard A. Fox, Carlo Bifulco, Zipei Feng, Jose Lutzky, Stephen Michael Schultz, Sigrun Hallmeyer, Lynn E. Spitler, Karl Zhou, Christopher Paustian, Robert H.I. Andtbacka, Howard L. Kaufman, and John Nemunaitis

Subjects
Cancer Research, Strain (chemistry), business.industry, medicine.medical_treatment, Coxsackievirus A21, Dynamics (mechanics), Immunotherapy, Tumor response, Oncolytic virus, Oncology, Lytic cycle, Cancer research, Medicine, business, Advanced melanoma
Abstract

9553Background: CAVATAK, an oncolytic immunotherapy, is a bio-selected oncolytic strain of Coxsackievirus A21 (CVA21). Intratumoral (IT) injection of CVA21 induces lytic tumor cell infection, up-re...

Published
2016
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26. Final data from CALM: A phase II study of Coxsackievirus A21 (CVA21) oncolytic virus immunotherapy in patients with advanced melanoma

Author

Howard L. Kaufman, Darren R. Shafren, Karl Zhou, Robert H.I. Andtbacka, Mark Grose, Jose Lutzky, Stephen Michael Schultz, Lynn E. Spitler, Jeffrey Ira Weisberg, Roberta Karpathy, Sigrun Hallmeyer, Eric D. Whitman, Gregory A. Daniels, Brendan D. Curti, and John Nemunaitis

Subjects
Cancer Research, business.industry, medicine.medical_treatment, Coxsackievirus A21, Phases of clinical research, Tumor cells, Immunotherapy, Virology, Oncolytic virus, Oncology, medicine, In patient, business, Advanced melanoma
Abstract

9030 Background: CVA21 (CAVATAK) is a novel bio-selected oncolytic and immunotherapeutic strain of Coxsackievirus A21. Intratumoral (i.t) CVA21 injection initiates preferential tumor cell infection...

Published
2015
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27. Phase II calm extension study: Coxsackievirus A21 delivered intratumorally to patients with advanced melanoma induces immune-cell infiltration in the tumor microenvironment

Author

Carlo Bifulco, Darren R. Shafren, Mark Grose, Zipei Feng, Robert H.I. Andtbacka, Bernard Fox, Sigrun Hallmeyer, Christopher Paustian, and Brendan D. Curti

Subjects
Pharmacology, Cancer Research, Tumor microenvironment, Lysis, business.industry, medicine.medical_treatment, Immunology, Coxsackievirus A21, Immunotherapy, Bioinformatics, Oncolytic virus, Immune system, Oncology, Viral replication, Poster Presentation, Cancer research, Molecular Medicine, Immunology and Allergy, Medicine, business, Advanced melanoma
Abstract

Meeting abstracts CAVATAK, an oncolytic immunotherapy, is a bio-selected oncolytic strain of Coxsackievirus A21 (CVA21). Following intratumoral (IT) injection, CVA21 preferentially infects ICAM-1 expressing tumor cells, resulting in viral replication, cell lysis, and a systemic anti-tumor immune

Published
2015
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28. Abstract 2939: CAVATAK-mediated oncolytic immunotherapy in advanced melanoma patients

Author

Robert H.I. Andtbacka, Mark Grose, Darren R. Shafren, Jeffrey Ira Weisberg, and Len Post

Subjects
Cancer Research, biology, business.industry, medicine.medical_treatment, Melanoma, Coxsackievirus A21, Cancer, Immunotherapy, medicine.disease, Proinflammatory cytokine, Oncolytic virus, Immune system, Oncology, Immunology, medicine, biology.protein, Antibody, business
Abstract

Background: Coxsackievirus A21 (CVA21) is a naturally occurring “common cold” intercellular adhesion molecule-1 (ICAM-1) targeted RNA virus. Surface ICAM-1 is up-regulated on a number of cancers including melanoma, non-small cell lung, bladder, breast and prostate cancers. CAVATAK is a novel bio-selected formulation of CVA21, which displays potent oncolytic activity against in vitro cultures of cancer cells and in vivo xenografts of a number of cancers. In addition, in vivo tumor challenge studies in immune-competent mouse models have shown that CVA21 lysed tumor cells can induce a secondary systemic host-generated anti-tumor immune response. In this report, advanced melanoma patients were administered multiple intralesional injections of CAVATAK and monitored for markers of host anti-tumor activity on metastatic non-injected lesions. Methods: The Phase II CALM (CAVATAK in Late stage Melanoma) study is investigating the efficacy and safety of intratumoral CAVATAK in 54 advanced melanoma patients. Patient tumors are injected with up to 3 x 10e8 TCID50 CAVATAK on study days 1, 3, 5, 8 and 22 then every 3 weeks for a further 5 injections. CAVATAK-mediated immune anti-tumor activity was assessed by monitoring reductions in non-injected lesions (CT-scan and callipers) and assessing the relative serum levels of a panel of immune inflammatory cytokines. In addition, levels of serum CAVATAK and anti-CAVATAK neutralizing antibodies were assessed on multiple occasions prior to intralesional injections. Results: Intralesional CAVATAK injections resulted in significant responses in a number of melanoma lesions. However, in addition to melanoma tumor responses directly from CAVATAK-mediated oncolysis, a number of non-injected metatastic lesions displayed significant reductions or even complete destruction. Such anti-tumor activity in non-injected lesions is highly suggestive of being mediated via a host generated anti-tumor immune response. Such responses have occurred at times when no circulating infectious CAVATAK was detected in patient serum and in an environment of high levels of anti-CAVATAK neutralizing antibody. In further support of the generation of CAVATAK-mediated immune anti-tumor activity is the identification a possible novel serum cytokine signature of elevated levels of IL-8 and γ-IFN in treated patients linked to systemic tumor response. IL-8 is known to be secreted by activated macrophages, while γ-IFN is produced by stimulated cytotoxic T-cells / NK cells. Conclusion: With a number of patients in the Phase II CALM study displaying reductions in non-injected lesions, together with elevated serum levels of the immune inflammatory cytokines IL-8 and γ-IFN, at times with no detectable levels of circulating infectious CAVATAK, we conclude the generation of a targeted CAVATAK-mediated host anti-tumor response acting on metastatic melanoma lesions is highly likely. Clinical trial information: NCT01227551. Citation Format: Robert H. Andtbacka, Darren R. Shafren, Mark Grose, Len Post, Jeffrey Weisberg. CAVATAK-mediated oncolytic immunotherapy in advanced melanoma patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2939. doi:10.1158/1538-7445.AM2014-2939

Published
2014
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29. Oncolytic immunotherapy for the treatment of non-muscle invasive bladder cancer using intravesical coxsackievirus A21

Author

M. Denyer, Hugh Mostafid, Kevin J. Harrington, Attya Iqbal, Darren R. Shafren, Guy Simpson, Sarbjinder S Sandhu, Nicola E. Annels, Alan Melcher, Mehreen Arif, Hardev Pandha, David Mansfield, Gough G. Au, and Mark Grose

Subjects
Pharmacology, Cancer Research, Bladder cancer, business.industry, medicine.medical_treatment, Bladder cancer cell, Immunology, Coxsackievirus A21, Immunotherapy, medicine.disease, Bioinformatics, Oncolytic virus, Oncology, Poster Presentation, Cancer research, medicine, Molecular Medicine, Immunology and Allergy, Non muscle invasive, business
Abstract

Meeting abstracts As a clinical setting in which local live biological therapy is already well established, nonmuscle invasive bladder cancer (NMIBC) presents intriguing opportunities for oncolytic virotherapy. Coxsackievirus A21 (CVA21) is a novel intercellular adhesion molecule-1 (ICAM-1)

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30. Phase I/II storm study: Intravenous delivery of a novel oncolytic immunotherapy agent, Coxsackievirus A21, in advanced cancer patients

Author

Hardev Pandha, Alan Melcher, Kevin J. Harrington, Darren R. Shafren, Christy Ralph, and Mark Grose

Subjects
Pharmacology, Cancer Research, biology, business.industry, medicine.medical_treatment, Melanoma, Immunology, Cell, Coxsackievirus A21, RNA virus, Common cold, Immunotherapy, biology.organism_classification, Bioinformatics, medicine.disease, Oncolytic virus, medicine.anatomical_structure, Oncology, Prostate, Poster Presentation, medicine, Cancer research, Molecular Medicine, Immunology and Allergy, business
Abstract

Meeting abstracts Coxsackievirus A21 (CVA21) is a naturally occurring “common cold” intercellular adhesion molecule-1 (ICAM-1)-targeted RNA virus. Surface ICAM-1 is up-regulated on a number of cancers including melanoma, non-small cell lung, bladder and prostate cancers. CAVATAK is a novel bio

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