A tumor-selective adenoviral vector platform induces transient antiphospholipid antibodies, without increased risk of thrombosis, in phase 1 clinical studies.
Activated partial thromboplastin time
Adenoviral vector
Antiphospholipid antibody
Clinical study
Safety
Journal
Investigational new drugs
ISSN: 1573-0646
Titre abrégé: Invest New Drugs
Pays: United States
ID NLM: 8309330
Informations de publication
Date de publication:
04 2023
04 2023
Historique:
received:
16
11
2022
accepted:
22
02
2023
medline:
1
5
2023
pubmed:
11
3
2023
entrez:
10
3
2023
Statut:
ppublish
Résumé
Tumor-selective viruses are a novel therapeutic approach for treating cancer. Tumor-Specific Immuno Gene Therapy (T-SIGn) vectors are tumor-selective adenoviral vectors designed to express immunomodulatory transgenes. Prolonged activated partial thromboplastin time (aPTT), associated with the presence of antiphospholipid antibodies (aPL), has been observed in patients with viral infections, and following administration of adenovirus-based medicines. aPL may be detected as lupus anticoagulant (LA), anti-cardiolipin (aCL) and/or anti-beta 2 glycoprotein antibodies (aβ2GPI). No subtype alone is definitive for development of clinical sequalae, however, patients who are 'triple positive' have a greater thrombotic risk. Additionally, isolated aCL and aβ2GPI IgM do not appear to add value in thrombotic association to aPL positivity, rather IgG subtypes must also be present to confer an increased risk. Here we report induction of prolonged aPTT and aPL in patients from eight Phase 1 studies who were treated with adenoviral vectors (n = 204). Prolonged aPTT (≥ Grade 2) was observed in 42% of patients, with a peak at 2-3 weeks post-treatment and resolution within ~ 2 months. Among patients with aPTT prolongation, LA, but not aCL IgG nor aβ2GPI IgG, was observed. The transience of the prolongation and discordance between positive LA and negative aCL/aβ2GPI IgG assays is not typical of a prothrombotic state. Among the patients with prolonged aPTT there was no evidence of an increased rate of thrombosis. These findings elucidate the relationship between viral exposure and aPL in the context of clinical trials. They suggest a framework in which hematologic changes can be monitored in patients receiving similar treatments.Clinical trial registration:NCT02028442, NCT02636036, NCT02028117, NCT03852511, NCT04053283, NCT05165433, NCT04830592, NCT05043714.
Identifiants
pubmed: 36897458
doi: 10.1007/s10637-023-01345-8
pii: 10.1007/s10637-023-01345-8
pmc: PMC9999314
doi:
Substances chimiques
Antibodies, Antiphospholipid
0
Lupus Coagulation Inhibitor
0
Antibodies, Anticardiolipin
0
Immunoglobulin G
0
Banques de données
ClinicalTrials.gov
['NCT04053283', 'NCT04830592', 'NCT05043714', 'NCT05165433', 'NCT02028442', 'NCT02636036', 'NCT02028117', 'NCT03852511']
Types de publication
Clinical Trial, Phase I
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
317-323Subventions
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Références
Machiels JP, Salazar R, Rottey S, Duran I, Dirix L, Geboes K et al (2019) A phase 1 dose escalation study of the oncolytic adenovirus enadenotucirev, administered intravenously to patients with epithelial solid tumors (EVOLVE). J Immunother Cancer 7(1):20
doi: 10.1186/s40425-019-0510-7
pubmed: 30691536
pmcid: 6348630
Moreno V, Barretina-Ginesta M-P, García-Donas J, Jayson GC, Roxburgh P, Vázquez RM et al (2021) Safety and efficacy of the tumor-selective adenovirus enadenotucirev with or without paclitaxel in platinum-resistant ovarian cancer: a phase 1 clinical trial. J Immunother Cancer 9(12):e003645
doi: 10.1136/jitc-2021-003645
pubmed: 34893524
pmcid: 8666888
Garcia-Carbonero R, Salazar R, Duran I, Osman-Garcia I, Paz-Ares L, Bozada JM et al (2017) Phase 1 study of intravenous administration of the chimeric adenovirus enadenotucirev in patients undergoing primary tumor resection. J Immunother Cancer 5(1):71
doi: 10.1186/s40425-017-0277-7
pubmed: 28923104
pmcid: 5604344
Garcia D, Erkan D (2018) Diagnosis and management of the Antiphospholipid Syndrome. N Engl J Med 378(21):2010–2021
doi: 10.1056/NEJMra1705454
pubmed: 29791828
Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, CERVERA R et al (2006) International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 4(2):295–306
doi: 10.1111/j.1538-7836.2006.01753.x
pubmed: 16420554
Devreese KM (2014) Antiphospholipid antibody testing and standardization. Int J Lab Hematol 36(3):352–363
doi: 10.1111/ijlh.12234
pubmed: 24750682
Chayoua W, Kelchtermans H, Moore GW, Musiał J, Wahl D, de Laat B et al (2018) Identification of high thrombotic risk triple-positive antiphospholipid syndrome patients is dependent on anti-cardiolipin and anti-β2glycoprotein I antibody detection assays. J Thromb Haemost 16(10):2016–2023
doi: 10.1111/jth.14261
pubmed: 30079628
Chayoua W, Kelchtermans H, Gris JC, Moore GW, Musiał J, Wahl D et al (2020) The (non-)sense of detecting anti-cardiolipin and anti-β2glycoprotein I IgM antibodies in the antiphospholipid syndrome. J Thromb Haemost 18(1):169–179
doi: 10.1111/jth.14633
pubmed: 31519058
Vandevelde A, Chayoua W, de Laat B, Gris J-C, Moore GW, Musiał J et al (2022) Semiquantitative interpretation of anticardiolipin and antiβ2glycoprotein I antibodies measured with various analytical platforms: communication from the ISTH SSC Subcommittee on Lupus Anticoagulant/Antiphospholipid antibodies. J Thromb Haemost 20(2):508–524
doi: 10.1111/jth.15585
pubmed: 34758192
Asherson RA, Cervera R (2003) Antiphospholipid antibodies and infections. Ann Rheum Dis 62(5):388–393
doi: 10.1136/ard.62.5.388
pubmed: 12695147
pmcid: 1754545
Abdel-Wahab N, Talathi S, Lopez-Olivo MA, Suarez-Almazor ME (2018) Risk of developing antiphospholipid antibodies following viral infection: a systematic review and meta-analysis. Lupus 27(4):572–583
doi: 10.1177/0961203317731532
pubmed: 28945149
Malaeb BS, Gardner TA, Margulis V, Yang L, Gillenwater JY, Chung LWK et al (2005) Elevated activated partial thromboplastin time during administration of first-generation adenoviral vectors for gene therapy for prostate cancer: identification of lupus anticoagulants. Urology 66(4):830–834
doi: 10.1016/j.urology.2005.04.041
pubmed: 16230147
Crank MC, Wilson EM, Novik L, Enama ME, Hendel CS, Gu W et al (2016) Safety and Immunogenicity of a rAd35-EnvA prototype HIV-1 vaccine in combination with rAd5-EnvA in healthy adults (VRC 012). PLoS ONE 11(11):e0166393
doi: 10.1371/journal.pone.0166393
pubmed: 27846256
pmcid: 5112788
Ledgerwood JE, Costner P, Desai N, Holman L, Enama ME, Yamshchikov G et al (2010) A replication defective recombinant Ad5 vaccine expressing Ebola virus GP is safe and immunogenic in healthy adults. Vaccine 29(2):304–313
doi: 10.1016/j.vaccine.2010.10.037
pubmed: 21034824
Sheets RL, Stein J, Bailer RT, Koup RA, Andrews C, Nason M et al (2008) Biodistribution and toxicological safety of adenovirus type 5 and type 35 vectored vaccines against human immunodeficiency virus-1 (HIV-1), Ebola, or Marburg are similar despite differing adenovirus serotype vector, manufacturer’s construct, or gene inserts. J Immunotoxicol 5(3):315–335
doi: 10.1080/15376510802312464
pubmed: 18830892
pmcid: 2777703
Mulder FI, Horváth-Puhó E, van Es N, van Laarhoven HWM, Pedersen L, Moik F et al (2021) Venous thromboembolism in cancer patients: a population-based cohort study. Blood 137(14):1959–1969
doi: 10.1182/blood.2020007338
pubmed: 33171494
Timp JF, Braekkan SK, Versteeg HH, Cannegieter SC (2013) Epidemiology of cancer-associated venous thrombosis. Blood 122(10):1712–1723
doi: 10.1182/blood-2013-04-460121
pubmed: 23908465
Fakih M, Wang D, Harb W, Rosen L, Mahadevan D, Berlin J et al (2019) A phase I multicenter study of enadenotucirev in combination with nivolumab in tumors of epithelial origin: an analysis of the metastatic colorectal cancer patients in the dose escalation phase. Ann Oncol 30(Suppl 5):V198–V252
Krige D, Fakih M, Rosen L, Wang D, Harb W, Babiker H et al (2021) 342 Combining enadenotucirev and nivolumab increased tumour immune cell infiltration/activation in patients with microsatellite-stable/instability-low metastatic colorectal cancer in a phase 1 study. J Immunother Cancer 9(Suppl 2):A368–A9
Naing A, Rosen L, Camidge RD, Khalil D, Davies J, Miles D et al (2021) 1011P FORTITUDE phase I study of NG-350A, a novel tumour-selective adenoviral vector expressing an anti-CD40 agonist antibody: Monotherapy dose escalation results. Ann Oncol 32:S853–S4
doi: 10.1016/j.annonc.2021.08.1395
Lillie T, O’Hara M, Ottensmeier C, Parkes E, Rosen L, Krige D et al (2022) Abstract CT213: a multicenter phase 1a/b study of NG-350A, a tumor-selective anti-CD40-antibody expressing adenoviral vector, and pembrolizumab in patients with metastatic or advanced epithelial tumors (FORTIFY). Cancer Res 82(12Supplement):CT213–CT
doi: 10.1158/1538-7445.AM2022-CT213
Simon G, Subbiah V, Rosen L, Lenz H-J, Park H, Patel M et al (2022) 762 First-in-human phase 1a study of NG-641, a tumour-selective vector expressing a FAP-TAc bispecific antibody and immune enhancer module, in patients with metastatic/advanced epithelial tumours (STAR). J Immunother Cancer 10(Suppl 2):A793–A
Ottensmeier C, Evans M, King E, Karydis I, Lillie T, Krige D et al (2021) 437 A multicentre phase 1b study of NG-641, a novel transgene-armed and tumour-selective adenoviral vector, and pembrolizumab as neoadjuvant treatment for squamous cell carcinoma of the head and neck. J Immunother Cancer 9(Suppl 2):A467–A
doi: 10.1136/jitc-2021-SITC2021.437
Lillie T, Parkes E, Ottensmeier C, Krige D, Ravanfar B, Evilevitch V et al (2022) Abstract CT214: a multicenter phase 1a/b study of NG-641, a tumor-selective transgene-expressing adenoviral vector, and nivolumab in patients with metastatic or advanced epithelial tumors (NEBULA). Cancer Res 82(12Supplement):CT214–CT
doi: 10.1158/1538-7445.AM2022-CT214
Wiwanitkit V (2004) Activated partial Thromboplastin Time abnormality in patients with Cholangiocarcinoma. Clin Appl Thromb Hemost 10(1):69–71
doi: 10.1177/107602960401000112
pubmed: 14979409
Liu J, Li F, Shu K, Chen T, Wang X, Xie Y et al (2018) The analysis of false prolongation of the activated partial thromboplastin time (activator: silica): interference of C-reactive protein. J Clin Lab Anal 32(8):e22571
doi: 10.1002/jcla.22571
pubmed: 29756266
pmcid: 6816841
Ay C, Pabinger I, Cohen AT (2017) Cancer-associated venous thromboembolism: Burden, mechanisms, and management. Thromb Haemost 117(2):219–230
doi: 10.1160/TH16-08-0615
pubmed: 27882374
Abdel-Wahab N, Lopez-Olivo MA, Pinto-Patarroyo GP, Suarez-Almazor ME (2016) Systematic review of case reports of antiphospholipid syndrome following infection. Lupus 25(14):1520–1531
doi: 10.1177/0961203316640912
pubmed: 27060064
pmcid: 7508159
Shoenfeld Y, Blank M, Cervera R, Font J, Raschi E, Meroni P-L (2006) Infectious origin of the antiphospholipid syndrome. Ann Rheum Dis 65(1):2–6
doi: 10.1136/ard.2005.045443
pubmed: 16344491
pmcid: 1797971
Gharavi AE, Pierangeli SS, Harris EN (2001) Origin of antiphospholipid antibodies. Rheum Dis Clin North Am 27(3):551–563
doi: 10.1016/S0889-857X(05)70219-2
pubmed: 11534259
de Laat B, Mertens K, de Groot PG (2008) Mechanisms of Disease: antiphospholipid antibodies—from clinical association to pathologic mechanism. Nat Clin Pract Rheumatol 4(4):192–199
doi: 10.1038/ncprheum0740
pubmed: 18285765