PMID- 33160076
OWN - NLM
STAT- MEDLINE
DCOM- 20211018
LR  - 20240214
IS  - 1525-0024 (Electronic)
IS  - 1525-0016 (Print)
IS  - 1525-0016 (Linking)
VI  - 29
IP  - 2
DP  - 2021 Feb 3
TI  - Neoadjuvant Gene-Mediated Cytotoxic Immunotherapy for Non-Small-Cell Lung Cancer: 
      Safety and Immunologic Activity.
PG  - 658-670
LID - S1525-0016(20)30599-2 [pii]
LID - 10.1016/j.ymthe.2020.11.001 [doi]
AB  - Gene-mediated cytotoxic immunotherapy (GMCI) is an immuno-oncology approach 
      involving local delivery of a replication-deficient adenovirus expressing herpes 
      simplex thymidine kinase (AdV-tk) followed by anti-herpetic prodrug activation 
      that promotes immunogenic tumor cell death, antigen-presenting cell activation, 
      and T cell stimulation. This phase I dose-escalation pilot trial assessed 
      bronchoscopic delivery of AdV-tk in patients with suspected lung cancer who were 
      candidates for surgery. A single intra-tumoral AdV-tk injection in three dose 
      cohorts (maximum 10(12) viral particles) was performed during diagnostic staging, 
      followed by a 14-day course of the prodrug valacyclovir, and subsequent surgery 
      1 week later. Twelve patients participated after appropriate informed consent. 
      Vector-related adverse events were minimal. Immune biomarkers were evaluated in 
      tumor and blood before and after GMCI. Significantly increased infiltration of 
      CD8(+) T cells was found in resected tumors. Expression of activation, 
      inhibitory, and proliferation markers, such as human leukocyte antigen (HLA)-DR, 
      CD38, Ki67, PD-1, CD39, and CTLA-4, were significantly increased in both the 
      tumor and peripheral CD8(+) T cells. Thus, intratumoral AdV-tk injection into 
      non-small-cell lung cancer (NSCLC) proved safe and feasible, and it effectively 
      induced CD8(+) T cell activation. These data provide a foundation for additional 
      clinical trials of GMCI for lung cancer patients with potential benefit if 
      combined with other immune therapies.
CI  - Copyright (c) 2020 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Predina, Jarrod D
AU  - Predina JD
AD  - Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, 
      Philadelphia, PA, USA; Division of Thoracic Surgery, Department of Surgery, 
      Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
FAU - Haas, Andrew R
AU  - Haas AR
AD  - Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, 
      Philadelphia, PA, USA; Division of Pulmonary, Allergy and Critical Care, Perelman 
      School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
FAU - Martinez, Marina
AU  - Martinez M
AD  - Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, 
      Philadelphia, PA, USA; Division of Pulmonary, Allergy and Critical Care, Perelman 
      School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
FAU - O'Brien, Shaun
AU  - O'Brien S
AD  - Division of Pulmonary, Allergy and Critical Care, Perelman School of Medicine, 
      University of Pennsylvania, Philadelphia, PA, USA.
FAU - Moon, Edmund K
AU  - Moon EK
AD  - Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, 
      Philadelphia, PA, USA; Division of Pulmonary, Allergy and Critical Care, Perelman 
      School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
FAU - Woodruff, Patrick
AU  - Woodruff P
AD  - Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, 
      Philadelphia, PA, USA; Division of Pulmonary, Allergy and Critical Care, Perelman 
      School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
FAU - Stadanlick, Jason
AU  - Stadanlick J
AD  - Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, 
      Philadelphia, PA, USA; Division of Thoracic Surgery, Department of Surgery, 
      Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
FAU - Corbett, Christopher
AU  - Corbett C
AD  - Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, 
      Philadelphia, PA, USA; Division of Thoracic Surgery, Department of Surgery, 
      Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
FAU - Frenzel-Sulyok, Lydia
AU  - Frenzel-Sulyok L
AD  - Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, 
      Philadelphia, PA, USA; Division of Thoracic Surgery, Department of Surgery, 
      Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
FAU - Bryski, Mitchell G
AU  - Bryski MG
AD  - Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, 
      Philadelphia, PA, USA; Division of Thoracic Surgery, Department of Surgery, 
      Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
FAU - Eruslanov, Evgeniy
AU  - Eruslanov E
AD  - Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, 
      Philadelphia, PA, USA; Division of Thoracic Surgery, Department of Surgery, 
      Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
FAU - Deshpande, Charuhas
AU  - Deshpande C
AD  - Pulmonary and Mediastinal Pathology, Department of Clinical Pathology and 
      Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, 
      Philadelphia, PA, USA.
FAU - Langer, Corey
AU  - Langer C
AD  - Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, 
      Philadelphia, PA, USA; Division of Hematology and Oncology, Perelman School of 
      Medicine, University of Pennsylvania, Philadelphia, MA, USA.
FAU - Aguilar, Laura K
AU  - Aguilar LK
AD  - Advantagene, Inc. d.b.a. Candel Therapeutics, Needham, MA, USA.
FAU - Guzik, Brian W
AU  - Guzik BW
AD  - Advantagene, Inc. d.b.a. Candel Therapeutics, Needham, MA, USA.
FAU - Manzanera, Andrea G
AU  - Manzanera AG
AD  - Advantagene, Inc. d.b.a. Candel Therapeutics, Needham, MA, USA.
FAU - Aguilar-Cordova, Estuardo
AU  - Aguilar-Cordova E
AD  - Advantagene, Inc. d.b.a. Candel Therapeutics, Needham, MA, USA.
FAU - Singhal, Sunil
AU  - Singhal S
AD  - Division of Thoracic Surgery, Department of Surgery, Perelman School of Medicine, 
      University of Pennsylvania, Philadelphia, PA, USA.
FAU - Albelda, Steven M
AU  - Albelda SM
AD  - Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, 
      Philadelphia, PA, USA; Division of Pulmonary, Allergy and Critical Care, Perelman 
      School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic 
      address: albelda@pennmedicine.upenn.edu.
LA  - eng
GR  - R01 CA187392/CA/NCI NIH HHS/United States
GR  - F32 CA210409/CA/NCI NIH HHS/United States
GR  - R01 CA193556/CA/NCI NIH HHS/United States
GR  - T32 CA009140/CA/NCI NIH HHS/United States
GR  - P01 CA087971/CA/NCI NIH HHS/United States
GR  - R01 CA172921/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20201105
PL  - United States
TA  - Mol Ther
JT  - Molecular therapy : the journal of the American Society of Gene Therapy
JID - 100890581
RN  - EC 2.7.1.21 (Thymidine Kinase)
SB  - IM
MH  - Adenoviridae/genetics
MH  - CD8-Positive T-Lymphocytes/immunology/metabolism
MH  - Carcinoma, Non-Small-Cell Lung/*immunology/pathology/*therapy
MH  - Cytotoxicity, Immunologic
MH  - *Genetic Therapy/methods
MH  - Genetic Vectors/administration & dosage/genetics
MH  - Humans
MH  - Immunotherapy/*methods
MH  - Lung Neoplasms/*immunology/pathology/*therapy
MH  - Neoadjuvant Therapy
MH  - Thymidine Kinase/genetics
PMC - PMC7854297
OTO - NOTNLM
OT  - PD-1
OT  - PD-L1
OT  - adenovirus
OT  - checkpoint inhibitor
OT  - gene therapy
OT  - gene-mediated cytotoxic immunotherapy
OT  - immunotherapy
OT  - intratumoral immunotherapy
OT  - lung cancer
OT  - neoadjuvant clinical trial
COIS- Declaration of Interests S.O., M.M., and S.M.A. were partially supported by a 
      clinical trial agreement with Advantagene. L.K.A., B.W.G., A.G.M., and E.A.-C. 
      are employees of Advantagene, who sponsored the trial. The remaining authors 
      declare no competing interests.
EDAT- 2020/11/08 06:00
MHDA- 2021/10/21 06:00
PMCR- 2022/02/03
CRDT- 2020/11/07 20:10
PHST- 2020/08/13 00:00 [received]
PHST- 2020/10/01 00:00 [revised]
PHST- 2020/10/31 00:00 [accepted]
PHST- 2020/11/08 06:00 [pubmed]
PHST- 2021/10/21 06:00 [medline]
PHST- 2020/11/07 20:10 [entrez]
PHST- 2022/02/03 00:00 [pmc-release]
AID - S1525-0016(20)30599-2 [pii]
AID - 10.1016/j.ymthe.2020.11.001 [doi]
PST - ppublish
SO  - Mol Ther. 2021 Feb 3;29(2):658-670. doi: 10.1016/j.ymthe.2020.11.001. Epub 2020 
      Nov 5.