Volume 8, Issue 3, Pages (September 2003)

Slides:



Advertisements
Similar presentations
Volume 14, Issue 3, Pages (September 2006)
Advertisements

Molecular Therapy - Oncolytics
Brian Hutzen, Chun-Yu Chen, Pin-Yi Wang, Les Sprague, Hayley M
Volume 17, Issue 7, Pages (July 2009)
Volume 15, Issue 1, Pages (January 2007)
Systemic administration of attenuated Salmonella choleraesuis in combination with cisplatin for cancer therapy  Che-Hsin Lee, Chao-Liang Wu, Yun-Sheng.
Volume 10, Issue 3, Pages (September 2004)
Volume 7, Issue 4, Pages (April 2003)
Volume 2, Issue 4, Pages (October 2000)
Molecular Therapy - Oncolytics
Volume 10, Issue 5, Pages (November 2004)
Volume 9, Issue 6, Pages (June 2004)
Pre-existing Immunity and Passive Immunity to Adenovirus 5 Prevents Toxicity Caused by an Oncolytic Adenovirus Vector in the Syrian Hamster Model  Debanjan.
Volume 9, Issue 4, Pages (April 2004)
Human Papilloma Virus E6 and E7 Proteins Support DNA Replication of Adenoviruses Deleted for the E1A and E1B Genes  Dirk S. Steinwaerder, Cheryl A. Carlson,
Gene therapy for lung cancer: Enhancement of tumor suppression by a combination of sequential systemic cisplatin and adenovirus-mediated p53 gene transfer 
Volume 10, Issue 6, Pages (December 2004)
Volume 14, Issue 1, Pages (July 2006)
Volume 20, Issue 12, Pages (December 2012)
Volume 18, Issue 11, Pages (November 2010)
Molecular Therapy - Oncolytics
Volume 18, Issue 9, Pages (September 2010)
Volume 3, Issue 2, Pages (February 2001)
The Immunocytokine L19–IL2 Eradicates Cancer When Used in Combination with CTLA-4 Blockade or with L19-TNF  Kathrin Schwager, Teresa Hemmerle, David Aebischer,
Molecular Therapy - Oncolytics
Volume 22, Issue 1, Pages (January 2014)
Incorporation of the B18R Gene of Vaccinia Virus Into an Oncolytic Herpes Simplex Virus Improves Antitumor Activity  Xinping Fu, Armando Rivera, Lihua.
Volume 9, Issue 6, Pages (June 2004)
Volume 2, Issue 4, Pages (October 2000)
Volume 23, Issue 4, Pages (April 2015)
Volume 23, Issue 4, Pages (April 2015)
Volume 12, Issue 5, Pages (November 2005)
Exosomes from M1-Polarized Macrophages Potentiate the Cancer Vaccine by Creating a Pro-inflammatory Microenvironment in the Lymph Node  Lifang Cheng,
Volume 21, Issue 1, Pages (January 2013)
Volume 15, Issue 9, Pages (September 2007)
Volume 16, Issue 6, Pages (June 2008)
Thomas S. Griffith, Elizabeth L. Broghammer  Molecular Therapy 
Volume 10, Issue 4, Pages (October 2004)
Volume 22, Issue 1, Pages (January 2014)
Volume 5, Issue 6, Pages (June 2002)
Volume 20, Issue 1, Pages (January 2012)
Volume 13, Issue 5, Pages (May 2006)
Volume 7, Issue 2, Pages (February 2003)
Elizabeth M Hadac, Elizabeth J Kelly, Stephen J Russell 
Sangeet Lal, Corey Raffel  Molecular Therapy - Oncolytics 
Volume 6, Issue 3, Pages (September 2002)
Volume 18, Issue 8, Pages (August 2010)
Molecular Therapy - Oncolytics
Molecular Therapy - Oncolytics
Volume 26, Issue 1, Pages (January 2018)
Newly Characterized Murine Undifferentiated Sarcoma Models Sensitive to Virotherapy with Oncolytic HSV-1 M002  Eric K. Ring, Rong Li, Blake P. Moore,
Volume 17, Issue 10, Pages (October 2009)
Volume 15, Issue 11, Pages (November 2007)
Valerie Künzi, Patrick A
Volume 10, Issue 6, Pages (December 2004)
Volume 8, Issue 2, Pages (August 2003)
Volume 18, Issue 3, Pages (March 2010)
Oncolytic therapy using a mutant type-1 herpes simplex virus and the role of the immune system  Eric S Lambright, MD, David J Caparrelli, MD, Abbas E.
Volume 6, Issue 5, Pages (November 2002)
Volume 23, Issue 3, Pages (March 2015)
Therapeutic Efficacy of G207, a Conditionally Replicating Herpes Simplex Virus Type 1 Mutant, for Gallbladder Carcinoma in Immunocompetent Hamsters  Kenji.
Volume 3, Issue 5, Pages (May 2001)
Single-Shot, Multicycle Suicide Gene Therapy by Replication-Competent Retrovirus Vectors Achieves Long-Term Survival Benefit in Experimental Glioma  Chien-Kuo.
Volume 20, Issue 4, Pages (April 2012)
The Enhanced Tumor Specificity of TG6002, an Armed Oncolytic Vaccinia Virus Deleted in Two Genes Involved in Nucleotide Metabolism  Johann Foloppe, Juliette.
Volume 16, Issue 10, Pages (October 2008)
Volume 20, Issue 6, Pages (June 2012)
Volume 18, Issue 10, Pages (October 2010)
Volume 15, Issue 2, Pages (February 2007)
Volume 12, Issue 5, Pages (November 2005)
Presentation transcript:

Volume 8, Issue 3, Pages 412-424 (September 2003) Novel immunocompetent murine tumor models for the assessment of replication- competent oncolytic adenovirus efficacy  Gunnel Halldén, Richard Hill, Yaohe Wang, Arthi Anand, Ta-Chiang Liu, Nick R Lemoine, Jennelle Francis, Lynda Hawkins, David Kirn  Molecular Therapy  Volume 8, Issue 3, Pages 412-424 (September 2003) DOI: 10.1016/S1525-0016(03)00199-0 Copyright © 2003 The American Society of Gene Therapy Terms and Conditions

FIG. 1. In vitro assessment of Ad5 uptake, replication, and cytopathic effects in murine and human carcinoma cell lines. (A) Cells were infected at 10 (black bars) or 100 (gray bars) particles/cell (ppc) with Ad-GFP and harvested 24 h postinfection to determine infectivity by FACS analysis. The data are from three experiments, each done in triplicate (±SE). (B) Subconfluent murine and human cell lines were infected with Ad5 wild-type virus at 1000 ppc for 1 h. Cells were harvested 48 and 96 h postinfection, and Western blots were carried out for E1A and late coat proteins (hexon, fiber) as described under Methods. All viral proteins expressed in the murine cell lines were of the same molecular weight as those expressed in the human cell lines. (C) Cells were infected at 100 ppc with Ad5 and harvested 96 h later and infectious virus units were quantitated by limiting dilution assay on HEK293 cells (results in triplicate, repeated twice, ±SE); A549 burst performed at 48 h due to induction of severe cytopathic effects. (D) Results from representative cytopathic effect assay showing Ad5 and dl312 (E1A-negative) activity on two human (H460, A549) and nine murine cancer lines. Cells were infected with either Ad5 or dl312 at the ppc shown and stained with crystal violet 5 days later. Molecular Therapy 2003 8, 412-424DOI: (10.1016/S1525-0016(03)00199-0) Copyright © 2003 The American Society of Gene Therapy Terms and Conditions

FIG. 2. In vivo screening for E1A and coat protein expression in immunocompetent murine tumor xenografts following intratumoral injection with Ad5. Murine tumors were grown subcutaneously in the flanks of immunocompetent mice and were subsequently injected directly with Ad5 on days 1–3. On day 6 ± 1 posttreatment tumors were harvested and processed and immunohistochemistry (IHC) was performed for Ad E1A or Ad coat proteins as described under Methods. Representative cross sections of JC (permissive) and CMT-tk (nonpermissive) tumors are shown. Brown-staining cells were positive for protein expression (Note. For JC tumors only, negative controls are not shown but they included tumors injected with UV-inactivated dl312, and for IHC the primary antibody was omitted). Cytopathic effects (C.P.E.) are shown on H and E staining of JC tumors only (cell rounding, eosinophilic cytoplasm, nuclear inclusions). Molecular Therapy 2003 8, 412-424DOI: (10.1016/S1525-0016(03)00199-0) Copyright © 2003 The American Society of Gene Therapy Terms and Conditions

FIG. 3. Evidence for intratumoral viral replication in JC and CMT-64 tumors growing in immunocompetent mice. CMT-93 (white bar), JC (black bar), and CMT-64 (hatched bar) tumors were grown subcutaneously in the flanks of immunocompetent mice and were subsequently injected directly with Ad5 or nonreplicating control adenovirus (PUV-dl312; not detectable). On days 1, 5, or 15 posttreatment tumors were harvested and processed and infectious units were quantitated as described under Methods. The mean values (±SE) are shown for six tumors per time point. *Undetectable. Molecular Therapy 2003 8, 412-424DOI: (10.1016/S1525-0016(03)00199-0) Copyright © 2003 The American Society of Gene Therapy Terms and Conditions

FIG. 4. Local cellular immune response following injection with Ad5 versus control adenovirus or PBS in immunocompetent murine tumor xenografts. JC or CMT-93 tumors were grown subcutaneously in the flanks of immunocompetent mice and were subsequently injected directly with Ad5, PBS, or replication-attenuated adenovirus (dl312) on days 1–3. On days 5, 15, and 22 posttreatment tumors were harvested, processed, and sectioned and H and E staining was performed to assess cellular immune infiltration, including eosinophils and PMNs. Immunohistochemistry (IHC) was performed for macrophage and CD8(+) cell infiltration between days 5 and 22. (A) Representative cross sections of CMT-93 and JC tumors demonstrating Ad5-associated eosinophilic infiltration (CMT-93) and macrophage infiltration (both models). (B) Representative IHC staining of CD8-positive cell infiltration in CMT-93 tumors on day 15 posttreatment. (C) Semiquantitative histopathology scoring of eosinophil, macrophage, and CD8(+) cell infiltration at the indicated time points in CMT-93 tumors (scored as described under Methods). Molecular Therapy 2003 8, 412-424DOI: (10.1016/S1525-0016(03)00199-0) Copyright © 2003 The American Society of Gene Therapy Terms and Conditions

FIG. 5. Antitumoral efficacy following treatment with Ad5 versus nonreplicating control adenovirus (PUV-inactivated dl312) in immunocompetent versus athymic murine tumor xenografts. (A) Kaplan–Meier curve for CMT-64 groups. CMT-64 tumors were injected as described with Ad5 (black circle), replication-deficient adenovirus (PUV-dl312; open circle), or PBS (open square) and were followed for progression (tumor volume >400 μl; P = 0.04 and 0.01, respectively). Kaplan–Meier curves for JC treatment groups in (B) immunocompetent BalbC mice or (C) athymic nu/nu mice are also shown. JC tumor cells were preinfected (5%) as described with Ad5 (black) or replication-incompetent adenovirus (PUV-dl312; open) prior to inoculation subcutaneously in the flanks of immunocompetent mice. The percentage of mice alive over time is shown (P = 0.04 for Ad5 versus control). CMT-93 tumors were grown subcutaneously in the flanks of (D) C57B/6 immunocompetent or (E) athymic (nu/nu) mice and were subsequently injected directly with PBS (open square), Ad5 (black square), adenovirus control particle (open triangle; PUV-dl312), or dl312 (open circle; E1A-negative control). The percentage of mice free from progression at each time point was estimated using the Kaplan–Meier method (±SE) (P = 0.004 for Ad5 vs control particle, P < 0.001 vs PBS, P = 0.03 vs dl312). Molecular Therapy 2003 8, 412-424DOI: (10.1016/S1525-0016(03)00199-0) Copyright © 2003 The American Society of Gene Therapy Terms and Conditions