The employment of vaccinia virus for colorectal cancer treatment: A review of preclinical and clinical studies

Figures & data

Figure 1. The strategies employed to improve the efficacy of VV for CRC treatment.

Table 1. Recombinant VVs in cancer vaccine for colon cancer.

VV	Strain	Modification	Antitumor mechanism	Combination	Administration	Ref.
TroVax	Modified vaccinia Ankara	H5T4	CD4+ T cells		i.p.	^1718
rV-CEA	Western Reserve	Human carcinoembryonic Ag	Mucosal vaccination was also associated with an increase in systemic CEA-specific IgG Ab titers, CD4 and CD8 T cell responses.		i.r.	^Citation15
rV-CD70	Wyeth	CD70	Stimulating T cell proliferation and cytokine production via CD27.	rV-CEA	s.c.	^Citation16
rV-ICAM-1	Wyeth	ICAM-1	Enhanced cytokine production or alloreactive cytotoxic T lymphocyte (CTL) activity.			^Citation17
NYVAC	Copenhagen	CD80/IL-2	IL-2 may play a role in the induction of antitumor response.			^Citation18
VJS6		Beta-gal	rVV-primed mice treated with IL-10 had enhanced vaccinia-specific cytotoxic T-lymphocyte activity.	IL-10	i.v.	^Citation19
B7-1β-gal rVV		B7-1/β-gal	The in vivo activity of IL-12 was independent of CD4+ T lymphocytes, whereas B7–1 rVV required both CD4+ and CD8+ T cells.	IL-12		^Citation20
rV		CEA/TRICOM	The combination of IFN-α and vaccine inhibited tumor growth, improved survival, and elicited CEA-specific CTL responses.	IFN-α	s.c.	^Citation21
Heat inactivated MVA	Modified vaccinia virus Ankara		Both cytosolic DNA-sensing and Batf3-dependent CD103+/CD8α+ DCs are essential for iMVA immunotherapy.		i.t.	^Citation22
rV-TRICOM/rV-CEA/TRICOM	Wyeth strain	B7-1, ICAM-1, LFA-3, CEA	An s.c. priming vaccination, followed by i.t. boosting vaccinations was superior to either s.c. or i.t. vaccination alone.		i.t./s.c.	^Citation23

i.p., intraperitoneal; i.t., intratumoral; s.c., subcutaneous; i.v., intravenous; i.r., intrarectal.

Table 2. Recombinant VV in oncolytic research for colon cancer.

VV	Strain	Modification	Antitumor mechanism	Combination	Animal models	Ref.
VVL15	Lister	TK-/firefly luciferase/the lacZ reporter gene	Inhibition of PI3Kδ enhanced antitumor efficacy via the inhibition of macrophages uptakes.	PI3Kδ inhibitor	i.v.	^Citation33
vvDD-SR-RFP		TK-/somatostatin receptor subtype 2/RFP	Tumor vasculature has a critical role in virus delivery and tumor response.		i.p.	^Citation34
CVV-PLGA	Wyeth strain	Tk-	PLGA nanofiber membranes help to deliver virus.		Implanted beneath the tumor	^Citation35
FUVAC		TK-/O1 L-	FUVAC decreased the tumor-associated immune suppressive factors locally and increased cytotoxic CD8+ T cells systemically.	Immune checkpoint inhibitor	i.t.	^Citation36
VVs	Western reserve	Deletion in N1 L, K1 L, K3 L, A46 R, or A52 R	ΔK1 L VV, ΔA46 R VV, and ΔA52 R VV demonstrated improved antitumor effect and survival compared to vvDD.		i.p.	^Citation37
vA34 R	Western reserve	Mutated A34 R	Improved spread and increased replication within the peritoneal cavity.		i.p.	^Citation38
vvDD; B18 R-	Western reserve	TK-/vgf-/B18 R-	Requirement of CD8+ T cells, NK cells, and IFNg, but not CD4+ T cells.	Anti-CTLA4 antibody	i.v.	^Citation39
vvDD/vvDD-CXCL11	Western reserve	TK-/vgf-/CXCL11	VV reduces PD-L1+ cells and facilitates non-redundant tumor infiltration of effector CD8+, CD4 + T cells.	Anti-PD-L1	i.t./i.p.	^Citation40
CVV	Wyeth	TK-/GFP/GPT	Antitumor effect correlated with the infiltration of CD8+PD-1+ T-cells.	Anti-PD-1	i.t.	^Citation41
CVV	Wyeth	Tk-	CVV was not affected by drug-resistance pathways.	5-Fu	i.p.	^Citation42
vvDD-mIL2	Western Reserve	mIL-2	The antitumoral activity depended on CD8+ T cells and IFN-γ, but not CD4+ T cells.		i.t.	^Citation43
vv	Western Reserve	Tethered IL-12	Tethered interleukin 12 (IL-12) could turn a “cold” tumor into a “hot” tumor while avoiding IL-12’s systemic toxicity.		i.v.	^Citation44
VSC20	Western Reserve	Vgf-/IL-23	Dependent on CD8+ and CD4+ T cells and IFN-γ.		i.t.	^Citation45
VVLDTKDN1 l-mIL-21	Lister	TK-/N1 L-/mIL-21	CD8+ T cells were required.		i.t.	^Citation46
VG9-IL-24	Tian Tan	IL-24/TK-	VV stimulated multiple antitumor immune responses and direct bystander antitumor activity.		i.t.	^Citation47
JX	Western Reserve	Murine GM-CSF	JX selectively infected and killed peritoneal colon cancer cells and promoted the intratumoral infiltration of DCs and CD8+ T cells.	Immune checkpoint inhibitors (ICIs)	i.p.	^Citation48
vvCCL19	Western Reserve	CCL19	Attracts DCs and CD4+ T cells.		i.p.	^Citation49
rVmSLC	Western Reserve	Secondary lymphoid chemokine	Enhanced infiltration of CD4 T cells, which correlated with inhibition of tumor growth.		i.t.	^Citation50
rV-CD40 L	Western Reserve	CD40 L	A subpopulation of NKT cells expressing CD40 (NK1.1 þ, CD3lo) appeared to be a major effector population responding to MC38/rV-CD40 L.			^Citation51
CF33-hNIS	Chimeric virus	Human sodium iodide symporter	hNIS made viral replication reliably imageable.		i.v.	^Citation52
GLV-1h151	Lister	TK-/GFP/β-galactosidase	GLV-1h151 is cytotoxic against a wide range of human cancer cell lines.		i.v./i.t.	^Citation53
GLV-1h153	Lister	GFP	GLV-1h153 can reach peritoneal carcinomatosis sites and kill malignant cells.		i.p.	^Citation54
SSTR2-expressing VV	Western Reserve	Human somatostatin receptor type 2	Tumors infected with the SSTR2-expressing VV accumulated higher concentrations of radioactivity for imaging.		i.p.	^Citation55
VG9	Tian Tan	TK-/CD	Intratumoral conversion of 5-FC prodrug into the anticancer drug 5-FU by CD gene.	5-FC	i.t.	^Citation56
VVCD	Western reserve	Cytosine deaminase CD	VVCD converts the prodrug 5-FC into 5-FU for antitumor effect.	5-FC	i.v./i.p.	^Citation57
VV-FCU1	Copenhagen	TK-/FCU1	Intratumoral conversion of 5-FC into 5-FU.	5-FC	i.t./i.v.	^Citation58
vvTRAIL		TK-/TRAIL	Oxaliplatin and TRAIL synergistically exerted antitumor activity.	Oxaliplatin	i.p.	^Citation59
NOV	Wyeth	TK-/VGF-/TRAIL/Ang1	Both Ang1 and TRAIL led to the induction of cancer-specific apoptosis and antitumor immunity.		i.p.	^Citation60
oncoVV-AVL	Western Reserve	Aphrocallistes vastus lectin	Virus replication upregulated by AVL was completely dependent on ERK activity.		i.t.	^Citation61
OVV-LG		Firefly luciferase and green fluorescent protein	Long noncoding RNA UCA1 enhances sensitivity to oncolytic vaccinia virus by sponging miR-18a miR-182 and modulating the Cdc42 filopodia axis.	Long noncoding RNA UCA1		^Citation62
vvDD	Western Reserve	Human somatostatin receptor (SR) and red fluorescent protein (RFP)	VV and CPT-11 synergistically exerted antitumor activity.	CPT-11 or SN-38	i.p.	^Citation63
VV	Western Reserve	TK-/VGF-/B18 R-	Trichostatin A (TSA) potently enhanced the spread and replication of VV.	Trichostatin A	i.v./i.p.	^Citation64

i.p. intraperitoneal; i.t. intratumoral; s.c. subcutaneous; i.v. intravenous.

Table 3. VVs employed in clinical trials for colon cancer.

Vaccinia virus	Modification	Study design	Case number	Clinical outcome	Ref.
BN-CV301	B7.1, ICAM-1, LFA-3	Phase I; open-label, 3 + 3 design, dose-escalation trial.	12	Single-agent BN-CV301 produced a confirmed partial response (PR) in 1 patient and prolonged stable disease (SD) in multiple patients.	^Citation82
rV-CEA(6D)-TRICOM/rF-CEA(6D)-TRICOM	B7.1, ICAM-1, LFA-3	Phase I; in Cycle 1, patients received thrice weekly s.c. injections of IFN-α-2b the week after rVCEA(6D)-TRICOM. In Cycles 2–4, patients received thrice weekly s.c. injections of IFN-α-2b the same week that rF-CEA(6D)-TRICOM was given.	33	No patients had a partial response, and eight patients exhibited SD of ≥3 months. Median progression-free survival and overall survival (OS) were 1.8 and 6.3 months, respectively. Significantly higher serum CD27 levels were observed after vaccine therapy and 42% of patients assayed developed CEA-specific T cell responses.	^Citation83
Pexa-Vec (JX-594)		Phase Ib; single-center, open-label.	15	Pexa-Vec administered as biweekly intravenous infusion was safe and well-tolerated.	^Citation84
vvDD	VGF-/TK-; Cytosine deaminase; somatostatin receptor	Phase I; open-label, dose-escalation trial using a single-dose group sequential dose-escalating design.	16	Intratumoral injection of the oncolytic vaccinia vvDD was well-tolerated in patients and resulted in selective infection of injected and noninjected tumors and antitumor activity.	^Citation85
vvDD	VGF-/TK-	Phase I; 11 patients were treated in three dose cohorts (3 × 108 pfu, 1 × 10^9 pfu, or 3 × 109 pfu). vvDD was infused in 250 ml of bicarbonate-buffered saline over 1 hour.	Colon cancer 7; pancreatic cancer 2; hepatocellular carcinoma 1; melanoma 1;	No dose-limiting toxicities and treatment-related severe adverse events were observed. One patient showed a mixed response on PET-CT with resolution of some liver metastases, and another patient with cutaneous melanoma demonstrated clinical regression of some lesions.	^Citation86
MVA-5T4	5T4	Phase I/II; Patients randomized to a cyclophosphamide group received 50 mg twice daily on treatment days 1 to 7 and 15 to 21. Patients randomized to a MVA-5T4 group received an intramuscular injection at a dose of 1 × 109 50% tissue culture infectious dose on treatment days 22, 36, 50, 64, 78, and 106.	55	Cyclophosphamide depleted regulatory T cells in 24 of 27 patients receiving MVA-5T4, prolonging PFS (5.0 vs 2.5 months; hazard ratio [HR], 0.48; 95% CI, 0.21–1.11; P = .09). MVA-5T4 doubled baseline anti-5T4 responses in 16 of 35 patients, resulting in prolonged PFS (5.6 vs 2.4 months; HR, 0.21; 95% CI, 0.09–0.47; P < .001) and OS.	^Citation87
TroVax	5T4	Phase I/II; an open-label upward titration study of TroVax given to patients via i.m. injection. In addition, a single dose level of TroVax, administered i.d., was included to explore the potential effect of this route on safety and immunogenicity.	22	TroVax was able to boost 5T4-specific immune responses in the presence of MVA-neutralizing antibodies. A positive association between the development of a 5T4 (but not MVA) antibody response and patient survival or time to disease progression.	^Citation88
TroVax	5T4	Phase II; an open label study of TroVax administered by i.m. injection to patients with advanced colorectal cancer receiving 5-FU/folinic acid plus oxaliplatin as first-line therapy.	17	Administration of TroVax alongside 5-fluorouracil, folinic acid, and oxaliplatin was safe and well tolerated with no serious adverse events. Of the 11 evaluable patients, 6 had complete or partial responses. 5T4-specific immune responses, but not MVA-specific immune responses, correlated with clinical benefit.	^Citation89
TroVax	5T4	Phase II; an open label study of TroVax administered by intramuscular injection to patients with advanced colorectal cancer receiving 5-FU, leukovorin and irinotecan as Wrst line therapy.	19	Administration of TroVax alongside chemotherapy was safe and well tolerated with no SAEs.	^Citation90

Table 4. Clinical trials for colon cancers and other solid tumors using VVs (https://clinicaltrials.gov/).

NCT number	Title	Conditions	Interventions	Phase	Case number
NCT00088933	Vaccine Therapy and Sargramostim With or Without Docetaxel in Treating Patients With Metastatic Lung Cancer or Metastatic Colorectal Cancer	•Extensive Stage Small Cell Lung Cancer •Recurrent Colon Cancer •Recurrent Non-small Cell Lung Cancer •Recurrent Rectal Cancer •Recurrent Small Cell Lung Cancer •Stage IV Colon Cancer •Stage IV Non-small Cell Lung Cancer •Stage IV Rectal Cancer	Recombinant fowlpox CEA(6D)/TRICOM vaccine Recombinant vaccinia CEA(6D)-TRICOM vaccine Docetaxel Sargramostim	Phase 1	60
NCT01191684	Vaccine Therapy in Treating Patients With Colorectal, Stomach, or Pancreatic Cancer	•Recurrent Colon Cancer •Recurrent Gastric Cancer •Recurrent Pancreatic Cancer •Recurrent Rectal Cancer •Stage III Colon Cancer •Stage III Gastric Cancer •Stage III Pancreatic Cancer •Stage III Rectal Cancer •Stage IV Colon Cancer •Stage IV Gastric Cancer •Stage IV Pancreatic Cancer •Stage IV Rectal Cancer	Modified vaccinia virus ankara vaccine expressing p53	Phase 1	12
NCT02432963	Vaccine Therapy and Pembrolizumab in Treating Patients With Solid Tumors That Have Failed Prior Therapy	•Adult Solid Neoplasm •Bladder Carcinoma •Colon Carcinoma •Estrogen Receptor Negative •Head and Neck Squamous Cell Carcinoma •Hepatocellular Carcinoma •HER2/Neu Negative •Melanoma •Non-Small Cell Lung Carcinoma •Pancreatic Carcinoma •and 7 more	Modified Vaccinia Virus Ankara Vaccine Expressing p53	Phase 1	19
NCT01329809	Neoadjuvant Study of Recombinant Vaccinia Virus to Treat Metastatic Colorectal Carcinoma in Patients Undergoing Complete Resection of Liver Tumors	•Colorectal Carcinoma	Recombinant Vaccinia GM CSF; RAC VAC GM-CSF (JX-594)	Phase 2	2
NCT01380600	Safety Study of Recombinant Vaccinia Virus Administered Intravenously in Patients With Metastatic, Refractory Colorectal Carcinoma	•Carcinoma, Colorectal	Recombinant Vaccinia GM CSF; RAC VAC GM-CSF (JX-594)	Phase 1	15
NCT01394939	Recombinant Vaccinia Virus Administered Intravenously in Patients With Metastatic, Refractory Colorectal Carcinoma	•Colorectal Carcinoma •CRC	JX-594 Irinotecan	Phase 1/2	52
NCT00103142	Vaccine Therapy in Treating Patients With Liver or Lung Metastases From Colorectal Cancer	•Colorectal Cancer •Metastatic Cancer	Falimarev Inalimarev Sargramostim Therapeutic autologous Dendritic cells	Phase 2	74

Kim-Schulze S, Kim HS, Wainstein A, Kim DW, Yang WC, Moroziewicz D, Mong PY, Bereta M, Taback B, Wang Q, et al. Intrarectal vaccination with recombinant vaccinia virus expressing carcinoembronic antigen induces mucosal and systemic immunity and prevents progression of colorectal cancer. J Immunol. 2008;181:8112–19. doi:10.4049/jimmunol.181.11.8112.

 PubMed Web of Science ®Google Scholar

Lorenz MG, Kantor JA, Schlom J, Hodge JW. Anti-tumor immunity elicited by a recombinant vaccinia virus expressing CD70 (CD27L). Hum Gene Ther. 1999;10:1095–103. doi:10.1089/10430349950018094.

 PubMed Web of Science ®Google Scholar

Uzendoski K, Kantor JA, Abrams SI, Schlom J, Hodge JW. Construction and characterization of a recombinant vaccinia virus expressing murine intercellular adhesion molecule-1: induction and potentiation of antitumor responses. Hum Gene Ther. 1997;8:851–60. doi:10.1089/hum.1997.8.7-851.

 PubMed Web of Science ®Google Scholar

Sivanandham M, Shaw P, Bernik SF, Paoletti E, Wallack MK. Colon cancer cell vaccine prepared with replication-deficient vaccinia viruses encoding B7.1 and interleukin-2 induce antitumor response in syngeneic mice. Cancer Immunol Immunother. 1998;46:261–67. doi:10.1007/s002620050486.

 PubMed Web of Science ®Google Scholar

Kaufman HL, Rao JB, Irvine KR, Bronte V, Rosenberg SA, Restifo NP. Interleukin-10 enhances the therapeutic effectiveness of a recombinant poxvirus-based vaccine in an experimental murine tumor model. J Immunother (1991). 1999;22:489–96. doi:10.1097/00002371-199911000-00003.

 PubMed Web of Science ®Google Scholar

Rao JB, Chamberlain RS, Bronte V, Carroll MW, Irvine KR, Moss B, Rosenberg SA, Restifo NP. IL-12 is an effective adjuvant to recombinant vaccinia virus-based tumor vaccines: enhancement by simultaneous B7-1 expression. J Immunol. 1996;156:3357–65.

 PubMed Web of Science ®Google Scholar

Hance KW, Rogers CJ, Zaharoff DA, Canter D, Schlom J, Greiner JW. The antitumor and immunoadjuvant effects of IFN-alpha in combination with recombinant poxvirus vaccines. Clin Cancer Res. 2009;15:2387–96. doi:10.1158/1078-0432.CCR-08-1752.

 PubMed Web of Science ®Google Scholar

Dai P, Wang W, Yang N, Serna-Tamayo C, Ricca JM, Zamarin D, Shuman S, Merghoub T, Wolchok JD, Deng L. Intratumoral delivery of inactivated modified vaccinia virus Ankara (iMVA) induces systemic antitumor immunity via STING and Batf3-dependent dendritic cells. Sci Immunol. 2017;2. doi:10.1126/sciimmunol.aal1713.

 Web of Science ®Google Scholar

Kudo-Saito C, Schlom J, Hodge JW. Intratumoral vaccination and diversified subcutaneous/intratumoral vaccination with recombinant poxviruses encoding a tumor antigen and multiple costimulatory molecules. Clin Cancer Res. 2004;10:1090–99. doi:10.1158/1078-0432.CCR-03-0145.

 PubMed Web of Science ®Google Scholar

Ferguson MS, Chard Dunmall LS, Gangeswaran R, Marelli G, Tysome JR, Burns E, Whitehead MA, Aksoy E, Alusi G, Hiley C, et al. Transient inhibition of PI3Kδ enhances the therapeutic effect of intravenous delivery of oncolytic vaccinia virus. Mol Ther. 2020;28:1263–75. doi:10.1016/j.ymthe.2020.02.017.

 PubMed Web of Science ®Google Scholar

Ottolino-Perry K, Tang N, Head R, Ng C, Arulanandam R, Angarita FA, Acuna SA, Chen Y, Bell J, DaCosta RS, et al. Tumor vascularization is critical for oncolytic vaccinia virus treatment of peritoneal carcinomatosis. Int J Cancer. 2014;134:717–30. doi:10.1002/ijc.28395.

 PubMed Web of Science ®Google Scholar

Badrinath N, Jeong YI, Woo HY, Bang SY, Kim C, Heo J, Kang DH, Yoo SY. Local delivery of a cancer-favoring oncolytic vaccinia virus via poly (lactic-co-glycolic acid) nanofiber for theranostic purposes. Int J Pharm. 2018;552:437–42. doi:10.1016/j.ijpharm.2018.10.020.

 PubMedGoogle Scholar

Nakatake M, Kuwano N, Kaitsurumaru E, Kurosaki H, Nakamura T. Fusogenic oncolytic vaccinia virus enhances systemic antitumor immune response by modulating the tumor microenvironment. Mol Ther. 2021;29:1782–93. doi:10.1016/j.ymthe.2020.12.024.

 PubMed Web of Science ®Google Scholar

Ho TY, Mealiea D, Okamoto L, Stojdl DF, McCart JA. Deletion of immunomodulatory genes as a novel approach to oncolytic vaccinia virus development. Mol Ther Oncolytics. 2021;22:85–97. doi:10.1016/j.omto.2021.05.007.

 PubMed Web of Science ®Google Scholar

Thirunavukarasu P, Sathaiah M, Gorry MC, O’Malley ME, Ravindranathan R, Austin F, Thorne SH, Guo ZS, Bartlett DL. A rationally designed A34R mutant oncolytic poxvirus: improved efficacy in peritoneal carcinomatosis. Mol Ther. 2013;21:1024–33. doi:10.1038/mt.2013.27.

 PubMed Web of Science ®Google Scholar

Rojas JJ, Sampath P, Hou W, Thorne SH. Defining effective combinations of immune checkpoint blockade and oncolytic virotherapy. Clin Cancer Res. 2015;21:5543–51. doi:10.1158/1078-0432.CCR-14-2009.

 PubMed Web of Science ®Google Scholar

Liu Z, Ravindranathan R, Kalinski P, Guo ZS, Bartlett DL. Rational combination of oncolytic vaccinia virus and PD-L1 blockade works synergistically to enhance therapeutic efficacy. Nat Commun. 2017;8:14754. doi:10.1038/ncomms14754.

 PubMed Web of Science ®Google Scholar

Yoo SY, Badrinath N, Jeong SN, Woo HY, Heo J. Overcoming tumor resistance to oncolyticvaccinia virus with anti-PD-1-based combination therapy by inducing antitumor immunity in the tumor microenvironment. Vaccines (Basel). 2020;8:321. doi:10.3390/vaccines8020321.

 PubMed Web of Science ®Google Scholar

Yoo SY, Bang SY, Jeong SN, Kang DH, Heo J. A cancer-favoring oncolytic vaccinia virus shows enhanced suppression of stem-cell like colon cancer. Oncotarget. 2016;7:16479–89. doi:10.18632/oncotarget.7660.

 PubMedGoogle Scholar

Liu W, Dai E, Liu Z, Ma C, Guo ZS, Bartlett DL. In Situ therapeutic cancer vaccination with an oncolytic virus expressing membrane-tethered IL-2. Mol Ther Oncolytics. 2020;17:350–60. doi:10.1016/j.omto.2020.04.006.

 PubMed Web of Science ®Google Scholar

Ge Y, Wang H, Ren J, Liu W, Chen L, Chen H, Ye J, Dai E, Ma C, Ju S, et al. Oncolytic vaccinia virus delivering tethered IL-12 enhances antitumor effects with improved safety. J Immunother Cancer. 2020;8:e000710. doi:10.1136/jitc-2020-000710.

 PubMed Web of Science ®Google Scholar

Chen L, Chen H, Ye J, Ge Y, Wang H, Dai E, Ren J, Liu W, Ma C, Ju S, et al. Intratumoral expression of interleukin 23 variants using oncolytic vaccinia virus elicit potent antitumor effects on multiple tumor models via tumor microenvironment modulation. Theranostics. 2021;11:6668–81. doi:10.7150/thno.56494.

 PubMed Web of Science ®Google Scholar

Wang N, Wang J, Zhang Z, Cao H, Yan W, Chu Y, Chard Dunmall LS, Wang Y. A novel vaccinia virus enhances anti-tumor efficacy and promotes a long-term anti-tumor response in a murine model of colorectal cancer. Mol Ther Oncolytics. 2021;20:71–81. doi:10.1016/j.omto.2020.11.002.

 PubMed Web of Science ®Google Scholar

Deng L, Yang X, Fan J, Ding Y, Peng Y, Xu D, Huang B, Hu Z. IL-24-armed oncolytic vaccinia virus exerts potent antitumor effects via multiple pathways in colorectal cancer. Oncol Res. 2021;28:579–90. doi:10.3727/096504020X15942028641011.

 PubMed Web of Science ®Google Scholar

Lee YS, Lee WS, Kim CW, Lee SJ, Yang H, Kong SJ, Ning J, Yang K-M, Kang B, Kim WR, et al. Oncolytic vaccinia virus reinvigorates peritoneal immunity and cooperates with immune checkpoint inhibitor to suppress peritoneal carcinomatosis in colon cancer. J Immunother Cancer. 2020;8:e000857. doi:10.1136/jitc-2020-000857.

 PubMed Web of Science ®Google Scholar

Li J, O’Malley M, Sampath P, Kalinski P, Bartlett DL, Thorne SH. Expression of CCL19 from oncolytic vaccinia enhances immunotherapeutic potential while maintaining oncolytic activity. Neoplasia. 2012;14:1115–21. doi:10.1593/neo.121272.

 PubMed Web of Science ®Google Scholar

Flanagan K, Glover RT, Horig H, Yang W, Kaufman HL. Local delivery of recombinant vaccinia virus expressing secondary lymphoid chemokine (SLC) results in a CD4 T-cell dependent antitumor response. Vaccine. 2004;22:2894–903. doi:10.1016/j.vaccine.2003.12.021.

 PubMed Web of Science ®Google Scholar

Bereta M, Bereta J, Park J, Medina F, Kwak H, Kaufman HL. Immune properties of recombinant vaccinia virus encoding CD154 (CD40L) are determined by expression of virally encoded CD40L and the presence of CD40L protein in viral particles. Cancer Gene Ther. 2004;11:808–18. doi:10.1038/sj.cgt.7700762.

 PubMed Web of Science ®Google Scholar

Warner SG, Kim SI, Chaurasiya S, O’Leary MP, Lu J, Sivanandam V, Woo Y, Chen NG, Fong Y. A novel chimeric poxvirus encoding hNIS is tumor-tropic, imageable, and synergistic with radioiodine to sustain colon cancer regression. Mol Ther Oncolytics. 2019;13:82–92. doi:10.1016/j.omto.2019.04.001.

 PubMed Web of Science ®Google Scholar

Haddad D, Chen N, Zhang Q, Chen CH, Yu YA, Gonzalez L, Aguilar J, Li P, Wong J, Szalay AA, et al. A novel genetically modified oncolytic vaccinia virus in experimental models is effective against a wide range of human cancers. Ann Surg Oncol. 2012;19(Suppl 3):S665–74. doi:10.1245/s10434-011-2198-x.

 PubMedGoogle Scholar

Eveno C, Mojica K, Ady JW, Thorek DL, Longo V, Belin LJ, Gholami S, Johnsen C, Zanzonico P, Chen N, et al. Gene therapy using therapeutic and diagnostic recombinant oncolytic vaccinia virus GLV-1h153 for management of colorectal peritoneal carcinomatosis. Surgery. 2015;157:331–37. doi:10.1016/j.surg.2014.09.008.

 PubMed Web of Science ®Google Scholar

McCart JA, Mehta N, Scollard D, Reilly RM, Carrasquillo JA, Tang N, Deng H, Miller M, Xu H, Libutti SK, et al. Oncolytic vaccinia virus expressing the human somatostatin receptor SSTR2: molecular imaging after systemic delivery using 111in-pentetreotide. Mol Ther. 2004;10:553–61. doi:10.1016/j.ymthe.2004.06.158.

 PubMed Web of Science ®Google Scholar

Ding Y, Fan J, Deng L, Huang B, Zhou B. Antitumor efficacy of cytosine deaminase-armed vaccinia virus plus 5-fluorocytosine in colorectal cancers. Cancer Cell Int. 2020;20:243. doi:10.1186/s12935-020-01340-6.

 PubMed Web of Science ®Google Scholar

McCart JA, Puhlmann M, Lee J, Hu Y, Libutti SK, Alexander HR, Bartlett DL. Complex interactions between the replicating oncolytic effect and the enzyme/prodrug effect of vaccinia-mediated tumor regression. Gene Ther. 2000;7:1217–23. doi:10.1038/sj.gt.3301237.

 PubMed Web of Science ®Google Scholar

Foloppe J, Kintz J, Futin N, Findeli A, Cordier P, Schlesinger Y, Hoffmann C, Tosch C, Balloul J-M, Erbs P. Targeted delivery of a suicide gene to human colorectal tumors by a conditionally replicating vaccinia virus. Gene Ther. 2008;15:1361–71. doi:10.1038/gt.2008.82.

 PubMed Web of Science ®Google Scholar

Ziauddin MF, Guo ZS, O’Malley ME, Austin F, Popovic PJ, Kavanagh MA, Li J, Sathaiah M, Thirunavukarasu P, Fang B, et al. TRAIL gene-armed oncolytic poxvirus and oxaliplatin can work synergistically against colorectal cancer. Gene Ther. 2010;17:550–59. doi:10.1038/gt.2010.5.

 PubMed Web of Science ®Google Scholar

Jeong SN, Yoo SY. Novel oncolytic virus armed with cancer suicide gene and normal vasculogenic gene for improved anti-tumor activity. Cancers (Basel). 2020;12:1070. doi:10.3390/cancers12051070.

 PubMed Web of Science ®Google Scholar

Wu T, Xiang Y, Liu T, Wang X, Ren X, Ye T, Li G. Oncolytic vaccinia virus expressing aphrocallistes vastus lectin as a cancer therapeutic agent. Mar Drugs. 2019;17:363. doi:10.3390/md17060363.

 PubMed Web of Science ®Google Scholar

Horita K, Kurosaki H, Nakatake M, Ito M, Kono H, Nakamura T. Long noncoding RNA UCA1 enhances sensitivity to oncolytic vaccinia virus by sponging miR-18a/mir-182 and modulating the Cdc42/filopodia axis in colorectal cancer. Biochem Biophys Res Commun. 2019;516:831–38. doi:10.1016/j.bbrc.2019.06.125.

 PubMed Web of Science ®Google Scholar

Ottolino-Perry K, Acuna SA, Angarita FA, Sellers C, Zerhouni S, Tang N, McCart JA. Oncolytic vaccinia virus synergizes with irinotecan in colorectal cancer. Mol Oncol. 2015;9:1539–52. doi:10.1016/j.molonc.2015.04.009.

 PubMed Web of Science ®Google Scholar

MacTavish H, Diallo JS, Huang B, Stanford M, Le Boeuf F, De Silva N, Cox J, Simmons JG, Guimond T, Falls T, et al. Enhancement of vaccinia virus based oncolysis with histone deacetylase inhibitors. PLoS One. 2010;5:e14462. doi:10.1371/journal.pone.0014462.

 PubMed Web of Science ®Google Scholar

Gatti-Mays ME, Strauss J, Donahue RN, Palena C, Del Rivero J, Redman JM, Madan RA, Marté JL, Cordes LM, Lamping E, et al. A phase I dose-escalation trial of BN-CV301, a recombinant poxviral vaccine targeting MUC1 and CEA with costimulatory molecules. Clin Cancer Res. 2019;25:4933–44. doi:10.1158/1078-0432.CCR-19-0183.

 PubMed Web of Science ®Google Scholar

Duggan MC, Jochems C, Donahue RN, Richards J, Karpa V, Foust E, Paul B, Brooks T, Tridandapani S, Olencki T, et al. A phase I study of recombinant (r) vaccinia-CEA(6D)-TRICOM and rFowlpox-CEA(6D)-TRICOM vaccines with GM-CSF and IFN-α-2b in patients with CEA-expressing carcinomas. Cancer Immunol Immunother. 2016;65:1353–64. doi:10.1007/s00262-016-1893-7.

 PubMed Web of Science ®Google Scholar

Park SH, Breitbach CJ, Lee J, Park JO, Lim HY, Kang WK, Moon A, Mun J-H, Sommermann EM, Maruri Avidal L, et al. Phase 1b trial of biweekly intravenous Pexa-Vec (JX-594), an oncolytic and immunotherapeutic vaccinia virus in colorectal cancer. Mol Ther. 2015;23:1532–40. doi:10.1038/mt.2015.109.

 PubMed Web of Science ®Google Scholar

Zeh HJ, Downs-Canner S, McCart JA, Guo ZS, Rao UN, Ramalingam L, Thorne SH, Jones HL, Kalinski P, Wieckowski E, et al. First-in-man study of western reserve strain oncolytic vaccinia virus: safety, systemic spread, and antitumor activity. Mol Ther. 2015;23:202–14. doi:10.1038/mt.2014.194.

 PubMed Web of Science ®Google Scholar

Downs-Canner S, Guo ZS, Ravindranathan R, Breitbach CJ, O’Malley ME, Jones HL, Moon A, McCart JA, Shuai Y, Zeh HJ, et al. Phase 1 study of intravenous oncolytic poxvirus (vvDD) in patients with advanced solid cancers. Mol Ther. 2016;24:1492–501. doi:10.1038/mt.2016.101.

 PubMed Web of Science ®Google Scholar

Scurr M, Pembroke T, Bloom A, Roberts D, Thomson A, Smart K, Bridgeman H, Adams R, Brewster A, Jones R, et al. Effect of modified vaccinia Ankara–5T4 and low-dose cyclophosphamide on antitumor immunity in metastatic colorectal cancer. JAMA Oncol. 2017;3:e172579. doi:10.1001/jamaoncol.2017.2579.

 PubMed Web of Science ®Google Scholar

Harrop R, Connolly N, Redchenko I, Valle J, Saunders M, Ryan MG, Myers KA, Drury N, Kingsman SM, Hawkins RE, et al. Vaccination of colorectal cancer patients with modified vaccinia Ankara delivering the tumor antigen 5T4 (TroVax) induces immune responses which correlate with disease control: a phase I/II trial. Clin Cancer Res. 2006;12:3416–24. doi:10.1158/1078-0432.CCR-05-2732.

 PubMed Web of Science ®Google Scholar

Harrop R, Drury N, Shingler W, Chikoti P, Redchenko I, Carroll MW, Kingsman SM, Naylor S, Melcher A, Nicholls J, et al. Vaccination of colorectal cancer patients with modified vaccinia ankara encoding the tumor antigen 5T4 (TroVax) given alongside chemotherapy induces potent immune responses. Clin Cancer Res. 2007;13:4487–94. doi:10.1158/1078-0432.CCR-07-0704.

 PubMed Web of Science ®Google Scholar

Harrop R, Drury N, Shingler W, Chikoti P, Redchenko I, Carroll MW, Kingsman SM, Naylor S, Griffiths R, Steven N, et al. Vaccination of colorectal cancer patients with TroVax given alongside chemotherapy (5-fluorouracil, leukovorin and irinotecan) is safe and induces potent immune responses. Cancer Immunol Immunother. 2008;57:977–86. doi:10.1007/s00262-007-0428-7.

 PubMed Web of Science ®Google Scholar