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Systemic treatment of xenografts with vaccinia virus GLV-1h68 reveals the immunologic facet of oncolytic therapy.

Worschech A, Chen N, Yu YA, Zhang Q, Pos Z, Weibel S, Raab V, Sabatino M, Monaco A, Liu H, MonsurrĂ³ V, Buller RM, Stroncek DF, Wang E, Szalay AA, Marincola FM - BMC Genomics (2009)

Bottom Line: These signatures precisely reproduce those observed in humans during immune-mediated tissue-specific destruction (TSD) that causes tumor or allograft rejection, autoimmunity or clearance of pathogens.We recently defined these common pathways in the "immunologic constant of rejection" hypothesis (ICR).This study provides the first prospective validation of a universal mechanism associated with TSD.

View Article: PubMed Central - HTML - PubMed

Affiliation: Genelux Corporation, San Diego Science Center, San Diego, California, USA. worschecha@mail.nih.gov

ABSTRACT

Background: GLV-1h68 is an attenuated recombinant vaccinia virus (VACV) that selectively colonizes established human xenografts inducing their complete regression.

Results: Here, we explored xenograft/VACV/host interactions in vivo adopting organism-specific expression arrays and tumor cell/VACV in vitro comparing VACV replication patterns. There were no clear-cut differences in vitro among responding and non-responding tumors, however, tumor rejection was associated in vivo with activation of interferon-stimulated genes (ISGs) and innate immune host's effector functions (IEFs) correlating with VACV colonization of the xenografts. These signatures precisely reproduce those observed in humans during immune-mediated tissue-specific destruction (TSD) that causes tumor or allograft rejection, autoimmunity or clearance of pathogens. We recently defined these common pathways in the "immunologic constant of rejection" hypothesis (ICR).

Conclusion: This study provides the first prospective validation of a universal mechanism associated with TSD. Thus, xenograft infection by oncolytic VACV, beyond offering a promising therapy of established cancers, may represent a reliable pre-clinical model to test therapeutic strategies aimed at modulating the central pathways leading to TSD; this information may lead to the identification of principles that could refine the treatment of cancer and chronic infection by immune stimulation or autoimmunity and allograft rejection through immune tolerance.

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Human Cancer signatures. (A) Time course analysis of infected GI-101A xenografts (parameters for gene selection; F test p-value < 0.005, 80% presence call, ratio of > 2 and false discovery rate < 0.1). Gene distribution is shown based on 893 genes of 17,500 present in the human cDNA platform that passed the statistical criteria and presented according to Spearman rank correlation. The dashed box outlines the 2 time points most affected by VACV infection. The heat map information is presented according to the central method for normalization [30]. (B) Multiple dimensional scaling based on the 36 k oligo array human platform comparing HT-29 and GI-101 xenografts. (C) Self organizing heat map based on 841 out of 1,073 genes differentially expressed between GI-101A xenografts from infected compared to non-infected mice that passed the standard filter conditions (presence call in at least 80% and at least 3 fold ratio change). HT-29 samples are also represented as a reference, color coding of samples is as per panel (B). The green bar underlines the genes specifically expressed by Gl-101A xenografts from infected animals; the 2 yellow arrows (a) and (b) point at genes who expression was profoundly depressed in xenografts from infected animals. (D) Ingenuity pathway analysis showing canonical pathways significantly down-regulated in GI-101A xenografts at day 41 following GLV-1h68 injection; IPA analysis based on an unpaired, two-tailed Student t test comparing infected to non-infected GI-101A xenografts at day 42 (threshold p2-value < 0.001).
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Figure 2: Human Cancer signatures. (A) Time course analysis of infected GI-101A xenografts (parameters for gene selection; F test p-value < 0.005, 80% presence call, ratio of > 2 and false discovery rate < 0.1). Gene distribution is shown based on 893 genes of 17,500 present in the human cDNA platform that passed the statistical criteria and presented according to Spearman rank correlation. The dashed box outlines the 2 time points most affected by VACV infection. The heat map information is presented according to the central method for normalization [30]. (B) Multiple dimensional scaling based on the 36 k oligo array human platform comparing HT-29 and GI-101 xenografts. (C) Self organizing heat map based on 841 out of 1,073 genes differentially expressed between GI-101A xenografts from infected compared to non-infected mice that passed the standard filter conditions (presence call in at least 80% and at least 3 fold ratio change). HT-29 samples are also represented as a reference, color coding of samples is as per panel (B). The green bar underlines the genes specifically expressed by Gl-101A xenografts from infected animals; the 2 yellow arrows (a) and (b) point at genes who expression was profoundly depressed in xenografts from infected animals. (D) Ingenuity pathway analysis showing canonical pathways significantly down-regulated in GI-101A xenografts at day 41 following GLV-1h68 injection; IPA analysis based on an unpaired, two-tailed Student t test comparing infected to non-infected GI-101A xenografts at day 42 (threshold p2-value < 0.001).

Mentions: A time course analysis evaluating the in vivo effects of viral replication on the permissive GI-101A human xenografts was performed using a custom-made 17.5 k human cDNA array platform [29]. 4 experimental groups of 4 mice each received systemic GLV-1h68 administration 1, 7, 21 and 42 days before xenograft excision (Figure 2A[30]). The transcriptional profile of infected GI-101A tumors was altered significantly by 21 days and increasingly so at 42 days after GLV-1h68 administration. Since the time course demonstrated that even in permissive xenografts significant changes occurred only at 21 and 42 days, we limited the subsequent analysis to these time points.


Systemic treatment of xenografts with vaccinia virus GLV-1h68 reveals the immunologic facet of oncolytic therapy.

Worschech A, Chen N, Yu YA, Zhang Q, Pos Z, Weibel S, Raab V, Sabatino M, Monaco A, Liu H, MonsurrĂ³ V, Buller RM, Stroncek DF, Wang E, Szalay AA, Marincola FM - BMC Genomics (2009)

Human Cancer signatures. (A) Time course analysis of infected GI-101A xenografts (parameters for gene selection; F test p-value < 0.005, 80% presence call, ratio of > 2 and false discovery rate < 0.1). Gene distribution is shown based on 893 genes of 17,500 present in the human cDNA platform that passed the statistical criteria and presented according to Spearman rank correlation. The dashed box outlines the 2 time points most affected by VACV infection. The heat map information is presented according to the central method for normalization [30]. (B) Multiple dimensional scaling based on the 36 k oligo array human platform comparing HT-29 and GI-101 xenografts. (C) Self organizing heat map based on 841 out of 1,073 genes differentially expressed between GI-101A xenografts from infected compared to non-infected mice that passed the standard filter conditions (presence call in at least 80% and at least 3 fold ratio change). HT-29 samples are also represented as a reference, color coding of samples is as per panel (B). The green bar underlines the genes specifically expressed by Gl-101A xenografts from infected animals; the 2 yellow arrows (a) and (b) point at genes who expression was profoundly depressed in xenografts from infected animals. (D) Ingenuity pathway analysis showing canonical pathways significantly down-regulated in GI-101A xenografts at day 41 following GLV-1h68 injection; IPA analysis based on an unpaired, two-tailed Student t test comparing infected to non-infected GI-101A xenografts at day 42 (threshold p2-value < 0.001).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC2713268&req=5

Figure 2: Human Cancer signatures. (A) Time course analysis of infected GI-101A xenografts (parameters for gene selection; F test p-value < 0.005, 80% presence call, ratio of > 2 and false discovery rate < 0.1). Gene distribution is shown based on 893 genes of 17,500 present in the human cDNA platform that passed the statistical criteria and presented according to Spearman rank correlation. The dashed box outlines the 2 time points most affected by VACV infection. The heat map information is presented according to the central method for normalization [30]. (B) Multiple dimensional scaling based on the 36 k oligo array human platform comparing HT-29 and GI-101 xenografts. (C) Self organizing heat map based on 841 out of 1,073 genes differentially expressed between GI-101A xenografts from infected compared to non-infected mice that passed the standard filter conditions (presence call in at least 80% and at least 3 fold ratio change). HT-29 samples are also represented as a reference, color coding of samples is as per panel (B). The green bar underlines the genes specifically expressed by Gl-101A xenografts from infected animals; the 2 yellow arrows (a) and (b) point at genes who expression was profoundly depressed in xenografts from infected animals. (D) Ingenuity pathway analysis showing canonical pathways significantly down-regulated in GI-101A xenografts at day 41 following GLV-1h68 injection; IPA analysis based on an unpaired, two-tailed Student t test comparing infected to non-infected GI-101A xenografts at day 42 (threshold p2-value < 0.001).
Mentions: A time course analysis evaluating the in vivo effects of viral replication on the permissive GI-101A human xenografts was performed using a custom-made 17.5 k human cDNA array platform [29]. 4 experimental groups of 4 mice each received systemic GLV-1h68 administration 1, 7, 21 and 42 days before xenograft excision (Figure 2A[30]). The transcriptional profile of infected GI-101A tumors was altered significantly by 21 days and increasingly so at 42 days after GLV-1h68 administration. Since the time course demonstrated that even in permissive xenografts significant changes occurred only at 21 and 42 days, we limited the subsequent analysis to these time points.

Bottom Line: These signatures precisely reproduce those observed in humans during immune-mediated tissue-specific destruction (TSD) that causes tumor or allograft rejection, autoimmunity or clearance of pathogens.We recently defined these common pathways in the "immunologic constant of rejection" hypothesis (ICR).This study provides the first prospective validation of a universal mechanism associated with TSD.

View Article: PubMed Central - HTML - PubMed

Affiliation: Genelux Corporation, San Diego Science Center, San Diego, California, USA. worschecha@mail.nih.gov

ABSTRACT

Background: GLV-1h68 is an attenuated recombinant vaccinia virus (VACV) that selectively colonizes established human xenografts inducing their complete regression.

Results: Here, we explored xenograft/VACV/host interactions in vivo adopting organism-specific expression arrays and tumor cell/VACV in vitro comparing VACV replication patterns. There were no clear-cut differences in vitro among responding and non-responding tumors, however, tumor rejection was associated in vivo with activation of interferon-stimulated genes (ISGs) and innate immune host's effector functions (IEFs) correlating with VACV colonization of the xenografts. These signatures precisely reproduce those observed in humans during immune-mediated tissue-specific destruction (TSD) that causes tumor or allograft rejection, autoimmunity or clearance of pathogens. We recently defined these common pathways in the "immunologic constant of rejection" hypothesis (ICR).

Conclusion: This study provides the first prospective validation of a universal mechanism associated with TSD. Thus, xenograft infection by oncolytic VACV, beyond offering a promising therapy of established cancers, may represent a reliable pre-clinical model to test therapeutic strategies aimed at modulating the central pathways leading to TSD; this information may lead to the identification of principles that could refine the treatment of cancer and chronic infection by immune stimulation or autoimmunity and allograft rejection through immune tolerance.

Show MeSH
Related in: MedlinePlus