OncoSec Medical Inc (ONCSQ)

[hschlauch]

I immerse myself in journal publications to keep myself current.

To keep this post relevant to Oncosec, I've included several publications that ought to be relevant to their new multigene construct. I think "Spark", their new multigene product, will demonstrate improvements to IL-12 transfection efficiency, downregulation of PD-1 checkpoints on T cells, better trafficking of T cells to the tumor microenvironment, and improved T cell activation.

If the "licensing" model is correct for anti-PD-1 therapy, then direct, protracted and adequate expression of IL-12 in the TME will lead to significantly lowered PD-1 on T cells. I am pretty confident that rescuing exhausted T cells is possible without anti-PD-1 checkpoint inhibitors. It can be accomplished through adequate expression of local IL-12 through the upregulation of T-bet (induced by interferon gamma).

Of course, IL-12 also triggers interferon gamma production. This improves MHC I and II cancer antigen presentation. We should be seeing improvements in interferon gamma levels and antigen presentation following local administration of Spark.

Very few people I gather actually understand the implications of this first multigene product and how simple improvements to IL-12 production (through a new plasmid construct) will have major downstream effects, including downregulation of immune checkpoints.

Here are some published data to back up what I'm saying and to let everyone know that I'm not just pulling this from you know where...


IL-12 Effect on PD-1 Expression

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3720703/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342548/

http://cancerres.aacrjournals.org/content/76/21/6266

http://www.jimmunol.org/content/186/5/3093

http://www.mdpi.com/2072-6694/10/12/498/pdf

https://www.nature.com/articles/s41434-018-0044-5

https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1003208

https://www.ncbi.nlm.nih.gov/pubmed/30552459

https://jitc.biomedcentral.com/articles/10.1186/2051-1426-2-S3-P10

https://www.cell.com/immunity/fulltext/S1074-7613(18)30439-4?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1074761318304394%3Fshowall%3Dtrue


IL-12 Upregulates T-bet Via STAT4-Interferon gamma-STAT1 Pathway

https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1003208

https://www.ncbi.nlm.nih.gov/pubmed/17114419

https://www.ncbi.nlm.nih.gov/pubmed/16220539

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1774174/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2768040/

https://www.sciencedirect.com/science/article/pii/S1074761312004177

https://www.sciencedirect.com/science/article/pii/S0954611106005075

http://www.medsci.org/v14p0977.htm

https://iai.asm.org/content/75/4/1738
https://www.ncbi.nlm.nih.gov/pubmed/12893768

http://www.bioscirep.org/content/38/3/BSR20171420

https://journals.lww.com/transplantjournal/Fulltext/2011/01150/Treatment_With_Interleukin_12_23p40_Antibody.6.aspx

http://rbmb.net/article-1-115-en.pdf


T-bet Regulates PD-1 Expression on T Cells

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6112830/

https://www.nature.com/articles/ni.2046

http://cancerres.aacrjournals.org/content/79/4_Supplement/P4-06-22

http://www.jimmunol.org/content/jimmunol/196/6/2431.full.pdf

https://www.cell.com/immunity/pdf/S1074-7613(16)30005-X.pdf

https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1004251

http://tcr.amegroups.com/article/view/20796

https://jvi.asm.org/content/90/19/8934

https://www.cellmolbiol.org/index.php/CMB/article/view/2455

https://www.hindawi.com/journals/jir/2016/8941260/


CXCL9 Recruits T Cells to the Tumor Microenvironment

http://www.jimmunol.org/content/196/1_Supplement/212.1

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4305179/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2885704/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5119981/

https://www.nature.com/articles/bjc2016172

https://www.tandfonline.com/doi/full/10.4161/onci.25752

https://www.researchgate.net/figure/CXCL9-and-CXCL10-promote-the-migration-of-antigen-specific-T-cells-in-the-absence-of-Type_fig3_316358401

http://ascopubs.org/doi/abs/10.1200/jco.2015.33.3_suppl.627


Membrane-Bound anti-CD3 Provides Signal 1 for T Cell Activation

http://www.jimmunol.org/content/jimmunol/163/7/3948.full.pdf

https://www.nrcresearchpress.com/doi/10.1139/O07-013#.XI7tP63My9s

https://www.ncbi.nlm.nih.gov/pubmed/10694815

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5502409/