OncoSec Medical Inc (ONCSQ)

[hschlauch]

This has got to be the most interesting journal article I have seen in quite some time:

https://www.nature.com/articles/s41591-018-0085-8

Published: 25 June 2018, Nature Medicine (2018)

A natural killer–dendritic cell axis defines checkpoint therapy–responsive tumor microenvironments

Kevin C. Barry, Joy Hsu, Miranda L. Broz, Francisco J. Cueto, Mikhail Binnewies, Alexis J. Combes, Amanda E. Nelson, Kimberly Loo, Raj Kumar, Michael D. Rosenblum, Michael D. Alvarado, Denise M. Wolf, Dusan Bogunovic, Nina Bhardwaj, Adil I. Daud, Patrick K. Ha, William R. Ryan, Joshua L. Pollack, Bushra Samad, Saurabh Asthana, Vincent Chan & Matthew F. Krummel

Abstract:

Intratumoral stimulatory dendritic cells (SDCs) play an important role in stimulating cytotoxic T cells and driving immune responses against cancer. Understanding the mechanisms that regulate their abundance in the tumor microenvironment (TME) could unveil new therapeutic opportunities. We find that in human melanoma, SDC abundance is associated with intratumoral expression of the gene encoding the cytokine FLT3LG. FLT3LG is predominantly produced by lymphocytes, notably natural killer (NK) cells in mouse and human tumors. NK cells stably form conjugates with SDCs in the mouse TME, and genetic and cellular ablation of NK cells in mice demonstrates their importance in positively regulating SDC abundance in tumor through production of FLT3L. Although anti-PD-1 ‘checkpoint’ immunotherapy for cancer largely targets T cells, we find that NK cell frequency correlates with protective SDCs in human cancers, with patient responsiveness to anti-PD-1 immunotherapy, and with increased overall survival. Our studies reveal that innate immune SDCs and NK cells cluster together as an excellent prognostic tool for T cell–directed immunotherapy and that these innate cells are necessary for enhanced T cell tumor responses, suggesting this axis as a target for new therapies

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Now, what happens when you electroporate DNA-encoded flt3 ligand intratumorally and bypass the need for local NK cell recruitment/expansion? This, I think, is the direction we’re heading with the first multigene product. The key components of one multigene construct have already been presented, and it contained encoded flt3 ligand along with an antigen and IL-12. Imagine being able to access any tumor or tumor draining lymph node virtually anywhere in the body to deliver a payload that would theoretically prime immune responses for any and all cancer antigens.

The one weakness I’ve observed in a vast majority of cancer immunotherapies under development is that they do not adequately address the early stages of immunity. For instance, what allows tumor recognition and cytotoxic T cell expansion if your therapy doesn’t mitigate intratumoral or TDLN Tregs or improve antigen presentation/trafficking to lymphoid tissue? Again, I firmly believe that you can numerically overwhelm Treg suppression (CTLA-4) and vastly improve cancer antigen presentation/trafficking through the intratumoral and/or TDLN presence of flt3 ligand. The application of the encoded ligand intratumorally and/or in lymphoid tissue expands populations of dendritic cells where they are needed most.

Oncosec’s technology, intratumoral platform, and multigene constructs together will be completely disruptive. In my estimation, any solid tumor cancer is fair game.