Sunday, April 19, 2015

Checkpoints Drugs Promise to Unlock RNA Therapeutics Cancer Potential

If you are involved in cancer drug development, you are probably thinking of ways to exploit checkpoint inhibitors for your purposes.  Checkpoints are the mechanisms whereby cancer cells avoid being recognized by the immune system as foreign and the initial clinical results of inhibiting them, e.g. by targeting CTLA4 and PD-1/PD-L1, has caused immune-oncology as a whole to take the cancer drug development space by storm.

Suddenly, every scientist and their technician believe that by taking checkpoints out of the equation, their immune approach to cancer, which in many cases was marked by failure after failure in the past, will work. 

Take e.g. cancer vaccines and the idea of grinding up tumors and use the cell mash to train dendritic cells.  Sounds compelling to me, but I also know that I lost a bunch much money on the very same idea 10 or so years ago with nothing, but some early promising data from the clinical Wild East to support it. 

Others meanwhile believe that their technologies may enable immune-oncology by e.g. being able to modulate the tumor microenvironment so as to permit better access of the tumor killing cells.

RNA Therapeutics are no exception.  RNA Therapeutics, due to its endless targeting opportunities, has always been considered promising for oncology, but has struggled to show clear-cut success either due to drug delivery issues or due to the difficulties of predicting immune activities based on rodent studies.

Emblematic of this reversal of fortunes is the toll-like receptor (TLR) field of activating the innate immune system with oligonucleotide stimulants.  The idea here is to provide an environment that is more conducive to tumor cell killing and/or to directly impact tumor cell survival (e.g. interferon stimulation).  Art Krieg, of TLR9 (CpG) fame, but who has been erring as its lost son in the (blooming) deserts of RNAi, RNaseH antisense, splice modulation, and RNA activation, is apparently re-energized enough to go back to TLR Therapeutics and has started Checkmate Pharmaceuticals which will likely try and harness TLR agonists for cancer immunotherapy.

Nanoparticle delivery may also see a revival.  This is because they have a propensity, usually undesired, to be taken up by phagocytic cells, some of which may be effective in antigen presentation (e.g. dendritic cells).  I have thus noticed that a number of mRNA cancer vaccine approaches involve nanoparticle delivery with the aim of expressing tumor antigens in the training camps of the immune system, the lymph nodes.  

Nanoparticles may also be a way to knock down the gate-keepers in the tumor microenvironment which inhibit tumor infiltration by cytotoxic T (incl. CAR T-cells) and other helpful immune cells.  Since gate-keepers should be most useful when positioned at the entrance, this might actually take advantage of another limitation of many nanoparticle delivery technologies, namely getting stuck close to the vasculature instead of penetrating deep into the tumor.

Once deeper into the tumor, the struggle may not be over for cytotoxic T cells and tumor eating cells due to potentially immunosuppressive activities in the tumor microenvironment.  This is the new positioning for the phosphorothioate-based antisense molecule ISIS-STAT3 by Isis Pharmaceuticals and AstraZeneca for which, like for other phosphorothioate-based approaches, the demonstration of robust uptake and gene knockdown activity in tumor cells themselves is lacking, but functional uptake in cells of the tumor microenvironment has been reported.

Finally, RNA Therapeutics such as CRISPR genome editing or straightforward self-delivering RNAi (see recent license of MirImmune from RXi Pharmaceuticals) can be tools for the ex vivo preparation of T- and dendritic cells.  A self-delivering approach may be advantageous here as it may function in normal cell culture media and thus not confound cell signaling pathways in the maturation of these cells.

Investor, tread carefully

Overall, I’m convinced that there are synergistic potentials to be exploited and checkpoint inhibition may open the door to certain that have failed in the past.  Nevertheless, one should be mindful that most immune oncology drugs only work in a fraction (maybe 25%) of patients and the current hype around immune oncology guarantees that there will be many bad apples for investors to avoid.  Trust me, I've seen it when RNAi was indiscrimately hyped and abused for short-term financial gain in 2006-8.  Just because you can contrive a link to immune oncology or because a desperate Big Pharma does a deal, does not mean that all the biological problems will dissolve.  The bubble will burst after which mostly only well-financed quality plays will recover.

Disclosure: I am fishing for short opportunities in the immune oncology space as a hedge against a (hopefully temporary) correction to what seems to be an in a number of areas (e.g. gene therapies, immune oncology, one-drug orphan wonders such as Alexion etc) overheated biotech space.

1 comment:

fezziwig2008 said...

The PD(L)-1 Inhibitors are large monoclonal Antibodies with diffusion difficulties inherent in their molecular size. Hyaluronan is a ubiquitous barrier to their diffusion and work presented by Halozyme @ AACR-
Hyaluronan (HA) depletion increases tumor accessibility of T cell and therapeutic PD-L1 monoclonal antibody in HAhigh tumors shows they are making progress in this area, as they are in solid tumor CAR-T.

By Dirk Haussecker. All rights reserved.

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