Wednesday, October 18, 2017

Can Transient RNAi Augment Cell Therapy-based Immune Oncology?

Unlike all the major RNAi pure plays (Alnylam, Arrowhead, Dicerna, and Silence Therapeutics), RXi Pharmaceuticals is not pursuing GalNAc-based gene knockdown in the liver.  Instead, it applies its self-delivering RNAi (sdRNAi) triggers to local and, more recently, ex vivo gene suppression.

Its ex vivo efforts involve the addition of the silencing triggers to immune cells in the absence of extraneous transfection reagents with the goal of enhancing the performance of cell therapy-based immune oncology.  Immune oncology, of course, is a hot area in drug development.  Notable clinical successes mechanistically aim at immunologically unmasking tumor cells (à checkpoint inhibitors) or sending T-cell killers after them (à CAR-T).

Transient RNAi non-obvious application to cell therapy

When sdRNAi licensee MirImmune, now part of RXi came forward with the idea of applying transient RNAi strategies to cell therapy, I was very skeptical.  Cell therapies after all suggest that long-lived pharmacodynamics are desired, whereas RNAi gene silencing in dividing cells is known to be limited in duration, maybe a week or so.  Wouldn’t therefore gene therapy and in particular genome editing for gene ablation be much more useful?  Or what about that half-forgotten DNA-directed RNAi?  

Certainly, for gene silencing effects that ideally should last throughout the active life of the adopted cells in the patient, transient RNAi is not attractive given all the alternative technologies out there such as genome editing and of monoclonal antibodies.

On closer inspection, however, transient RNAi may be able to uniquely achieve a number of goals that could uniquely enhance adoptive cell therapy for cancer and potentially other applications, too.  One of them is to simply increase the number of cells with the desired phenotype.  After all, the patient-derived cells used for adoptive cell transfer are a precious resource and manufacturing issues could result in cell numbers too low to be useful.  Accordingly, self-delivering RNAi triggers may increase the number of useful cells either by expanding them, e.g. by targeting cell cycle-related genes, or by more effectively directing them to the desired phenotype (e.g. tumor-attacking vs protecting/tolerogenic cells).   

Importantly, as sdRNAi does not require electroporation or transfection reagents, there is less risk that the procedure itself reduces cell numbers or has undesirable effects on the cell phenotype. 

Out of the test tube and into patients, transient RNAi could also be useful in helping in the early tasks of the adopted cells.  One such early step is infiltrating the tumor which is thought to have a major impact on immune oncology treatment success.  While tumor infiltration can be expected to be largely guided by proteins interacting on the cell surface and would seem a suitable application of monoclonal antibodies, monoclonal antibodies often have difficulties getting into tumors.  

It is also conceivable that an early performance provided by transient RNAi may have a lasting effect on eventual therapeutic outcome, e.g. by hitting the cancer hard initially so that the risk of immunologic escape by mutation is minimized.  This is similar to how early reductions in pathogens predict the treatment success of most infectious diseases such as HCV.

Finally, RNAi may be applied to multiple genes at once.  This is more difficult to do with systemically administered monoclonal antibodies, and unlike monoclonal antibodies, RNAi can also inhibit proteins not accessible to monoclonal antibodies; multi-targeting is also less effective with genome editing.

Looking ahead

Transient RNAi for adoptive (immune) cell therapy is in its early stages.  Given some of its unique characteristics, it could be a useful addition to the gene toolbox next to genome editing, DNA-directed RNAi, or simple gene addition.  While RXi is planning to plod along with preclinical proof-of-concept studies, as a non-immune oncology person and given the poor capitalization of the company, I particularly look towards clinical collaborations and corporate partnerships to judge just how compelling a tool transient RNAi really is here.

RXi as an investment or trade

RXi Pharmaceuticals is a small biotech company with a tiny market cap of ~$13M and I would be remiss not to mention that I currently own somewhat more than 2% of the outstanding shares (ticker: RXII).  This is a relatively small gamble on my part, but certainly enough to keep me interested and engaged. 

Right now, it is probably not much more than a gamble given that RXi’s management has displayed an extraordinary degree of naivete about the capital markets.  Accordingly, their continued operations currently largely rely on an ATM-type arrangement with Lincoln Park Capital Fund which appears to only have accelerated putting down the stock, and possibly eventually the company down a death spiral. 

Near-term, RXII is therefore a bet that management will finally stop this nonsense and instead rely on the upcoming multiple (!) clinical trial outcomes catalysts by year-end from at least 3 (dermal scarring, cutaneous warts, consumer skin products) of its non-immune oncology portfolio to create some excitement about the stock.  Results from a retinal scarring trial are expected in early 2018.  Considering the tiny market cap of ~$13M, the sheer number of upcoming data read-outs alone could result in mouth-watering stock returns if the stock gets discovered.  Such a run-up would of course also provide financing opportunities to feed its immune oncology ambitions, so please management: don't put a lid on it by activating the ATM.

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By Dirk Haussecker. All rights reserved.

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