Why could Tocagen be different from previous suicide gene/prodrug clinical trials?
Toca 511/FC is an elegant combo, but not a unique one. In fact, several trials have attempted this strategy, but none have succeeded. In 2000, a clinical trial using a similar concept in gbm failed, using a non-replicating adenovirus encoding herpes simplex virus thymidine kinase (HSV-tk) and ganciclovir (GCV), called Cerepro (Ark Therapeutics). Similar to Toca 5, the virus is injected after resection and GCV given by IV. GCV is converted into a toxic metabolite (GCV-triphosphate). Significant therapeutic effect was seen when ~10% of tumor cells were transduced. In a Phase 1, 21 rGBM patients were tested, and mean survival was 15 months vs 7.4 months control. However, in a Phase 3, 248 ndGBM patients were enrolled. Median survival was 365 days vs 354 days in the control arm (not sig). So what happened? One of the biggest benefits of prodrug therapy is the bystander effect, in which the converted toxic metabolite kills surrounding, non-transduced, cells. GCV does show the bystander effect, but is very reliant on gap junctional intercellular communication – meaning the cells have to be neighboring for the metabolite to be diffused between cells. Tumor tissues, however, rarely have such ordered cell junctions. Another bottleneck is the efficiency of GCV conversion, when HSV-tk also has a high affinity to its natural substrate, thymidine. Lastly, the efficacy of transducing enough cells via non-replicating vectors has been shown to be a hurdle, as others attempted to use adenoviruses with GCV, but also ran into similar issues. (Karjoo 2016, Tobias 2013, Rainov 2000).
Toca 511/FC is a replicating retroviral vector, and converts 5-FC (oral) to 5-FU via the inserted gene cytosine deaminase (not naturally occurring in humans). 5-FU has a neutral charge and small size, letting it diffuse into neighboring cells, which means it is not dependent on gap junctions. Using a bacterial CD gene does have a natural affinity to a substrate, cytosine. However, Tocagen designed their vector to use CD from yeast, which has a significantly higher affinity for 5-FC. A major limitation can still arise from % viral transduction, but Tocagen designed their vector to have improved stability and gene expression. Toca 511 was shown to have 3x increased activity over the prototype RRV (Perez 2012). What this translates to, in mice, is roughly 60x the amount 5-FU than what is seen in humans given 5-FU in colorectal tumors. In mice, clinical benefit was seen at 3% viral transduction, dose-dependent until about ~15%. Immune response seems to be the dominant mechanism of action, since mice in remission that were re-challenged with tumors still showed long-term protection (Hiroaka 2017).
Finally, why have so many early trials in rGBM shown promising results, but all falter in larger stages? This could be due to favorable baseline criteria, and of course, lack of power to show efficacy. In the Phase 1, of 6 patients, 2 were AA and had IDH mutations, 4 were less than 45 years old. All also had a KPS score over 80+ (most 90). However, responding patients tended to have low genomic burdens, which contrasts the idea that IO-type therapies works best in high mutational cancers. Importantly, Tocagen has stressed that the Phase 3 design is similar to parts of the Phase 1, which has not always been true, in the cases of Ark, Celldex, and VBL (Chiocca 2018).
The suicide gene/prodrug system is very complex, and much can go wrong. Is the new vector able to transduce enough cells? Will enough 5-FC cross the BBB and be converted to 5-FU? Is the amount of 5-FU enough to induce cytotoxicity and an immune response? Is there some other factor not seen that is preventing an immune response? There are a lot of variables, but when it goes right, it works. Past therapies have been inefficient and unreliable. Not to say this isn’t the case for Tocagen, but 6 patients in complete response for over 2 years is impressive, with signs pointing to an IO-like immune mechanism behind the response. Will the Toca 5 trial hit the interim or the final readout? After all this, the answer is, I have no idea. I sure hope it does, as not many therapies have been able to move the needle in decades. Given the benefits of the vector and trial design, it certainly has a better chance than previous trials.
MS Biotech Thoughts 