So what were the key takeaways from last time? (Read part 1 here: https://msbio.tech.blog/2019/01/06/thoughts-on-toca-5/). There have been previous, unsuccessful trials using suicide gene/prodrugs in the past. Tocagen may overcome some of these challenges by converting the prodrug into a more potent molecule, and by using a vector that has increased stability and activity. I’ll talk about some more tidbits I’ve learned on the improvements Tocagen has made vs past preclinical/clinical studies using vectors. Additionally, I lightly touched on some trials in the previous post that were successful in small trials, but ultimately failed in larger trials. I think it’s important to dig deeper into some of those trials to see if there are any takeaways.
Differences Between Past Oncolytic Virus Studies
Toca 511 is a non-lytic, retroviral replicating vector (RRV). This is actually a pretty important distinction, if you comb through previous suicide gene/prodrug literature. The failed Ark Therapeutics (HSV-tk + GCV) trial was tested with a non-replicating adenovirus. Subsequent preclinical studies showed that transducing the tk gene with a replicating adenovirus showed increased transgene expression. This replicating adenovirus itself was lytic, and showed oncolytic capabilities. Surprisingly, the addition of GCV did not significantly reduce tumor size (Wildner 1999, Lambright 2001). To explain, a study done in 2000 showed in vivo that the cytotoxic nature of vectors actually is inversely correlated with suicide gene effectiveness. The hypothesis is that the viral cytotoxicity interferes with the production of the TK gene, and thus with the bystander effect. More importantly, the oncolytic power of the vectors, without a prodrug, doesn’t consistently inhibit tumor growth on its own (Moriuchi 2000).
Preclinical studies show that RRVs, like Toca 511, do not naturally induce type I interferon response (IFN), while lentiviruses do, which slows their spread. Exogenous IFN will inhibit RRV spread, as expected (Lin 2014). This signals that the nonlytic nature and the use of an RRV in Toca 511 may be less likely to trigger a response that could inhibit the spread of the virus. Not to mention, Toca 511 does not rely on the lysis of host cells to spread, unlike other vectors. Adenoviruses, which lyse the host cell, may alert the immune system to attack the virus. Furthermore, human gliomas tend to have defects in IFN signaling, and it is theorized that Toca 511 spreads preferentially in IFN-defective cells. Residual cancer cells may also serve as a viral reservoir and enable a longer-term protection against tumor growth.
Comparison with Non-suicide Gene Studies
Some of the more recent high-profile failures using different approaches were VBL Therapeutics and Celldex (and in a similar vein, ABT-414). There are differences in each of the Phase 3 trials from the prior Phase 2 that may have contributed to the disappointing results of the studies. Starting with VBL-111, the Phase 2 study began with a priming of VBL-111 only, followed by the addition of bevacizumab. The Phase 3, however, had patients on the combination of VBL-111 and bevacizumab, which may have contributed to the vastly different results (15 months in Phase 2 vs 7.9 months in Phase 3). In the press release, VBL noted: “the only significant change between the Phase 2 and Phase 3 treatment cohorts was in the treatment regimen”.
Celldex (vaccine) and ABT-414 (monoclonal antibody + toxic payload) targeted EGFRvIII, which is often over-amplified in glioblastomas. However, neither of these studies showed a treatment benefit, and there was no trend with EGFR expression and survival. One explanation is that between 50-82% of patients lose EGFR expression upon recurrence (Sampson 2010). Single-antigen targeting in glioblastomas may be unable to overcome the challenge of epitope escape. Another difference in the Celldex Phase 2 and Phase 3 studies is the inclusion criteria for resection. In the Phase 2, they defined gross total resection as < 1cm3. However, in the Phase 3, resection was < 2cm3. Celldex defended this notion by proposing that the vaccine should have worked better with more tumor, since more EGFR would be expressed (Weller 2017).
There are a few studies that lead me to disagree with Celldex’s defense. Tumor size may play an important role in resistance to therapies. After reaching a certain tumor size, poor T cell trafficking and higher immunosuppressive features negated any cytotoxicity in preclinical studies with an adenovirus + GCV. CD8 cells were still being generated in the larger tumors, but were unable to inhibit growth (Predina 2012). Even a partial resection of these larger tumors showed significant cytoreduction. The less tumor, the better – hardly a surprising conclusion. However, it’s hard to calculate what this threshold will be for human patients. This study also potentially gives us an insight into why intratumoral trials (without resection) fail to see as lengthy of benefit. Menei in the early 2000s attempted to treat GBM by implanting 5-FU microspheres. One of the trials was attempted by implanting into the tumor, and the other into the cavity wall after resection. The resection studies had patients that survived longer than the intratumoral (Menei 1997, 2003). However, these were small studies (n=8, n=10) with varying baseline criteria, so I’m hesitant to draw too many conclusions from this. Of note, VBL Therapeutics also saw a trend for better outcomes in patients with smaller tumors. Tocagen has done its best to keep the trial design as consistent as possible with the Phase 1.
Conclusion
Previous suicide gene/prodrug trials used a different vector or a different prodrug. Both of these differences may play a critical role in the efficacy of the therapy. Perhaps Tocagen’s improvements will enable them to overcome the survival improvement hurdle. However, it’s important to stress that this is still a high-risk trial, and while I do think there’s a better chance of success because of an improved vector and consistent trial design, it’s no guarantee of success. I’ll talk about some risks I’ve identified to the trial outcome next time.
MS Biotech Thoughts 