In previous posts, I’ve covered several improvements of Tocagen’s regimen versus historical attempts. However, it’s been said over and over that this is a high-risk trial. It’s important to discuss why. (Previous posts: https://msbio.tech.blog/category/tocagen/)
Pre-clinically
There are a few points of interest surrounding the retrovirus and FC combo. First, several studies have shown adenoviruses alert the host immune system and generate IFN and potentially neutralizing antibodies (Alvarez 2000). Retroviruses have not been shown to generate an IFN response, preclinical studies have found anti-RRV antibodies (Tai 2008). There were no changes in overall transgene expression in cells, but these antibodies may slow replication. Retroviruses also cause minor inflammation, which has led to the use of concomitant bevacizumab. While there are no preclinical studies testing Toca 511 with bevacizumab, VBL-111’s activity was shown to be inhibited by co-administration of bevacizumab, which may partially explain VBL’s trial failure. Bevacizumab is also known to phenotypically change glioblastomas into more invasive forms. A few other viruses tested with bevacizumab do not seem to lower viral activity, but it is not out of the real of possibility that bevacizumab or another agent has an effect on Toca 511 (Thaci 2013). In fact, temozolomide + Toca 511 administration delays RRV spread, though the same amount of CD gene was eventually transduced (Huang 2013). Though there may be a more significant reduction effect in patients than in cells.
Finally, there is evidence in early studies of GCV resistance due to TK gene splicing with the HSV-tk+GCV combo. The cells with the spliced gene survived treatment, and eventually spread. After multiple rounds, GCV was no longer effective (Garin 2001). While we have not yet seen this with Toca FC, it must also be considered. To add to this, the bystander effect is critical to this treatment’s effectiveness. Some preclinical studies showed a threshold of prodrug needed in order for the bystander effect to be meaningful (Barese 2012). This specific threshold is not known for FC, but it does mean enough CD gene will have to be transduced for optimal anti-tumor effect.
Clinically
From the Phase 1 analysis, responders didn’t show a significant improvement in CD8 T cells vs non-responders, which is thought to be important for lengthy tumor immunity. The tumor microenvironment is complex, and while the patient numbers were small and other biomarkers were significant, it’s hard to tell if the responses are a direct result of the Toca treatment.
One major question IV administration didn’t work as well as the resection arm. Toca 511 was first given via IV, then a resection was performed, and Toca 511 injected into the resection cavity. Thus, it’s reasonable to expect a similar response rate from both arms. While the IV arm mOS was comparable at 13.6 months, only 1 PR (in AA) and 1 CR (GBM) was seen. ** Correction: It was pointed out to me that the ORR% between IV and resection arms are consistent**
Several studies have mapped the recurrence pattern of GBM. Distant tumor growth (away from the original site of resection) occurs in 3-15% of patients, and resection technique didn’t change this pattern (Zhou 2016). I do not see a reason why Toca 511/FC would be effective in patients with distant tumor regrowth.
Phase 2/3 Trial
The biggest danger is comparing the Phase 1 trial to historical results. The baseline characteristics of patients between trials differs so much that the comparison can be confounded. For example, historical data do not necessarily stratify by the same factors as TOCA 5. TOCA 5 requires a smaller than 5cm3 tumor, which is not the case in many historical chemotherapy trials. In fact, the TOCA 5 population is one of the more enhanced populations out of any previous rGBM trial. Thus, the SoC comparator arm may outperform historical controls. GBM patients eligible for resection may have a naturally better prognostic course course (Lu 2018). To add to that, cancer trials tend to show longer SoC survival in modern years. As physicians become better at diagnosing and choosing treatments, patients tend to live longer. In a specific subset of patients, mOS was seen to reach 10.4 months (Carson 2007).
Taking another glance at the responders in the Phase 1 trial, there is a slight imbalance in baseline. There were a disproportionate number of patients with a KPS (Karnofsky Performance Score) of 90-100, and they are younger patients. KPS and age are two of the biggest prognostic factors for longer survival. The Phase 2/3 criteria were also decided based on a retrospective analysis, which could over-inflate the perceived benefit. Furthermore, the SD and PD patients in the Phase 1 resection study also showed robust survival, and the mechanism behind that is unknown. A combination of the SoC arm outperforming expectations (9.8 months) and a lessening effect of the treatment arm would make the success of the trial less likely.
Finally, is this combination best approach? Tocagen tested a combination of temozolomide and Toca 511/FC in a preclinical model. The two treatments showed synergy, and demonstrated significantly more potent anti-tumor activity (Huang 2013). With so many pieces of the suicide gene + prodrug system, there may be a more optimal approach than what is currently being tested. A general theme we are beginning to see across cancer types is the use of combination treatments. A combination in rGBM may also post the best efficacy.
Conclusion
Overall, this has been an intriguing dive into a promising treatment for recurrent GBM – a field that has not seen any progress in decades. The indication is tough, but any benefit seen in this trial would likely lead to approval in some aspect. I stay cautiously optimistic in terms of a financial investment, but incredibly hopeful for the patients and families battling this disease.
MS Biotech Thoughts 