This study is unique in capitalizing on AdV-tk synergy with radiation by starting radiation within 1 week of injection to overlap the therapeutic effects. The safety of AdV-tk and other adenoviral-based approaches has been demonstrated in recurrent malignant gliomas.25,33,34,40–43
This phase IB study demonstrated that AdV-tk/prodrug can be safely delivered intracranially up front in combination with surgery, intensive timing radiation, and chemotherapy. In addition, the use of valacyclovir, an oral antiherpetic prodrug, significantly decreased inconvenience, toxicity, and cost compared with intravenous ganciclovir used in previous studies. Although DLT was not reached, further dose escalation was not pursued. Early AdV-tk data in prostate cancer suggested that efficacy was not dose dependent.26,27
Toxicity, however, was seen at 2 × 1012
vp in our phase I study in recurrent malignant glioma.25
Thus, escalation beyond 5 × 1011
vp was not considered necessary.
The vector, as well as the transgene, is a key component of the approach. A phase III study with a retroviral vector failed, in large part because of poor transduction.44–46
Adenoviral vectors significantly enhance in vivo gene transfer to malignant gliomas.47
In a small controlled study in malignant gliomas, an adenoviral-tk vector led to a doubling of mean survival compared with a retroviral-tk vector or an adenoviral-marker vector.40
The infiltrative nature of malignant gliomas and natural inhibitory factors, such as inflammatory and immune response, suggest that achieving vector delivery to all tumor cells is unlikely. The potential immune stimulation by AdV-tk/valacyclovir could provide an innovative tumor vaccine mechanism to inhibit residual tumor cells after debulking therapy.
A European group has evaluated a similar adenoviral vector, AdvHSV-tk, in malignant gliomas. A phase II study48
that included primary and recurrent patients showed a significant survival advantage. A subsequent phase III study randomly assigned 251 patients to AdvHSV-tk versus SOC alone. The study suffered from patient and SOC variability and was not sufficiently powered for definitive evaluation. Nonetheless, it showed a trend toward improved outcomes for a composed primary end point of time to reintervention and OS.
AdV-tk has shown synergy with all components of malignant glioma SOC, including surgery,49
For radiation and surgery, synergistic systemic effects suggest a mechanism involving potentiation of TK-mediated immunostimulation.8,49
Synergy with temozolomide has been shown to be due to inhibition of DNA cross-link repair by phosphorylated prodrug.50
Temozolomide inhibition of regulatory T cells may augment tumor vaccine effects.51,52
The study design, based in part on these proposed mechanisms, included accelerated radiation timing, which was well tolerated, and temozolomide per SOC.
AdV-tk immunostimulation, recently reviewed,53
is the result of a complex interaction from the delivery vehicle being a virus, the mode of cell death induced, the immunogenic properties of the transgene itself, and the synergy of AdV-tk with a local insult such as radiation.8,17–19,27,54–56
In vivo, the systemic antitumor effect requires prodrug, indicating that tumor cytotoxicity is required to release antigens to be used by antigen-presenting cells. In addition, CD8+
T-depletion studies showed that these cells are critical for the response.54
Preclinical data support the proposed mechanism of local cytotoxicity in the context of an immune stimulatory milieu leading to a polyvalent tumor vaccine effect. If accurate, this mechanism is not limited to a specific antigen, and it reduces the potential of immunologic escape from single-antigen vaccines.57,58
The observed pseudoprogressions, with subsequent gradual resolution, may reflect an immune reaction. In a mesothelioma study that used a similar AdV-tk delivered to the pleural space, two patients showed no initial imaging response but had long-term durable responses (> 6.5 years) after gradual resolution of the initial tumor many months after treatment.59
Immunotherapies may require re-evaluation of traditional response measures. In addition to imaging abnormalities, median survival may not reflect a real benefit. Immunotherapy may not have any impact on patients with aggressive tumors that progress early. If 50% of the treatment population had aggressive tumors, the median would not change. Patients with minimal residual disease, in which immunotherapy is most likely to be effective, may be represented in the tail of the survival curve. This may be addressed by selecting against rapid progressors, as in the EGFRvIII [epidermal growth factor receptor variant III] vaccine trial for GBM58
that selected patients who had not progressed 3 months after surgery. However, this approach delays immunotherapy while the residual tumor mass increases. The observation that immunotherapy may not meet traditional end points but may still prolong survival was demonstrated in two randomized phase III trials of Sipuleucel-T.60
promoter methylation would not be expected to affect immunotherapy. In an EGFRvIII vaccine trial, the PFS and OS were actually longer in patients with unmethylated MGMT
The evaluable tumors from this study were insufficient to make conclusions, but there were no evident patterns, and one patient with GBM with an unmethylated tumor survived more than 46 months.
This study has demonstrated the potential for neoadjuvant use of AdV-tk plus valacyclovir and accelerated radiation in treatment of malignant gliomas. In addition, although not powered to evaluate clinical efficacy, the 2- and 3-year survival rates of 33% and 25%, respectively, are encouraging, especially since two patients surviving more than 2 years had unfavorable GBMs, one with unmethylated MGMT and the other with a subtotal resection. A phase II study to further evaluate safety, MGMT status, and potential efficacy is ongoing.