Recurrent Glioblastoma Treated with Recombinant Poliovirus

Characteristics of the Patients and Controls

Table 1. Table 1. Demographic and Clinical Characteristics of the Patients and Historical Controls.

From May 2012 through May 2017, a total of 61 consecutive patients with recurrent WHO grade IV malignant glioma were treated during the study. The demographic and clinical characteristics of the patients who received PVSRIPO and the historical control group differed with respect to extent of resection at diagnosis and previous treatment failure with bevacizumab (Table 1). A total of 41% of the patients who received PVSRIPO and 38% of the historical controls were women.

Dose-Limiting Toxic Effects and Adverse Events

Table 2. Table 2. Adverse Events Attributable to PVSRIPO, According to Dose Level, in the 9 Patients in the Dose-Escalation Phase.

Table 3. Table 3. Adverse Events Attributable to PVSRIPO, According to Grade, in the 52 Patients in the Dose-Expansion Phase.

In the dose-escalation phase of the study, one patient each received dose level 1, 2, and 3; two patients received dose level 4; and four received dose level 5. The adverse events according to dose level in the dose-escalation phase are reported in Table 2. In the dose-expansion phase of the study, dose level 2 included 6 patients, dose level −1 included 31 patients, and dose level −2 included 15 patients (Table 3).

One dose-limiting toxic effect, a grade 4 intracranial hemorrhage immediately after catheter removal, occurred in the last patient who was treated at dose level 5 (Table S3 in the Supplementary Appendix). After surgical evacuation of the hemorrhage, the patient had right hemiparesis and aphasia. Histopathological analysis of tissue that was obtained with debulking of the hemorrhage did not reveal evidence of vascular alterations, viral activity, or inflammatory events related to PVSRIPO infusion, which had been completed 5 hours earlier. The patient remained alive more than 57.5 months after PVSRIPO infusion (see below) with moderate residual right hemiparesis and aphasia. After this event, one additional patient was treated at dose level 4 before the study shifted to the dose-expansion phase.

Tissue from a resection (obtained at first diagnosis or at the time of previous disease progression) in all 43 patients who were enrolled in this study and for whom resection specimens were available stained positive on CD155 immunohistochemical testing (Fig. S1 in the Supplementary Appendix). PVSRIPO infusion was not associated with evidence of encephalomyelitis, poliomyelitis, meningitis, or systemic autoimmune reactions in any patient at any dose level. Positive antipoliovirus (type 1)–neutralizing antibody titers (>1:8) increased after boost immunization with IPOL, an inactivated polio vaccine, in all the patients (Fig. S2 in the Supplementary Appendix). Tests of infectious PVSRIPO shedding in stool were negative in all the patients, in line with Investigational New Drug–directed shedding studies involving nonhuman primates.10

Two deaths occurred during the trial. One patient (who received dose level −2) had a seizure related to cerebral edema that was probably related to autopsy-confirmed tumor progression at 4.8 months after the PVSRIPO infusion. Since PVSRIPO causation could not be ruled out at the time of the events, the events were attributed to PVSRIPO as grade 4 cerebral edema and grade 5 seizure (Table 3). Another patient (who received dose level −1) died 10.5 months after the PVSRIPO infusion from complications of an intracranial hemorrhage while receiving anticoagulation and bevacizumab; this event was attributed to bevacizumab (Table S2 in the Supplementary Appendix).

Among all the patients who received PVSRIPO, 69% had a grade 1 or 2 event that was attributed to PVSRIPO as their most severe adverse event (Table 2 and Table 3). Adverse events that affected more than 20% of the patients in the dose-expansion phase included headache (in 52% of the patients), the pyramidal tract syndrome (hemiparesis) (in 50%), seizure (in 45%), dysphasia (in 28%), and cognitive disturbance (in 25%) (Table 3). Less common adverse events that were attributed to PVSRIPO (occurring in 10 to 20% of the patients in the dose-expansion phase) included hemianopia (in 19%), confusion (in 18%), paresthesia (in 13%), fatigue (in 12%), nausea (in 10%), and gait disturbance (in 10%). In the dose-expansion phase, 19% of the patients had a PVSRIPO-related adverse event of grade 3 or higher. Adverse events that were considered by the investigators to be related to PVSRIPO were dependent on the specific area of the cerebrum that was exposed to the localized inflammatory reaction associated with PVSRIPO. A summary of all the adverse events in the dose-escalation and the dose-expansion phases of the study, regardless of attribution, is provided in Table S3 in the Supplementary Appendix.

The median follow-up of the patients who received PVSRIPO was 27.6 months (95% confidence interval [CI], 20.5 to 41.1). All but 1 patient in the historical control group are known to have died (the remaining patient was lost to follow-up). The median overall survival among all 61 patients who received PVSRIPO was 12.5 months (95% CI, 9.9 to 15.2), which was longer than the 11.3 months (95% CI, 9.8 to 12.5) in the historical control group and the 6.6 months in the NovoTTF-100A treatment group.19

Figure 1. Figure 1. Overall Survival among Patients Who Received PVSRIPO and Historical Controls. Tick marks indicate censored data. PVSRIPO denotes recombinant nonpathogenic polio–rhinovirus chimera.

However, overall survival among the patients who received PVSRIPO reached a plateau beginning at 24 months, with the overall survival rate being 21% (95% CI, 11 to 33) at 24 months and 36 months, whereas overall survival in the historical control group continued to decline, with overall survival rates of 14% (95% CI, 8 to 21) at 24 months and 4% (95% CI, 1 to 9) at 36 months (Figure 1). A sensitivity analysis evaluating the effect of including patients in the historical control group who only underwent biopsy revealed that their inclusion had no effect on survival estimates (Table 1, and Fig. S3 in the Supplementary Appendix). In comparison, the use of NovoTTF-100A in patients with recurrent glioblastoma led to an overall survival rate of 8% at 24 months and of 3% at 36 months. It is too early to evaluate our statistical hypothesis of survival at 24 months, because only 20 of the 31 patients at dose level −1 were treated with PVSRIPO more than 24 months before the data-cutoff date of March 20, 2018.

Because patients who have tumors with the IDH1 R132 mutation are thought to have a survival advantage, we examined whether long-term survivors who have tumors with the IDH1 R132 mutation disproportionately contributed to the overall survival in the entire group. Survival analyses involving only the patients who received PVSRIPO whose tumors were confirmed to have nonmutant IDH1 R132 (Table 1) revealed a median overall survival of 12.5 months among the 45 patients with nonmutant IDH1 R132 and 12.5 months among all 61 patients who received PVSRIPO. Moreover, the overall survival rate at 24 months and 36 months was 21% among the 45 patients with nonmutant IDH1 R132 and among all 61 patients who received PVSRIPO. These findings are consistent with reports that IDH1 R132 status has no bearing on survival among patients with recurrent glioblastoma.20

A median cross-sectional area of tumor of 873 mm2, measured at the largest dimension, was observed among all the patients in the study. Figure S4 in the Supplementary Appendix shows the results regarding survival according to the cross-sectional area of tumor (<873 mm2 vs. ≥873 mm2). Results regarding survival according to Karnofsky performance status are presented in Figure S5 in the Supplementary Appendix.

As with other types of immunotherapy, complete and partial responses to PVSRIPO were easily recognizable, but assessment of tumor progression was difficult. Initially, most patients had increased fluid-attenuated inversion recovery (FLAIR; a method to prevent cerebrospinal-fluid suppression of lesion detection) signal abnormalities on MRI that receded over time. From the standpoint of disease shown on contrast enhancement, an initial increase in lesion size that was associated with polycystic degradation (“soap bubble” appearance) was observed in all the patients (Figs. S8 and S10 in the Supplementary Appendix). This finding frequently entailed enhancing-disease extension into previously nonenhancing infiltrative disease, followed by tumor contraction (Fig. S8 in the Supplementary Appendix). Depending on the size of the tumor, imaging changes that were suggestive of inflammatory tissue responses (an increase in the extent of FLAIR abnormalities and an increase in the size of enhancing disease with a soap-bubble appearance) were evident up to 12 months after the administration of PVSRIPO.

During the dose-escalation phase, imaging changes that were suggestive of localized inflammation were managed with glucocorticoids if they were associated with neurologic symptoms. Given the protracted course of such peritumoral inflammation before tumor contraction, symptomatic patients had to continue taking glucocorticoids for extended periods, which exposed them to substantial side effects. To mitigate peritumoral inflammation, the PVSRIPO dose was deescalated gradually to dose level 2 and then to dose levels −1 and −2. For patients with neurologic symptoms, glucocorticoids were limited to a maximum of 4 mg of dexamethasone daily, and a short course of bevacizumab, at a dose of 7.5 mg per kilogram administered intravenously every 3 weeks, was empirically initiated and continued for as long as needed to control the symptoms from the localized inflammatory reaction.

Figure 2. Figure 2. Axial T 1 -Weighted MRI, Obtained with the Use of Contrast Material, of the First Patient Treated in the Study, at Dose Level 1. Panel A shows the baseline MRI of this patient, who received dose level 1 (108 50% tissue-culture infectious doses [TCID 50 ]). Panel B shows the expansion of tumor 2 months after the PVSRIPO infusion. Panel C shows the initial tumor contraction 6 months after the infusion, and Panels D and E show the results at 12 months and 24 months, respectively. Panel F shows the contraction of the resection cavity and the treated tumor 58 months after the infusion.

Figure 3. Figure 3. Axial T 1 -Weighted MRI, Obtained with the Use of Contrast Material, of the Eighth Patient Treated in the Study, at Dose Level 5. Panel A shows the baseline MRI of this patient, who received dose level 5 (1010 TCID 50 ). Panel B shows the image obtained after surgery for evacuation of intracranial hemorrhage after the removal of the infusion catheter. Panel C shows the image obtained at the time of disease progression, 7 months after the PVSRIPO infusion. Panel D shows the image obtained after the first cycle of lomustine, and Panel E the image obtained at the completion of nine cycles of lomustine. Panel F shows the results 1 year after the discontinuation of lomustine and 32 months after the PVSRIPO infusion.

As of March 20, 2018, eight patients had a durable radiographic response of the treated tumor. Of these eight patients, two patients had a complete response and remained alive at more than 70.4 months and more than 15.1 months after the PVSRIPO infusion (Figure 2, and Fig. S7 in the Supplementary Appendix). Three patients had stable to partial radiographic responses for 60 months, 34 months, and 26 months each (Figs. S8 through S10 in the Supplementary Appendix). Three of the eight patients received a short course of bevacizumab at a dose of 7.5 mg per kilogram, administered intravenously every 3 weeks, and were without signs of active tumor and without use of additional treatment at more than 34.1 months, more than 27.1 months, and more than 15.4 months after the PVSRIPO infusion. FLAIR images corresponding to all the MRIs shown in Figure 2 and Figure 3 and in Figures S7 through S10 are provided in Figure S11 in the Supplementary Appendix.

As of March 20, 2018, a total of 4 patients had undergone reoperation and 34 patients had received bevacizumab (7.5 mg per kilogram every 3 weeks) after the administration of PVSRIPO to mitigate peritumoral inflammation. This practice was initiated only in the dose-expansion phase. Patients were considered to have discontinued the study when tumor progression was observed on histologic testing or when the treating physician thought that it was in the patient’s best interest to escalate therapy beyond bevacizumab at a dose of 7.5 mg per kilogram every 3 weeks. For details regarding the interventions that were received by patients after the PVSRIPO infusion, see Table S4 in the Supplementary Appendix. Information regarding survival among patients who received bevacizumab during the study, as compared with those who did not, and on survival among patients who received any bevacizumab after PVSRIPO infusion, as compared with those who did not, is provided in Figure S6 in the Supplementary Appendix.

A relevant finding was first observed in the patient who had a dose-limiting toxic effect at dose level 5 (hemorrhage on catheter removal; see above) (Figure 3A and Figure 3B). At 7 months after the PVSRIPO infusion, the patient had radiographic and histopathological evidence of recurrence of a WHO grade IV malignant glioma (Figure 3C). Lomustine therapy was then initiated. After the first cycle of lomustine, cystic degeneration of the lesion was observed (Figure 3D). At the completion of more than 12 months of lomustine therapy, the patient had a complete response and remained disease-free for an additional 20 months and remained alive more than 57.5 months after the hemorrhage that occurred after the PVSRIPO infusion. After this observation, 37 patients with radiographic evidence of possible disease progression were treated with temozolomide, lomustine, or other agents. At least 11 patients had radiographic signs of cystic tumor degradation and a rapid decline in tumor volume. This phenomenon typically occurred after the first cycle of chemotherapy (Table S4 in the Supplementary Appendix).