Discussion
cancers, tumor, Glioblastoma, glioma, glioblastoma, tumors, DNX-2401, retinoblastoma
ADENOVIRUS, CANCERS, RECURRENCE, VIRUS, TUMOR, DISEASE, GLIOBLASTOMA, BRAIN TUMOR, GLIOMA, DELETION, GLIOBLASTOMA, TUMORS, RETINOBLASTOMA
Glioblastoma is a devastating disease, and recurrence of disease is inevitable after initial treatment with radiotherapy and concurrent and adjuvant temozolomide chemotherapy. At progression, treatment options are very limited and of marginal efficacy. Immune checkpoint blockade in other advanced solid cancers such as melanomaDNX-2401 (Delta-24-RGD) is a conditionally replicative oncolytic adenovirus with a 24 base pair deletion in the E1A gene that renders selective replication of the virus in malignant cells with defective retinoblastoma signaling. DNX-2401 also has an RGD peptide insertion into the fiber knob that allows the virus to anchor directly to integrins and improve the infectability of glioblastoma cellsTreatment with oncolytic virus and immune checkpoint blockade combines the initial local effects of the oncolytic virus on the tumor microenvironment with the systemic effects of innate and adaptive immune responses from virus replication and PD-1 inhibitionHere we report the results of a two-part, phase 1/2, multicenter, open-label clinical trial evaluating the safety and efficacy of combined intratumoral delivery of DNX-2401 with systemic pembrolizumab for patients with recurrent glioblastoma treated at 13 institutions in North America. All centers used purpose-built cannulas to standardize the delivery of virus into the tumor, eliminating backflow and ensuring full administration of virus to the tumor. A total of 48 of 49 patients successfully received treatment with DNX-2401 and pembrolizumab.We tested between 5 × 10In total, five patients had objective responses, with two patients showing durable complete responses >45 months and three patients remaining alive at the writing of this manuscript. The objective response rate was 10.4% (90% CI 4.2–20.7%). It is noteworthy that there was one additional patient who received the declared dose of DNX-2401 with complete response at the site of treatment; however, this patient developed a new lesion at a distant site resulting in a classification of progressive disease. This patient remained alive a total of 12.3 months after treatment. In the previous phase 1 trial evaluating DNX-2401 monotherapy in recurrent glioma, there was also one patient with a complete response who developed a distant nodule several years after treatmentThe median overall survival was 12.5 months (10.7–13.5 months) and overall survival at 12 months was 52.7% (95% CI 40.1–69.2%), which was greater than the prespecified threshold of 20% using approved treatment of tumor-treating fields by Novo-TTFWhile the use of bevacizumab may complicate response assessment in trials by inducing changes in contrast enhancement seen on imaging, none of the patients with objective responses received bevacizumab during the study. Moreover, we did not find that baseline corticosteroid use was associated with outcomes in our study, confirming the findings in a prior study evaluating neoadjuvant checkpoint blockade in recurrent glioblastomaWe obtained matched mutational data and gene expression data on tumor specimens from patients, where available. Three of the patients with objective responses (60%) had tumors with mutational burden (TMB) greater than 10 mutations MbUsing gene expression data, we found that objective responses exclusively occurred in patients with moderately inflamed microenvironment, and modest PD-1 expression (TMEThere are limitations to this study that require further investigation. First, this trial did not include a comparator cohort. Further trials to directly compare combination therapy to monotherapy are needed before considering large-scale randomized trials. Second, this trial evaluated a single dose of intratumoral oncolytic virus. Emerging data since the conception of this study have shown some potential benefit with multiple doses of oncolytic virusTo our knowledge, the present study is the first to report on the combined direct delivery of oncolytic viral therapy and systemic checkpoint inhibition for any brain tumor. We identified a safe dose of DNX2401 combined with pembrolizumab with objective and durable responses, including two complete responses, and survival benefit for select patients across multiple institutions. These results are promising and particularly relevant in this population of patients who did not receive repeat resection of tumor and for whom efficacious and nontoxic treatments are entirely lacking. As well, we demonstrate the value that translational analyses and endpoints can add in advancing our understanding of the molecular mechanisms and biomarkers of response and/or resistance to treatment in clinical trial settings.