While current oncology research is revealing both diagnostic and prognostic markers as well as predictive cell states, and identities with implications for drug and diagnostic development, it is challenged in that only a minority of patients respond. This is especially prevalent using therapies that rely on immune activation such as immune checkpoint inhibitors (ICIs) due to the complex and heterogeneous immune escape mechanisms which can develop in each patient. Recently, the use of oncolytic viruses (OVs) could provide a much-needed option for cancers, especially those that are resistant to existing treatments, such as radiotherapy, chemotherapy, ICIs and targeted therapy. The innovative biological therapeutic approach to cancer treatment using OVs employs native or genetically modified viruses as therapeutic agents and transgenic delivery platforms that can selectively replicate within tumors, but not in cells of normal tissues, thereby specifically targeting and killing cancer cells, while simultaneously potentiating antitumor immunity by releasing antigens and activating inflammatory responses in the tumor microenvironment (TME). Indeed, several clinical trials have already demonstrated the ability of OVs to exploit multiple lytic mechanisms to kill cancer cells that are resistant to conventional and targeted therapies.
While cancer treatment with for example ICIs has been somewhat effective in treatment of solid malignancies, such success has been tempered in CNS tumors such as Glioblastoma Multiforme (GBM) perhaps in part due to the immunosuppressive nature of CNS. Unfortunately, GBM remains the most common malignant brain tumor and despite advances in therapy options, recurrence is universal, and 5-year overall survival is poor at ~7%, effective treatments for this disease are therefore urgently needed. A recent exciting publication by Nassari et al., 20231 has been the first to report on the combined tolerated direct delivery of OV therapy together with systemic checkpoint inhibition for GBM by employing a multicenter phase 1/2 study to evaluate intratumoral delivery of the novel oncolytic virus, DNX-2401 followed by intravenous ICI, anti-PD-1 antibody pembrolizumab in recurrent GBM, first in a dose-escalation and then in a dose-expansion phase, in a small cohort of patients.
NeoGenomics laboratories was selected to perform the targeted next-generation sequencing on DNA extracted from FFPE using the comprehensive 336 test profile, NeoTYPE® Discovery Profile for Solid Tumor that combines NGS, FISH and IHC to allow for the accurate and sensitive detection of genomic alterations in the genes most relevant to various solid tumor cancers (for more information, please refer to, https://neogenomics.com/test-menu/neotyper-discovery-profile-solid-tumors ). As noted by the authors, “certain pathogenic mutations are potentially associated with prognosis and specific response to checkpoint inhibition in glioblastoma”. Specifically, while a number of pathogenic mutations, including those in TP53, NF1, PTEN, MTOR and RB1 were detected, as were a few mutations in POLE and POLD1, there was no clear association between these specific molecular features, including tumor mutational burden (TMB), on response to treatment. The authors did concede that, “although this suggests that the antitumor responses after combined oncolytic virus and checkpoint inhibition in glioblastomas may be less dependent on TMB than in other solid cancers, further investigation in much larger cohorts are warranted for definitive conclusions”.
Gene expression analysis using the NanoString nCounter platform, also offered by NeoGenomics (for more information, please refer to https://neogenomics.com/pharma-services/lab-services/molecular/nanostring) afforded a retrospective analysis on all the patient samples, with a cohort available at the time of disease progression affording examination of gene expression changes before and after treatment in matched samples. The group found that objective responses exclusively occurred in patients with a moderately inflamed microenvironment coupled to modest PD-1 expression (performed by NeoGenomics Laboratories using the PD-L1 IHC 22C3 assay) before treatment that they termed TMEmedium. Clinical benefit rates and overall survival was also further supported in the TMEmedium tumors cohorts. These findings suggest that TMEmedium tumors are primed with a moderate degree of immune cells and potentially the use of OVs can induce further infiltration of cytotoxic T cells and expression of PD-1 in these tumors that can be further targeted with subsequent anti-PD-1 treatment without immunosuppression from alternative checkpoint proteins.
While much work is still needed to demonstrate efficacy of combined direct delivery of oncolytic viral therapy and systemic checkpoint inhibition the results presented in the publication are promising and particularly relevant in this population of patients who did not receive repeat resection of tumor and for whom viable treatments are entirely lacking. Further, with the advanced understanding of antitumor mechanisms presented by OVs using a variety of tools some of which highlighted herein, there is real hope that OVs can become the personalized and precision medicine of the future.
Resources:
- Oncolytic DNX-2401 virotherapy plus pembrolizumab in recurrent glioblastoma: a phase 1/2 trial. Nassiri et al., 2023. https://www.nature.com/articles/s41591-023-02347-y