Oncolytic virus combined with PD-1 inhibitor overcomes malignant brain tumors

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Oncolytic virus combined with PD-1 inhibitor overcomes malignant brain tumors

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Oncolytic virus combined with PD-1 inhibitor overcomes malignant brain tumors, and some patients survive for more than 5 years.

Glioblastoma multiforme (GBM), the most common and lethal primary brain tumor in adults, continues to pose a significant challenge.

Despite maximal surgical resection, postoperative chemoradiotherapy, and innovative tumor-treating fields therapy, the recurrence rate remains nearly 100%. Recurrent GBM not only presents greater treatment complexity but also suffers from limited therapeutic options.

Consequently, the median overall survival (OS) for recurrent GBM patients is a mere six months, underscoring the pressing need for more effective and innovative treatment strategies.

Immunotherapy, exemplified by PD-1/L1 checkpoint inhibitors, has witnessed numerous attempts in the GBM treatment landscape in recent years.

However, GBM’s characteristic immune-suppressive microenvironment often renders PD-1/L1 monotherapies or their combination with anti-angiogenic agents ineffective.

This challenge has spurred a hotbed of research into novel partnerships to enhance immunotherapy’s impact on GBM.

In a recent development, a research team led by Professor Gelareh Zadeh from the University of Toronto in Canada published a clinical Phase I/II study in the prestigious journal “Nature Medicine”.

Their findings showcased a promising avenue for treating recurrent GBM [1]. By employing oncolytic viral therapy DNX-2401 in conjunction with the monoclonal antibody pembrolizumab (commonly known as Keytruda), the team achieved a 1-year survival rate of 52.7%.

Impressively, some patients even demonstrated survival after 60 months of treatment, marking this approach as a potential groundbreaking choice for recurrent GBM treatment.

The synergy between oncolytic viral therapy and PD-1/L1 checkpoint inhibitors can be attributed to the unique mechanism of oncolytic viruses.

These viruses not only directly target cancer cells but also activate the patient’s immune response related to pathogen infections and damage.

This dual action helps effectively reverse the immune-suppressive microenvironment of GBM, synergizing with immune checkpoint inhibitors to enhance therapeutic outcomes [2].

Figure 1. Mechanism of action of oncolytic virus therapy

The oncolytic virus therapy DNX-2401 selected for the study had previously been listed in the New England Journal of Medicine [3] for its breakthrough efficacy in the treatment of diffuse intrapontine glioma (DIPG) in 2022, and was published in the In the early clinical research on the treatment of recurrent glioma, the tumors of some patients were effectively shrunk and long-term survival was achieved [4] .

The results of this multi-center, open-label, clinical phase I/II study are also the first combination of DNX-2401 and immune checkpoint inhibitors in the treatment of recurrent GBM, and the included patients are histologically confirmed recurrent glioblastoma/ Gliosarcoma with prior surgical resection, chemotherapy, and/or radiation, KPS score ≥70, and MRI assessment of at least one tumor of any size 1-4 cm in diameter (i.e., multifocal disease excluded), and tumor relapse Surgery.

The study was divided into two phases of dose escalation and dose expansion.

The dose escalation phase adopted a 3+3 design to evaluate DNX-2401 with viral loads of 5×108, 5×109 and 5×1010 (vp), combined with standard doses of Paboli The safety of zizumab therapy; in the dose expansion phase, a single dose of DNX-2401 stereotaxic injection (administered at a rate of 0.9 ml/h through a single microtip, the whole process is about 1 hour) was given when the patient received a standard tumor biopsy.

Pembrolizumab was administered every 3 weeks starting 7 days later and continued for up to 2 years, or until disease progression, severe toxicity, or patient withdrawal from the trial.

The primary efficacy endpoint of the study is the objective response rate (ORR), and the secondary efficacy endpoints are the 12-month OS rate and the clinical benefit rate (CBR, that is, the proportion of patients whose response is complete response/partial response/stable disease); according to previous relapse According to the data of clinical research on non-positive GBM, the researchers estimated that the treatment ORR was 5%, and the 12-month OS rate was 20%.

A total of 49 patients were included in the study, with a median age of 53 years, 41% were female, 80% were first relapses, 90% were IDH1 wild type (another 8% were IDH1 mutant), and all patients had received temozolomide treatment and radiotherapy, 6 patients had received bevacizumab therapy, and 5 patients had received tumor treatment electric field therapy.

A total of 48 patients received a single injection of DNX-2401 following a standard biopsy and pembrolizumab was initiated 7 days later (1 patient was not treated for delirium related to anesthesia at the time of biopsy), and no DNX was observed in the study Due to the dose-limiting toxicity of -2401, the maximum dose tested (5×1010 vp) was used in the subsequent dose expansion phase; the median exposure duration of patients to DNX-2401 and pembrolizumab was 153 days, and 3 patients received pembrolizumab Zizumab treatment for up to 2 years.

Adverse events (AEs) in the study were mostly grade 1-2 (see Table 1 for details), the most common being cerebral edema (37%), headache (31%) and fatigue (29%); treatment-related serious AEs included brain Edema (16%), dyspnea (6%), and hemiplegia (6%), pembrolizumab was suspended in 4 patients due to cerebral edema, but none of the severe cerebral edema required surgical intervention, and there were no deaths due to treatment-related AEs occurred, suggesting that DNX-2401+PD-1 inhibitor therapy is safe and well tolerated.

Table 1 Summary of treatment-related adverse events

Two patients achieved complete remission (CR) and three patients achieved partial remission (PR) based on the modified Response Assessment in Neuro-Oncology (mRANO) criteria.

The objective response rate (ORR) in the intent-to-treat population was 10.4% (90% CI: 4.2-20.7%) when evaluated according to the highest tested dose (recommended dose).

The ORR for patients treated at the maximum tested dose was 11.9%, surpassing the predefined threshold but not reaching statistical significance.

The clinical benefit rates in the aforementioned two groups were 56.2% and 54.8% respectively. The maximum changes in tumor volume are illustrated in Figure 2.

The median time from the start of treatment to remission was 3.0 months, and the median duration of remission (DoR) was 9.4 months.

Figure 2. The maximum change in tumor volume of patients during treatment

Five patients who achieved objective relief did not all possess favorable prognostic features described in previous studies.

Their tumors were all IDH1 wildtype, with only 2 cases testing positive for MGMT promoter methylation. Two patients who reached complete response (CR) exhibited tumor volume reduction of over 80% at around 6 months post-treatment, meeting CR criteria at 15-18 months of treatment.

Subsequently, they underwent 2 years of treatment with pembrolizumab. These patients are still alive with no evidence of disease progression to date. Tumor dynamics during the treatment period are illustrated in Figure 3.

Figure 3. Case of 2 Patients with Complete Response to DNX-2401 and Pembrolizumab

However, this study met the secondary efficacy endpoint, the 12-month OS rate of patients: the 12-month OS rate in the intention-to-treat population was 52.7% (95% CI: 40.1–69.2%), and the median OS was 12.5 months,

The patients treated according to the declared dose were 53.1% and 12.5 months, and the survival time of patients who achieved objective response was significantly longer (HR = 0.20, P = 0.02); a total of 3 patients completed 2 years of pembrolizumab treatment , and are still alive as of this writing, and the survival time has reached 45, 48 and 60 months, respectively.

Another surviving patient who received 6 cycles of pembrolizumab treatment has a survival time of 34 months.

Figure 4. OS Data in the Intention-to-Treat Population

Exploratory analysis reveals a significant correlation between elevated PDCD-1 gene expression levels in patients’ tumors before treatment and substantial reduction in tumor volume.

When tumor mutation burden (TMB) levels are moderate, there’s a notable association with clinical benefits (OR = 4.08).

Biopsies from 10 patients who experienced disease progression after treatment demonstrated that patients achieving objective relief with DNX-2401 + pembrolizumab therapy exhibited significantly enhanced immune activity within their bodies, and T cells in the tumor microenvironment demonstrated an “inflammatory” shift.

However, the study did not identify gene mutations associated with combined treatment responses, and the immunogenic response to DNX-2401 didn’t show a significant correlation with patient survival.

In conclusion, this early-stage clinical study for the first time illustrates that oncolytic viral therapy, when combined with existing immune checkpoint inhibitors, can lead to objective relief and even long-term survival for some recurrent GBM patients.

This highlights the initial clinical value of the immunotherapy combination strategy.

Nonetheless, external experts cautioned against drawing definitive conclusions from these early-stage clinical findings in GBM treatment.

Many previously promising treatment approaches have faltered in Phase III clinical trials.

Subsequent research should promptly identify patient characteristics and biomarkers linked to treatment response to achieve precise immune-based therapy for recurrent GBM.

references:

[1] Nassiri F, Patil V, Yefet LS, et al. Oncolytic DNX-2401 virotherapy plus pembrolizumab in recurrent glioblastoma: a phase 1/2 trial[J]. Nature Medicine, 2023, 29(6): 1370-1378.

[2] Ribas A, Dummer R, Puzanov I, et al. Oncolytic virotherapy promotes intratumoral T cell infection and improves anti-PD-1 immunotherapy[J]. Cell, 2017, 170(6): 1109-1119. e10.

[3] Gállego Pérez-Larraya J, Garcia-Moure M, Labiano S, et al. Oncolytic DNX-2401 virus for pediatric diffuse intrinsic pontine glioma[J]. New England Journal of Medicine, 2022, 386(26): 2471- 2481.

[4] Lang FF, Conrad C, Gomez-Manzano C, et al. Phase I Study of DNX-2401 (Delta-24-RGD) Oncolytic Adenovirus: Replication and Immunotherapeutic Effects in Recurrent Malignant Glioma[J]. Journal of Clinical Oncology , 2018, 36(14): 1419-1427.

[5] https://www.the-scientist.com/news/turning-up-the-heat-on-brain-tumors-71219

Oncolytic virus combined with PD-1 inhibitor overcomes malignant brain tumorsOncolytic virus combined with PD-1 inhibitor overcomes malignant brain tumors, and some patients survive for more than 5 years.

(source:internet, reference only)

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