KEY TAKEAWAYS
- The phase 2 trial aimed to analyze safety, tumor response, and immune changes in patients with resistant MSS CLM.
- VB-111 + nivolumab lacked significant benefits in MSS CLM, showing limited immune response and clinical efficacy.
In patients with microsatellite stable colorectal liver metastases (MSS CLM) instability, the tumor microenvironment (TME) suppresses the immune system, hindering effective treatments. VB-111, a modified adenoviral vector, targets this environment, triggering both an immune response and blocking abnormal blood vessel formation.
Combining VB-111 with nivolumab, a checkpoint inhibitor, could enhance the immune response. So, for this study, researchers aimed to assess safety, tumor response, and immune changes in patients with resistant MSS CLM. It involved adults diagnosed with confirmed MSS CLM that had advanced despite prior treatment.
Patients received an initial dose of VB-111 1×1013, followed by regular biweekly administrations of nivolumab 240mg for 6 weeks. Treatment continued until disease progression or if side effects became intolerable.
The researchers focused on assessing the treatment’s effectiveness in terms of overall response rate (ORR) and safety. Additionally, secondary goals involved evaluating progression-free survival (mPFS) and overall survival (mOS) and conducting additional studies analyzing paired tumor biopsies and blood samples.
Between August 2020 and December 2021, the study enrolled 14 patients with a median age of 50.5 (ranging from 40 to 75), and 14% were female. Out of the 10 patients evaluated, the combined use of VB-111 and nivolumab didn’t show significant radiographic responses. At best, two patients experienced stable disease.
Over a median follow-up period of 5.5 months, the mOS was 5.5 months (with a 95% confidence interval [CI] of 2.3–10.8 months), and the mPFS was 1.8 months (95% CI: 1.4–1.9 months).
The most frequently observed severe (grade 3–4) treatment-related adverse events included fever/chills, flu-like symptoms, and lymphopenia. No deaths linked to the treatment were reported.
When examining paired tumor biopsies using immunohistochemical staining, there was a lack of substantial immune infiltration post-treatment, except for one patient who survived for 25.7 months.
The analysis of peripheral blood mononuclear cells (PBMCs) indicated an increase in PD1highKi67highCD8+ T-cells and HLA-DRhigh T-cells after the initial dose of VB-111. Additionally, plasma cytokines IL-10 and TNFα increased following treatment with both medications.
In patients with MSS CLM, the combination of VB-111 and nivolumab didn’t enhance objective response rate or survival, yet exhibited tolerability with minimal side effects.
Correlative studies indicated an antigen-specific immune response, activating CD8+ T-cells systemically, albeit the response was brief, with sparse immune cell infiltration in treated tumor biopsies.
This suggests a single priming dose might not be optimal for viral-mediated therapies. Sequential doses of the viral vector and earlier checkpoint inhibition administration could elicit a more robust immune response for effective tumor elimination.
Source: https://jitc.bmj.com/content/11/Suppl_1/A665
Clinical Trial: https://classic.clinicaltrials.gov/ct2/show/NCT04166383
Coffman K, Myojin Y, Monge C, et al585 Ofranergene obadenovec (VB-111) in combination with nivolumab in patients with microsatellite stable colorectal liver metastases: a single-center, single-arm phase II trialJournal for ImmunoTherapy of Cancer 2023;11:doi: 10.1136/jitc-2023-SITC2023.0585.
