Oncovir, Inc.

Neoadjuvant therapies for high-risk PCa have shown promise but remain confined to clinical trials. Translating neoadjuvant approaches into routine care thus underscores the critical need for innovative early-phase neoadjuvant trials to evaluate safety and efficacy in localized disease, where tumors are more responsive to intervention.

In this open-label phase 1 trial (NCT03262103), 12 patients with clinically localized intermediate- to high-risk PCa scheduled for radical prostatectomy (RP) received sequential intratumoral and intramuscular injections of poly-ICLC (Hiltonol®), with the primary endpoint to define a safe dose and schedule and one of the secondary endpoints to characterize associated adverse events.

All patients tolerated poly-ICLC without dose-limiting toxicity or treatment withdrawal. Median follow-up was 4.5 years. Seventy percent of the evaluable patients had PSA₀ (measured as PSA <0.1 ng/mL) 1 year post-RP. Gleason score at final pathology was downgraded in 66.7% of all patients and 70% of the high-risk subgroup. Tissue transcriptomic analysis revealed decreased metastasis signature post-treatment, with upregulation of immune cell-related and favorable-prognosis genes. Intratumoral and intramuscular poly-ICLC also enhanced immune activation signatures in the blood and increased NK cells in both blood and tissues. Treatment increased post-treatment infiltration of CD4⁺, CD8⁺, and PD-1⁺ T cells; CD56⁺ NK cells; CD20⁺ B cells; and tertiary lymphoid structure-like aggregates.

Intratumoral poly-ICLC immunotherapy for PCa is safe and may modulate the tumor microenvironment, enhancing antitumor responses. These findings support larger, controlled trials to assess effects on long-term clinical outcomes.

This work was funded by the Arthur M. Blank Family Foundation.

Immunotherapies like immune checkpoint inhibitors (ICI) have changed the standard of care for patients with cancer, often leading to durable responses. However, many patients remain or become refractory to ICIs owing to factors such as a lack of primed neoantigen-reactive T cells. We developed a peptide-based vaccination platform that utilizes fully personalized genome vaccines (PGV) and targets neoantigens predicted by our OpenVax computational pipeline. In this study, we report results from the PGV001 study (NCT02721043) targeting up to 10 neoantigens, administered in the adjuvant setting to patients with both solid and hematologic malignancies who have high risk of recurrence. Our data indicate that PGV001 is feasible and safe, with 13 of 14 enrolled patients receiving the vaccine and 11 completing the treatment. 100% of vaccinated patients developed targeted T-cell and B-cell responses, highlighting the capacity of OpenVax to predict immunogenic neoantigens and the potential of PGV001 for safely inducing targeted immunity.

The PGV001 platform is feasible, safe, and immunogenic. The OpenVax pipeline predicted immunogenic neoantigens in tumors with wide-ranging mutational burdens. Data from this study prompted three additional PGV001 trials, one in newly diagnosed glioblastoma, one in urothelial cancer in combination with an ICI, and another in prostate cancer.

Central nervous system (CNS) WHO grade 2 low-grade glioma (LGG) patients are at high risk for recurrence and with unfavorable long-term prognosis due to the treatment resistance and malignant transformation to high-grade glioma. Considering the relatively intact systemic immunity and slow-growing nature, immunotherapy may offer an effective treatment option for LGG patients.

We conducted a prospective, randomized pilot study to evaluate the safety and immunological response of the multipeptide IMA950 vaccine with agonistic anti-CD27 antibody, varlilumab, in CNS WHO grade 2 LGG patients. Patients were randomized to receive combination therapy with IMA950 + poly-ICLC and varlilumab (Arm 1) or IMA950 + poly-ICLC (Arm 2) before surgery, followed by adjuvant vaccines.

A total of 14 eligible patients were enrolled in the study. Four patients received pre-surgery vaccines but were excluded from postsurgery vaccines due to the high-grade diagnosis of the resected tumor. No regimen-limiting toxicity was observed. All patients demonstrated a significant increase of anti-IMA950 CD8+ T-cell response postvaccine in the peripheral blood, but no IMA950-reactive CD8+ T cells were detected in the resected tumor. Mass cytometry analyses revealed that adding varlilumab promoted T helper type 1 effector memory CD4+ and effector memory CD8+ T-cell differentiation in the PBMC but not in the tumor microenvironment.

The combinational immunotherapy, including varlilumab, was well-tolerated and induced vaccine-reactive T-cell expansion in the peripheral blood but without a detectable response in the tumor. Further developments of strategies to overcome the blood-tumor barrier are warranted to improve the efficacy of immunotherapy for LGG patients.