Convection Enhanced Delivery in the Setting of High-Grade Gliomas.

Development of effective treatments for high-grade glioma (HGG) is hampered by (1) the blood-brain barrier (BBB), (2) an infiltrative growth pattern, (3) rapid development of therapeutic resistance, and, in many cases, (4) dose-limiting toxicity due to systemic exposure. Convection-enhanced delivery (CED) has the potential to significantly limit systemic toxicity and increase therapeutic index by directly delivering homogenous drug concentrations to the site of disease. In this review, we present clinical experiences and preclinical developments of CED in the setting of high-grade gliomas.

Clinically Explored Virus-Based Therapies for the Treatment of Recurrent High-Grade Glioma in Adults.

As new treatment modalities are being explored in neuro-oncology, viruses are emerging as a promising class of therapeutics. Virotherapy consists of the introduction of either wild-type or engineered viruses to the site of disease, where they exert an antitumor effect. These viruses can either be non-lytic, in which case they are used to deliver gene therapy, or lytic, which induces tumor cell lysis and subsequent host immunologic response. Replication-competent viruses can then go on to further infect and lyse neighboring glioma cells. This treatment paradigm is being explored extensively in both preclinical and clinical studies for a variety of indications. Virus-based therapies are advantageous due to the natural susceptibility of glioma cells to viral infection, which improves therapeutic selectivity. Furthermore, lytic viruses expose glioma antigens to the host immune system and subsequently stimulate an immune response that specifically targets tumor cells. This review surveys the current landscape of oncolytic virotherapy clinical trials in high-grade glioma, summarizes preclinical experiences, identifies challenges associated with this modality across multiple trials, and highlights the potential to integrate this therapeutic strategy into promising combinatory approaches.

Endpoint in ovarian cancer xenograft model predicted by nighttime motion metrics.

Despite several therapeutics showing promise in nonclinical studies, survival from ovarian cancer remains poor. New technologies are urgently needed to optimize the translation of nonclinical studies into clinical successes. While most nonclinical settings utilize subjective measures of physiological parameters, which can hamper the accuracy of the results, this study assessed the physical activity of mice in real time using an objective, non-invasive, cloud-based, digital vivarium monitoring platform. An initial range-finding study in which varying numbers of ovarian cancer cells were inoculated in mice was conducted to characterize disease progression using digital metrics such as motion and breathing rate. Data from the range-finding study were used to establish a motion threshold (MT) that might predict terminal endpoint. Using the MT, the efficacies of cisplatin and OS2966, an anti-CD29 antibody, were assessed. Results showed that MT predicted terminal endpoint significantly earlier than traditional parameters and correlated with therapeutic efficacy. Thus, continuous motion monitoring sensitively predicts terminal endpoint in nonclinical ovarian cancer models and could be applicable for drug efficacy testing.

Convection-Enhanced Delivery of a First-in-Class Anti-ß1 Integrin Antibody for the Treatment of High-Grade Glioma Utilizing Real-Time Imaging.

INTRODUCTION: OS2966 is a first-in-class, humanized and de-immunized monoclonal antibody which targets the adhesion receptor subunit, CD29/ß1 integrin. CD29 expression is highly upregulated in glioblastoma and has been shown to drive tumor progression, invasion, and resistance to multiple modalities of therapy. Here, we present a novel Phase I clinical trial design addressing several factors plaguing effective treatment of high-grade gliomas (HGG). STUDY DESIGN: This 2-part, ascending-dose, Phase I clinical trial will enroll patients with recurrent/progressive HGG requiring a clinically indicated resection. In Study Part 1, patients will undergo stereotactic tumor biopsy followed by placement of a purpose-built catheter which will be used for the intratumoral, convection-enhanced delivery (CED) of OS2966. Gadolinium contrast will be added to OS2966 before each infusion, enabling the real-time visualization of therapeutic distribution via MRI. Subsequently, patients will undergo their clinically indicated tumor resection followed by CED of OS2966 to the surrounding tumor-infiltrated brain. Matched pre- and post-infusion tumor specimens will be utilized for biomarker development and validation of target engagement by receptor occupancy. Dose escalation will be achieved using a unique concentration-based accelerated titration design. DISCUSSION: The present study design leverages multiple innovations including: (1) the latest CED technology, (2) 2-part design including neoadjuvant intratumoral administration, (3) a first-in-class investigational therapeutic, and (4) concentration-based dosing. TRIAL REGISTRATION: A U.S. Food and Drug Administration (FDA) Investigational New Drug application (IND) for the above protocol is now active.