AND ABSTRACT Conventional cancer treatments target fast-cycling cells, however slowly dividing populations tend to be spared recapitulating the tumor via their self-renewing abilities. We reported the existence of slow-cycling cells (SCCs) that are extremely resistant to therapies and play a critical role in recurrence of glioblastoma (GBM). Clinical strategies able to target this specific phenotype hold great promises for improving prognosis. Importantly, these pathogenic drivers demonstrated expression of predicted immunogenic antigens providing therapeutic opportunities that we propose to exploit in the context of immunotherapy. We have established a new platform for adoptive cellular therapy (ACT) employing the use of total tumor RNA-pulsed dendritic cells (DCs) to expand tumor reactive T lymphocytes. We are currently testing in multiple clinical trials this treatment modality in patients with brain tumors (ACTION-IND#17298, REMATCH-IND#14058, BRAVO-IND#17298). The goal of this project is to leverage the power of this therapeutic platform to achieve robust targeting of treatment-resistant clones using a novel model of recurrent GBM. We hypothesize that the cytotoxic activity of tumor-specific T cells can be directed toward clones promoting recurrence by SCC RNA-pulsed dendritic cells, thus impeding disease relapse. To test our hypothesis, the specific aims of this proposal are to:
Aim 1. Determine the immunogenicity and efficacy of slow-cycling cell RNA-based T cell treatment in a preclinical model of recurrent GBM Aim 2. Evaluate the slow-cycling cell RNA-based T cell platform in a human autologous setting. Successfully completed, this proposal has a strong likelihood to impact favorably on treatment options for patients with malignant gliomas.
The severity of glioblastoma is due to pathogenic drivers that are tolerant to conventional therapies. We have discovered a specific pool of slow-cycling cells showing greater treatment resistance and tumorigenicity. We propose to leverage our ability to purify these cells to develop a novel targeted immunotherapy strategy based on the use of immunogenic antigens isolated from these clinically relevant population of cells as activator of immune effectors in the context of adoptive cell therapy to prevent recurrence in GBM.
