Laser Interstitial Thermal Therapy for the Treatment of Glioblastoma

项目总结

Project Summary Very limited options are available for treating glioblastoma, the most common primary brain tumor in humans. Effective surgical options are particularly lacking, although resection has been shown to consistently be of value for some patients with glioma. Laser interstitial thermal therapy (LITT) is in clinical use for treating primary brain tumors, but how this technology affects the tumor microenvironment is poorly understood. We have generated an immunocompetent RCAS/Ntv-a murine model of LITT with survivable brain lesions that can be used to characterize LITT-induced changes in the tumor microenvironment. Importantly, we have extensive experience studying the tumor microenvironment in the context of endogenously forming, high-grade gliomas in this mouse model. We hypothesize that LITT-induced thermal damage can create a tumor microenvironment more responsive to adjunct therapies. In Specific Aim 1, we will characterize the longitudinal effects of LITT on the tumor microenvironment by examining treated mice for an influx of immune cells and induced genetic changes using NanoString technology. We will also use a murine anti-PD-1 antibody, which we have recently shown to be effective against glioblastoma in our tumor model, in neoadjuvant and adjuvant settings to determine if its efficacy can be enhanced by LITT. While anti-PD-1 monotherapy for glioblastoma has not been efficacious due to the low immunogenicity of the tumor environment, its use in the context of LITT-induced immune cell infiltration and neoantigen formation may lead to greater therapeutic benefits against this type of cancer. In Specific Aim 2, we will determine the ability of thermally-released doxorubicin from nanoparticles to improve survival rates of tumor-bearing mice following LITT. Although in clinical trials for extracranial cancers, the use of heat-activated nanoparticles for treating brain tumors is quite novel. Systemic doxorubicin has shown some benefit in other murine models of brain cancer, but its heat-activated nanoparticle release may permit more localized delivery and extended treatment beyond the LITT penumbra to the infiltrating edge of the tumor, which is the most common source of glioblastoma recurrence. With the completion of these aims, we will better understand how the population immune cells in the tumor microenvironment changes in response to thermal therapy. We will also understand what genetic programs are upregulated in the tumor microenvironment after thermal therapy potentially giving us new therapeutic targets to combine with LITT. The overall goal of this proposal is to demonstrate how thermal ablation affects the tumor microenvironment and how it can be combined with other treatments to improve outcomes for patients with glioblastoma. Given the availability of the treatments being investigated there is a low threshold for the clinical application of our results. These studies will serve as the groundwork for more extensive studies on the use of LITT for the treatment of brain tumors.