OS06.2A Local immunotherapy of glioblastoma via AAV-mediated gene transfer of checkpoint inhibitors in combination with CAR-NK cells

BACKGROUND Glioblastoma (GB) is the most common primary brain tumor which is characterized by low immunogenicity of tumor cells and prevalent immunosuppression in the tumor microenvironment (TME). Since expression of PD-L1 on GB cells has been described, immunotherapy with checkpoint inhibitors (CIs) may be a promising approach for GB treatment. However, systemic administration of CIs bears the risk of autoimmune-like side effects, while the intratumoral drug concentration reached may not be sufficient. METHODS We studied delivery of CIs through targeted Adeno-associated viral vectors (AAVs) encoding an anti PD-1 immunoadhesin (aPD-1) as a novel approach towards local immunotherapy in the syngeneic GL261-HER2 glioma model. Tumor cell-specific delivery was achieved by targeting HER2 via a specific designed ankyrin repeat protein (DARPin). We investigated the effects of this strategy alone and in combination with local injection of HER2-specific CAR-NK cells (NK-92/5.28.z), which have already shown efficacy in preclinical GB models and are currently under investigation in the CAR2BRAIN phase I clinical trial. Furthermore, aPD-1 functionality and cellular response to viral transduction as well as compatibility of both therapy approaches has been evaluated in various in vitro models. RESULTS HER2-AAV transduction efficacy of GB cells correlated with HER2 expression level, while target cells did not show anti-viral responses upon transduction. After transduction with aPD-1 HER2-AAVs, aPD-1 immunoadhesin was secreted in a time-dependent manner, bound its target on PD-1-expressing cells and was able to re-activate T-cells due to PD-1 blockade. AAV-transduction did not interfere with CAR-NK cell mediated tumor cell lysis. Biodistribution studies in mice revealed the presence of aPD-1 up to 10 days after a single HER2-AAV injection. In subcutaneous GL261-HER2 tumors, local treatment with HER2-AAVaPD-1 or HER2-AAVIgG-Fc+ NK-92/5.28.z therapy had no significant effect, whereas combination therapy profoundly delayed tumor growth. CONCLUSIONS Local therapy with aPD-1 encoding HER2-AAVs in combination with NK-92/5.28.z cells is a promising novel strategy for GB immunotherapy with the potential to enhance efficacy and reduce side effects.

Using viral vectors to deliver local immunotherapy to glioblastoma

The treatment for glioblastoma (GBM) has not seen significant improvement in over a decade. Immunotherapies target the immune system against tumor cells and have seen success in various cancer types. However, the efficacy of immunotherapies in GBM thus far has been limited. Systemic immunotherapies also carry with them concerns surrounding systemic toxicities as well as penetration of the blood-brain barrier. These concerns may potentially limit their efficacy in GBM and preclude the use of combinatorial immunotherapy, which may be needed to overcome the severe multidimensional immune suppression seen in GBM patients. The use of viral vectors to deliver immunotherapies directly to tumor cells has the potential to improve immunotherapy delivery to the CNS, reduce systemic toxicities, and increase treatment efficacy. Indeed, preclinical studies investigating the delivery of immunomodulators to GBM using viral vectors have demonstrated significant promise. In this review, the authors discuss previous studies investigating the delivery of local immunotherapy using viral vectors. They also discuss the future of these treatments, including the reasoning behind immunomodulator and vector selection, patient safety, personalized therapies, and the need for combinatorial treatment.

Emerging Prospects for Nanoparticle-Enabled Cancer Immunotherapy

One of the standards for cancer treatment is cancer immunotherapy which treats both primary and metastasized tumors. Although cancer immunotherapeutics show better outcomes as compared with conventional approaches of cancer treatment, the currently used cancer immunotherapeutics have limited application in delivering cancer antigens to immune cells. Conversely, in solid tumors, tumor microenvironment suppresses the immune system leading to the evasion of anticancer immunity. Some promising attempts have been made to overcome these drawbacks by using different approaches, for instance, the use of biomaterial-based nanoparticles. Accordingly, various studies involving the application of nanoparticles in cancer immunotherapy have been discussed in this review article. This review not only describes the modes of cancer immunotherapy to reveal the importance of nanoparticles in this modality but also narrates nanoparticle-mediated delivery of cancer antigens and therapeutic supplements. Moreover, the impact of nanoparticles on the immunosuppressive behavior of tumor environment has been discussed. The last part of this review deals with cancer immunotherapy using a combination of traditional interventional oncology approach and image-guided local immunotherapy against cancer. According to recent studies, cancer therapy can potentially be improved through nanoparticle-based immunotherapy. In addition, drawbacks associated with the currently used cancer immunotherapeutics can be fixed by using nanoparticles.