Synthetic High-density Lipoprotein Nanodiscs for Personalized Immunotherapy Against Gliomas

Abstract

◥Purpose: Gliomas are brain tumors with dismal prognoses. The standard-of-care treatments for gliomas include surgical resection, radiation, and temozolomide administration; however, they have been ineffective in providing significant increases in median survival. Antigen-specific cancer vaccines and immune checkpoint blockade may provide promising immunotherapeutic approaches for gliomas.Experimental Design: We have developed immunotherapy delivery vehicles based on synthetic high-density lipoprotein (sHDL) loaded with CpG, a Toll-like receptor-9 agonist, and tumor-specific neoantigens to target gliomas and elicit immunemediated tumor regression.Results: We demonstrate that vaccination with neoantigen peptide-sHDL/CpG cocktail in combination with anti-PD-L1 immune checkpoint blocker elicits robust neoantigen-specific T-cell responses against GL261 cells and eliminated established orthotopic GL261 glioma in 33% of mice. Mice remained tumor free upon tumor cell rechallenge in the contralateral hemisphere, indicating the development of immunologic memory. Moreover, in a genetically engineered murine model of orthotopic mutant IDH1 (mIDH1) glioma, sHDL vaccination with mIDH1 neoantigen eliminated glioma in 30% of animals and significantly extended the animal survival, demonstrating the versatility of our approach in multiple glioma models.Conclusions: Overall, our strategy provides a general roadmap for combination immunotherapy against gliomas and other cancer types.

Inhibition of 2-hydroxyglutarate elicits metabolic reprogramming and mutant IDH1 glioma immunity in mice

“…The reason for 40% of the mice treated with AGI-5198 to be tumor-free could be due the host's ability to mount a robust effector immune response, unlike the 60% of the mice which developed therapeutic resistance and succumbed due to tumor burden. The variability in the response to combination of radiotherapy, chemotherapy, and immunotherapy in brain tumor preclinical models has previously been demonstrated by several research groups (53)(54)(55)(56)(57). Mechanisms that contribute to treatment resistance are at present unknown and require further investigation (53)(54)(55)(56)(57).…”

Robust Anti‐Tumor T Cell Response with Efficient Intratumoral Infiltration by Nanodisc Cancer Immunotherapy

“…[4,12] In our previous work, we have shown that the nanodisc vaccine technology administered s.c. can efficiently drain to LNs and generate potent antigenspecific T cell responses. [5,19,20,43] In this work, we have utilized the nanodisc platform for therapeutic vaccination targeted against HPV16 E7 and shown elicitation of robust E7-specific CD8+ T cells, leading to the elimination of TC-1 tumors inoculated in various mucosal tissues, including intravaginal TC-1 model known for low T cell infiltration and aggressive features of HPV+ cervical cancer. [27,30,34] Importantly, in our head-to-head comparison studies, nanodisc vaccination induced comparable levels of antigen-specific CD8+ T cell responses as Listeria vectors ( Figures 6 and 7) but without any overt sign of toxicity or anti-vector immunity associated with live vector vaccines.…”

Cancer Vaccines: Antigen Selection Strategy

“…Application of neoantigen-based cancer vaccines in murine tumor models, including melanoma [ 44 , 45 , 46 ], glioma [ 47 , 48 ], pancreatic carcinoma [ 49 ], and esophageal squamous cell carcinoma [ 50 ], has shown their potential in clinical translation. With encouraging results from preclinical research, the assessment of neoantigen-based cancer vaccines in clinical trials has been boosted significantly in recent years.…”