Background TALLTM is a nanomedicine-based cellular immunotherapy for delivering synthetic antigenic peptides specifically to cancer cells and facilitating their presentation through the MHC Class I pathway, generating a robust secondary immune response against tumor cells. TALLTM comprises of three components: a liposome shell, encapsulated synthetic immunogenic HLA class I restricted peptides derived from measles virus, and a tumor-targeting peptide (called MGS5) on the liposome surface, which binds to a novel tumor-specific biomarker. In addition to evaluating its potential as a standalone immunotherapy, we have also determined the efficacy of combining TALLTM with an immune checkpoint inhibitor (ICI).
Methods In vitro and in vivo studies to demonstrate the high tumor-specificity of MGS5 and TALLTM liposomes were performed using flow cytometry, confocal microscopy and IVIS imaging. In vitro experiments were conducted to characterize the MOA of TALLTM, including biomarker/receptor identification for MGS5. Immunoprofiling studies along with staining of tumor tissues were used to confirm the increase in memory CD8+T-cells in tumors. Studies were conducted in C57BL/6 and Balb/c mice bearing syngeneic pancreatic (Pan02) and triple-negative breast (4T1) cancers respectively to demonstrate the efficacy of both TALL alone as well the TALL and anti-PD1 ICI combination immunotherapy.
Results Treatment with TALLTM substantially reduced tumor growth in both cancer models. TALL and ICI combination treatment showed complete response in breast cancer models and resulted in a 10-fold reduction in tumor burden in pancreatic cancer models, while completely halting metastasis. Analysis of tumor tissues showed a 10-fold increase in the presence of CD8+T-cells in TALL-treated animals. Our receptor identification studies determined that MGS5 binds to a novel cancer biomarker: N-glycolylneuraminic acid (Neu5Gc)-Sialyl LewisA.
Conclusions TALLTM is an excellent immunotherapy which can be synergistically used with ICIs, due to its ability to convert immune-cold tumors to immune-hot, by generating a robust cytotoxic T lymphocyte response directed specifically against the tumor.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.