Breast cancer has been shown to be resistant to immunotherapies. To overcome this challenge, researchers at the Wake Forest University School of Medicine have developed an active immunotherapy for personalized treatment based on a smart nanovesicle. This is achieved by anchoring membrane-bound bioactive interleukin 2 (IL2) and enriching T cell–promoting costimulatory factors on the surface of the dendritic cell–derived small extracellular vesicles. This nanovesicle also displays major histocompatibility complex–bound antigens inherited from tumor lysate–pulsed dendritic cell. When administrated, the surface-bound IL2 is able to guide the nanovesicle to lymphoid organs and activate the IL2 receptor on lymphocytes. Furthermore, it is able to perform antigen presentation in the replacement of professional antigen-presenting cells. This nanovesicle, named IL2-ep13nsEV, induced a strong immune reaction to rescue 50% of the mice in our humanized patient-derived xenografts, sensitized cancer cells to immune checkpoint inhibitor treatment, and prevented the recurrence of resected tumors. This paradigm presents a feasible strategy for the treatment and prevention of metastatic breast cancer.
Design of IL2-ep13nsEV and its utilization in treating breast cancer
To generate this active immunotherapy, the sEVs from autologous DCs are engineered with surface membrane–bound IL2 by expressing IL2-MFG-E8. This personalization of DC-derived sEV (p13nsEV) is achieved by loading lysed surgically harvested breast cancer cells onto engineered autologous DCs followed by collecting sEVs that are then used as personalized immunotherapy. We found that LPS and STING agonist worked together to promote the expression of costimulatory factors on the surface of this engineered vesicle. Therefore, this sEV, geared with tumor lysate–derived antigens and bioactive membrane–bound IL2 and enhanced with costimulatory factors, is named as IL2-ep13nsEV. IL2-ep13nsEV is designed to act as active immunotherapy to expand the pool of cancer-specific immune cells by facilitating neoantigen processing and presentation, as well as T cell activation. It can be used to prevent the recurrence of surgically removed primary tumor or to treat advanced breast cancer resistant to ICI. TCR, T cell receptor.