Delivery of foreign cytotoxic T lymphocyte epitopes to tumor tissues for effective antitumor immunotherapy against pre-established solid tumors in mice

Abstract

Cytotoxic T lymphocyte (CTL) can have remarkable abilities to kill tumor cells. However, the establishment of successful CTL-based anticancer therapy has met with many challenges. Within tumor cells, there exist subpopulations with low or no expression of the targeted antigen (termed as antigen-loss variants). In addition, tumor cells can downregulate the levels of major histocompatibility complex class I (MHC-I) molecules on cell surface due to immune pressure. As a result, some tumor cells can escape the immune pressure bestowed by CTLs, resulting in treatment failure. To address these difficulties, a new approach is developed to deliver foreign high-affinity CTL epitopes to tumor tissues utilizing pH-responsive “smart” microparticles (MPs). These MPs could encapsulate CTL peptide epitope, release the peptide under acidic condition encountered in tumor tissues and enhance CTL activation. Mice bearing pre-established tumor as “antigen-loss variant” solid tumor models were administered intratumorally with MPs containing the CTL peptide, which showed 100% survival following the treatment. In contrast, all control mice died from tumor. Significant protection from tumor-induced death was also observed with systemic administration of CTL peptide-MPs. The therapeutic efficacy can be attributed to enhanced delivery of the epitope to tumor tissues, presentation of the epitope by tumor cells as well as tumor stromal cells and/or generation of epitope-specific CTLs by the peptide-containing MPs. These findings offer a promising new direction for treating established solid tumor using CTL therapy.

Carbohydrate Conjugates in Vaccine Developments

“…At pH = 7.4, the particles were stable, while in pH = 5.5 buffers, the particles degraded within 24 h. T cell activation assay showed that OVA loaded Ac-Dex particles significantly increased MHC I presentation of SIINFEKL on RAW macrophages compared to free OVA group. The Huang group applied Ac-Dex to deliver foreign antigens for anti-tumor therapy (Kavunja et al, 2017). The SIINFEKL loaded Ac-Dex particles significantly enhanced the efficiency of SIINFEKL reaching tumor tissue and successfully slowed down tumor growth.…”

“…The SIINFEKL loaded Ac-Dex particles significantly enhanced the efficiency of SIINFEKL reaching tumor tissue and successfully slowed down tumor growth. In vivo CTL assay indicated the OVA loaded Ac-Dex induced CTL responses without additional adjuvants (Kavunja et al, 2017). With the ability of enhancing CTL activation, these Ac-Dex particles were highly efficacious in protecting mice from tumor induced death.…”

Engineered T Cell Therapy for Cancer in the Clinic

“…Because of their relatively isolated physiological locations and unique immunosuppressive microenvironments, immunotherapy is less effective for solid tumors than for hematological tumors. To overcome the isolated physiological locations of solid tumors, local injection of T cells into tumors was used in a mouse model (105). The effect from local injection is better than that achieved by systemic drug administration, such as injecting T cells into the cerebrospinal fluid in brain tumors.…”

Carbohydrate‐based vaccines for oncotherapy

“…They delivered foreign cytotoxic T lymphocyte epitopes to tumor tissues by nanoparticulate carriers, which can selectively accumulate in aberrant tissues with slow clearance due to the enhanced permeability and retention effect. Subsequently, the epitope was presented on the surface of tumor cells, evoking immune response …”

“…Subsequently, the epitope was presented on the surface of tumor cells, evoking immune response. 189 Although glycoengineering-based cancer vaccine strategy seems an efficient strategy to cure cancer, it maybe has some shortcomings. Sialic acids play many crucial roles in biological processes, so the expression of artificial sialic acids on normal cells would probably bring disorder to body.…”