<p>Superior Antitumor Efficacy of IFN-α2b-Incorporated Photo-Cross-Linked Hydrogels Combined with T Cell Transfer and Low-Dose Irradiation Against Gastric Cancer</p>

Abstract

The exhaustion and poor homing of activated lymphocytes are critical obstacles in adoptive cell immunotherapy for solid tumors. In order to effectively deliver immune cells into tumors, we encapsulated interferon-α2b (IFN-α2b) into macroporous hydrogels as an enhancement factor and utilized low-dose irradiation (LDI) as a tumoral attractor of T cells. Methods: Hydroxypropyl cellulose hydrogels were prepared by irradiation techniques, and the cross-sectional microstructure was characterized by scanning electron microscopy. The synergistic antitumor mechanism of combination of IFN-α2b and CIK cells was evaluated by detecting the expression of activation marker CD69 on CIK cell surface and IFN-γ production by CIK cells. The in vivo antitumor activity of IFN-α2b-incorporated hydroxypropyl cellulose hydrogels combined with CIK and radiation was evaluated in an MKN-45 xenografted nude mice model. Results: The bioactivity of IFN-α2b was well maintained in ultraviolet-reactive, rapidly cross-linkable hydroxypropyl cellulose hydrogels. In vitro studies demonstrated IFN-α2bactivated T cells, as evidenced by upregulating early activation marker CD69 and secretion inflammatory cytokine IFN-γ. In vivo real-time image showed our hydrogels kept a higher amount of drug delivery at the tumor site for a long time compared with free drug injection. Low-dose irradiation promoted T cell accumulation and infiltration in subcutaneous tumors. Combination of IFN-α2b-loaded hydrogels (Gel-IFN) with T cells and LDI exhibited higher efficacy to eradicate human gastric cancer xenograted tumors with less proliferating cells and more necrotic regions compared with IFN-α2b or T cells alone. Discussion: HPC hydrogels kept the activity of IFN-α2b and stably release of IFN-α2b to stimulate T cells for a long time. At the same time, low-dose radiation recruits T cells into tumors. This innovative integration mode of IFN-α2b-loaded hydrogels and radiotherapy offers a potent strategy to improve the therapeutic outcome of T cell therapy.

Tumor microenvironment-mediated immune tolerance in development and treatment of gastric cancer

“…Targeting Lewis Y and CD3 (m3s193 BsAb), a formatted novel T cell-binding bispecific antibody with IgG-[L]-scfv exhibited promising anti-GC activity in a mouse huPBMCs/GC co-transplantation model ( 164 ). Hydroxypropyl cellulose photocrosslinked hydrogel incorporating IFN-α2b can ensure the activity of IFN-α2b, stably release IFN-α2b to stimulate T cells over a long time, and combined with low-dose radiation of 5 Gy can induce activated T cells into tumor tissue, increasing the immunotherapy effect ( 165 ). The conjugation of αPD1 (i.e., nivolumab) to poly(ethylene glycol) (PEG) and poly(ϵ-caprolactone) (PCL) copolymers with PEG as linker (αPD1-PEG-PCL) by double emulsion solvent evaporation, encapsulating DAC in αPD1-PEG-PCL, this drug can better target PD1 + CD8 + TIL to inhibit and kill GC cells ( 166 ).…”

Interferon-Based Biopharmaceuticals: Overview on the Production, Purification, and Formulation

“…Thus, this elastomer-based formulation may be clinically useful for sustained and local protein drug delivery applications. In 2020, Liu and collaborators [ 141 ] prepared cross-linkable hydroxypropyl cellulose hydrogels by irradiation techniques. About 50% of the encapsulated IFNα-2b was released within the first 5 h. The burst pattern might have originated from IFNα-2b abrupt release of the exposed drug on the surface of the hydrogels.…”

“…At the same time, low-dose irradiation promoted T cell accumulation and infiltration in subcutaneous tumors. This innovative integration mode of IFNα-2b-loaded hydrogels and radiotherapy offers a potent strategy to improve the anticancer effects of T cells on gastric cancer [ 141 ].…”

Locally Injectable Hydrogels for Tumor Immunotherapy

“…In summary, this strategy is not only suitable for the elimination of large solid tumors, but also for eliminating metastatic tumors and preventing tumor recurrence; thus, it is expected to be applied in a wider range of tumors. In another study, they reported a radioimmunotherapy combined with antitumor therapy for hydroxy propyl cellulose (HPC) hydrogel-loaded IFN-α2b (Gel-IFN) combined with intraperitoneal T cell injection and low-dose X-ray irradiation (LDI) [ 75 ]. They performed a low-dose X-ray irradiation on tumor tissue and then injected T cells into the tumor site.…”