Enhanced Immunotherapy Based on Photodynamic Therapy for Both Primary and Lung Metastasis Tumor Eradication

Abstract

Metastasis and recurrence are two unavoidable and intractable problems in cancer therapy, despite various robust therapeutic approaches. Currently, it seems that immunotherapy is an effective approach to solve these problems, but the high heterogeneity of tumor tissue, inefficient presentation of tumor antigen, and deficient targeting ability of therapy usually blunt the efficacy of immunotherapy and hinder its clinical application. Herein, an approach based on combining photodynamic and immunological therapy was designed and developed. We synthesized a chimeric peptide, PpIX-1MT, which integrates photosensitizer PpIX with immune checkpoint inhibitor 1MT via a caspase-responsive peptide sequence, Asp-Glu-Val-Asp (DEVD), to realize a cascaded synergistic effect. The PpIX-1MT peptide could form nanoparticles in PBS and accumulate in tumor areas via the enhanced penetration retention effect. Upon 630 nm light irradiation, the PpIX-1MT nanoparticles produced reactive oxygen species, induced apoptosis of cancer cells, and thus facilitated the expression of caspase-3 and the production of tumor antigens, which could trigger an intense immune response. The subsequently released 1MT upon caspase-3 cleavage could further strengthen the immune system and help to activate CD8 T cells effectively. This cascaded synergistic effect could inhibit both primary and lung metastasis tumor effectively, which may provide the solution for solving tumor recurrence and metastasis clinically.

Immunomodulatory Nanosystems

“…[160] After accumulation at tumor site via the EPR effect, PpIX−1MT NPs generated ROS under the light irradiation, rapidly killing tumor cells and producing tumor antigens. Song et al designed a nanoparticle formed by photosensitizer PpIX and IDO inhibitor 1-methyl-Trp (1MT), connected by a caspase-sensitive peptide sequence.…”

Materials for Immunotherapy

“…However, given the ability to synthesize a broad range of sequence‐specific polypeptides and to append them to different molecules via post‐translation modifications, these examples represent only a small subset of all possible peptide‐based micelle structures. Peptide‐based micelles have been used for several immunomodulatory applications, including the delivery of i) PR8 virus antigen for mucosal immunity, ii) docetaxel and siRNA to knockdown an anti‐apoptotic gene for synergistic tumor therapy, iii) antigenic OVA, poly(I:C), and siRNA to knockdown STAT3 (an immunosuppressor), iv) influenza antigens and CpG ODNs to establish durable humoral immunity, v) Group A streptococcus B cell antigen (J8) to also induce humoral immunity, and vi) a photosensitizer and 1MT (an IDO inhibitor) to enable PDT for eradicating tumor lung metastases . Overall, peptide‐based micelles are a promising vehicle for delivering various immunomodulatory agents; however, a better understanding of their optimal size and loading parameters must be gained to fully benefit from their exquisite tunability.…”

Enhancing Triple Negative Breast Cancer Immunotherapy by ICG‐Templated Self‐Assembly of Paclitaxel Nanoparticles

“…[7][8][9] Despite promising, the TNBC patients rarely benefit from current ICB therapy due to low immunogenicity and immunosuppressive tumor micro environment (ITM) of TNBC tumors. [17][18][19][20] The combination of ICB therapy with chemotherapy, photodynamic therapy (PDT) or radiotherapy has displayed synergistic antitumor effect to facilitate intratumoral infiltration of cytotoxic T lymphocytes (CTLs) and overcome the ITM. [17][18][19][20] The combination of ICB therapy with chemotherapy, photodynamic therapy (PDT) or radiotherapy has displayed synergistic antitumor effect to facilitate intratumoral infiltration of cytotoxic T lymphocytes (CTLs) and overcome the ITM.…”