Immune Checkpoint Blockade Mediated by a Small‐Molecule Nanoinhibitor Targeting the PD‐1/PD‐L1 Pathway Synergizes with Photodynamic Therapy to Elicit Antitumor Immunity and Antimetastatic Effects on Breast Cancer

Abstract

In recent years, stimulating the host immune system to create a promising antitumor immune therapy has been demonstrated to control metastatic tumor growth. [1] Research enthusiasm has been fueled by recent clinical successes in which antibodies were used to block immune inhibitory pathways, specifically the axis between programmed cell death protein 1 (PD-1) and its ligand 1 (PD-L1). [2] However, therapeutic antibodies exhibit several disadvantages, such as limited tissue and tumor penetration, very long half-life time, immunogenicity, and costly production. Moreover, the current PD-1/PD-L1 axis-directed monoclonal antibodies lead to a tumor response only in a fraction of cases and tumor types. [3] Therefore, the application of alternative, nonantibody-based agents to inhibit PD-1/ PD-L1 axis is currently a new goal within the field. [4] The development of organic smallmole cule inhibitors is expected to introduce a number of advantages in the field of PD-1/PD-L1 immune checkpoint Targeting programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) immunologic checkpoint blockade with monoclonal antibodies has achieved recent clinical success in antitumor therapy. However, therapeutic antibodies exhibit several issues such as limited tumor penetration, immunogenicity, and costly production. Here, Bristol-Myers Squibb nanoparticles (NPs) are prepared using a reprecipitation method. The NPs have advantages including passive targeting, hydrophilic and nontoxic features, and a 100% drug loading rate. BMS-202 is a small-molecule inhibitor of the PD-1/PD-L1 interaction that is developed by BMS. Transfer of BMS-202 NPs to 4T1 tumor-bearing mice results in markedly slower tumor growth to the same degree as treatment with anti-PD-L1 monoclonal antibody (α-PD-L1). Consistently, the combination of Ce6 NPs with BMS-202 NPs or α-PD-L1 in parallel shows more efficacious antitumor and antimetastatic effects, accompanied by enhanced dendritic cell maturation and infiltration of antigen-specific T cells into the tumors. Thus, inhibition rates of primary and distant tumors reach >90%. In addition, BMS-202 NPs are able to attack spreading metastatic lung tumors and offer immune-memory protection to prevent tumor relapse. These results indicate that BMS-202 NPs possess effects similar to α-PD-L1 in the therapies of 4T1 tumors. Therefore, this work reveals the possibility of replacing the antibody used in immunotherapy for tumors with BMS-202 NPs.The ORCID identification number(s) for the author(s) of this article can be found under https://doi.

Crosstalk between HER2 and PD-1/PD-L1 in Breast Cancer: From Clinical Applications to Mathematical Models

“…As per available literature, potential predictive biomarkers that can be used to select patients who may benefit from combined treatment using HER2-targeted and PD-1/PD-L1 axis based therapeutic agents are (1) HER2 amplification/overexpression, (2) PD-1/PD-L1 expression, (3) presence of a greater number of TILs and fewer Tregs, (4) higher TMB (tumor mutation burden), (5) PTEN expression, and (6) expression of CD5, CD74, CD96, and CD226, to name only few [38,86,121,[131][132][133][134][135][136][137][138]. However, it is still not clear which combination of clinicopathological factors are most reliable predictive biomarkers to implement effective treatment protocols using anti-HER2 and/or PD-1/PD-L1 pathways [39,139].…”

Harnessing nanomedicine to overcome the immunosuppressive tumor microenvironment

“…Anti-PD-L1 [172,173] Anti-PD-1 [174] PD-L1 silencing siRNA [175] CpG [176,177] Hyperthermia therapy High temperature (40-45°C) generated locally by light, magnetic field, radiation or microwave causes tumor cell death, provoking antitumor immunity [178].…”

“… Photodynamic therapy combined with immune adjuvant or checkpoint regulator to promote immunological response and antigen presentation. Anti-PD-L1 [ 172 , 173 ] Anti-PD-1 [ 174 ] PD-L1 silencing siRNA [ 175 ] CpG [ 176 , 177 ] Hyperthermia therapy High temperature (40–45 °C) generated locally by light, magnetic field, radiation or microwave causes tumor cell death, provoking antitumor immunity [ 178 ]. Hyperthermia therapy combined with immune adjuvant, checkpoint regulator, or CAR-T therapy.…”

Photodynamic Therapy and Immune Checkpoint Blockade†

“…Other studies have tested combinations of nanoparticle PDT with PD-1/PD-L1 intervention via RNA interference or small molecules (59) with the goal of improving response rates. Wang et al developed a micelleplex with pheophorbide A as photosensitizer, an acid-activatable cationic micelle, and siRNA specific to PD-L1 (60).…”