Depletion of tumor associated macrophages enhances local and systemic platelet-mediated anti-PD-1 delivery for post-surgery tumor recurrence treatment

Abstract

Immunosuppressive cells residing in the tumor microenvironment, especially tumor associated macrophages (TAMs), hinder the infiltration and activation of T cells, limiting the anti-cancer outcomes of immune checkpoint blockade. Here, we report a biocompatible alginate-based hydrogel loaded with Pexidartinib (PLX)-encapsulated nanoparticles that gradually release PLX at the tumor site to block colony-stimulating factor 1 receptors (CSF1R) for depleting TAMs. The controlled TAM depletion creates a favorable milieu for facilitating local and systemic delivery of anti-programmed cell death protein 1 (aPD-1) antibody-conjugated platelets to inhibit post-surgery tumor recurrence. The tumor immunosuppressive microenvironment is also reprogrammed by TAM elimination, further promoting the infiltration of T cells into tumor tissues. Moreover, the inflammatory environment after surgery could trigger the activation of platelets to facilitate the release of aPD-1 accompanied with platelet-derived microparticles binding to PD-1 receptors for re-activating T cells. All these results collectively indicate that the immunotherapeutic efficacy against tumor recurrence of both local and systemic administration of aPD-1 antibody-conjugated platelets could be strengthened by local depletion of TAMs through the hydrogel reservoir.

Intracavity generation of glioma stem cell–specific CAR macrophages primes locoregional immunity for postoperative glioblastoma therapy

“…First, we only evaluated the antitumor efficacy of GSC-specific CAR macrophages and microglia on postoperative glioblastoma models. CD133 is also overexpressed in multiple cancers, including lung cancer, liver cancer, and other solid tumors, and the increased density of tumor-associated macrophages has been substantiated to correlate with postsurgery cancer recurrence ( 40 ); thus, it is crucial to further evaluate the antitumor efficacy of our GSC-specific CAR macrophages engineering approach with other tumor models. Second, in our animal studies, we did not observe any detectable toxicity of NP-pCAR, whereas before clinical translation, the long-term safety evaluation should be thoroughly investigated.…”

Targeting tumor-associated macrophages for cancer treatment

“…TLR9 agonist lefitolimod in combination with immune checkpoint inhibitor effectively regulates the TME and significantly enhance santitumor effect of anti-PD1/PD-L1 antibodies, which makes lefitolimod an ideal candidate for improving immune checkpoint therapy [ 79 ]. In addition, depletion of TAMs enhances local and systemic platelet-mediated anti-PD-1 delivery for postoperative treatment of tumor recurrence [ 107 ].…”

Platelets and platelet extracellular vesicles in drug delivery therapy: A review of the current status and future prospects

“…Leukemia (Kailashiya et al, 2019) Delivering bortezomib Multiple myeloma (Hu et al, 2016) Delivery of lamivudine and tenofovir Viral diseases (Bateman et al, 2016) Encapsulate streptokinase and release Thrombotic disease (Pawlowski et al, 2017) Delivery of aPD-1 antibodies Breast, colon, and melanoma recurrence after surgery (Li et al, 2022) These experimental results revealed that PEVs are highly effective in active targeted therapy. In another study, Li et al developed a platelet-binding αPD-1 antibody for the prognosis of tumor surgery.…”