Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 15

Published: Jan. 14, 2025

The ability of effector immune cells to target and eliminate tumor by focusing on tumor-associated antigens is crucial for the success immunotherapy. Chimeric Antigen Receptor (CAR)-modified have revolutionized cancer immunotherapy, primarily with CAR-T showing remarkable in hematological cancers. Numerous cell-based therapies, such as cell, TIL, CAR-NK T-cell receptor (TCR)-based are currently undergoing clinical pre-clinical evaluation across various types. However, these therapies possess limitations, including their inability penetrate stoma, change TME, exaggerated inflammatory responses. To overcome this, developing advanced flexible strategies precisely while preserving homeostasis patients imperative. One promising approach involves using engineered macrophages (TAMs), which plastic nature constitute approximately 50% microenvironment (TME) indispensable both progression regression. CAR-macrophages aim reprogram toward M1 TAM phenotype enable them immune-suppressive TME facilitate immune-mediated destruction tumors. Body textThe typically comprises cells, more than total cell mass play a role or Tumor-associated extremely can adapt function response environmental stimuli. TAMs within exist two distinct phenotypes: (regulatory) M2 (trophic). produces proinflammatory cytokines like IL-12 TNF-α, activates T attack demonstrate antitumor activity. presence tumors often linked better outcomes due regulate growth. advances, intrinsic extrinsic factors drive polarization tumor-infiltrating into [1], supports development. These M2-polarized secrete pro-tumoral angiogenic factors, IL-10, TGF-β, VEGF, contributing an immunosuppressive environment that favors growth [2]. Various efforts under progress engineering express receptors recognize vide range (TAA) pipeline, allowing selectively destroy cells. macrophages, known Macrophages (CAR-Macrophages) capable enough priming reactive T-cells keeping natural tumor-targeting [3]. Thus, it clear CAR-Macrophage (CAR-M) therapy would be potential asset immunotherapy many solid Underlying MechanismCAR-Macrophage recognizes specific through its chimeric antigen (CAR), leading enhanced phagocytosis concomitant presentation subsequent activation. CAR-Ms modulate secreting cytokines, metalloproteinases (MMPs), Reactive oxygen species (ROS) serine proteases altogether infiltration anti-tumor responses Each mechanisms (Figure 1) contributes overall effectiveness CAR-Macrophages targeting eliminating making therapeutic CAR-engineered were shown actively migrate sites, could locally deliver and/or cytotoxic substances antigen-specific environments when used drug delivery system, significantly alter [4]. leverage tumor-homing tendencies cargo induce activity niche. With help regenerative technologies, induced pluripotent stem (iPSCs) make CD19 / mesothelin+ M1programmed bear strong anti-tumoral [5]. Engineered derived from diverse sources, primary human monocytes/macrophages, (iPSCs), hematopoietic progenitor (HSPCs). Abdin et al. (2023) iPSCs, HSPCs generate anti-CD19 CAR-Ms. They generated αCD19 CAR constructs lentiviral vectors verified via sequencing. CD34+ isolated cord blood, transduced, differentiated macrophages. iPSCs cultured, mesoderm-primed, defined cytokines. Cancer lines patient-derived samples transduced co-cultured assess phagocytosis. Then they flow cytometry, confocal microscopy, western blotting verify action displayed CD19+ pro-inflammatory responses, adaptive recruitment, scRNA sequencing revealed activation pathways cytokine upregulation [6]. In another study Zhang (2023), utilized CRISPR-Cas9 gene editing integrate anti-GD2 AAVS1 locus (hPSCs). developed serum- feeder-free differentiation protocol (CAR-Ms) arterial endothelial-to-hematopoietic transition (EHT). this way demonstrated potent against GD2-expressing neuroblastoma melanoma vitro vivo. It useful generating off-the-shelf CAR-Ms, advancing applications [7]. improve efficiency functionality hPSC shen (2024) optimized monolayer-based system achieving stable expression tumoricidal vitro. address diminished vivo activity, employed interferon-γ monophosphoryl lipid-A innate activation, repolarizing hPSC-CAR-Ms Additionally, activating collaborative innate-adaptive amplifying effects [8]. Using high-throughput screening, Mukalel identified oxidized lipid nanoparticles (oLNPs) monocyte tropism effective mRNA delivery. C14-O2 oLNP successfully CD19-CAR monocytes vivo, significant B depletion, highlighting [9]. Similarly, numerous novel approaches being developed, efficacy existing methods continues undergo constant refinement enhancement. ongoing advancements precision, scalability, current ensuring meet evolving needs applications, particularly fields cellular. Reprogramming macrophage-directed strategy delivering [10] innovative improving rejection [11]. past, we amply returned/conditioned syngeneic donor mice dictated promoted high-grade highly invasive neuroendocrine pancreas. Most intriguingly, adoptive transfer reprogrammed (which regarded surrogate CAR-M) potentially normalized vasculature aided PanNETs [12-14]. On basis believe HER2 CD47-specific M, sensing clearing dead containing neighboring (immune) also skewed Th1 lymphocytes (CD8+ cells), secretion major effectors viz IFN-γ & IL-2, neutralizing exhaustion markers PD-1, TIGIT, LAG-3 [15]. This explained entitle niche [16]. mechanism might responsible HER2-directed CAR-macrophage (CT-0508) so far phase-1 trial (NCT04660929). interestingly was safe tolerable variety indicated CAR-M based raised hope large future. Challenges ProspectiveAlthough CAR-M-based several advantages however few bottlenecks still associated them. issues do not proliferate post-administration, amount tolerate limited, reduce interventions. Moreover, exogenous tend accumulate liver after passing lungs, neutralize potentials. complexity over murine model factor possesses challenge effective. Such heterogeneous restrict wide antigens, impact recognition/binding TSA/TAA –M TME. whether support local tumor-supportive should carefully addressed, especially at research stage. problem has been observed likely pose obstacle general. Both stability durability genetic modifications hurdle off-target stabilized CRISPR-based approach. prevent excessive inflammation, paramount maximizing therapies. achieved floxing iNOS Arginase CD47 promoter affording palliative iNOsFloxed/ArginaseFloxedCD47+CAR-M adverse impact. would, only enhance but ensure successful trials employ CAR-M. fidelity CAR–M program pave new patients.

Language: Английский