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Review
. 2024 Aug 5;13(1):76.
doi: 10.1186/s40164-024-00549-9.

The next frontier in immunotherapy: potential and challenges of CAR-macrophages

Affiliations
Review

The next frontier in immunotherapy: potential and challenges of CAR-macrophages

Jing Li et al. Exp Hematol Oncol. .

Abstract

Chimeric antigen receptor macrophage (CAR-MΦ) represents a significant advancement in immunotherapy, especially for treating solid tumors where traditional CAR-T therapies face limitations. CAR-MΦ offers a promising approach to target and eradicate tumor cells by utilizing macrophages' phagocytic and antigen-presenting abilities. However, challenges such as the complex tumor microenvironment (TME), variability in antigen expression, and immune suppression limit their efficacy. This review addresses these issues, exploring mechanisms of CAR-MΦ action, optimal construct designs, and interactions within the TME. It also delves into the ex vivo manufacturing challenges of CAR-MΦ, discussing autologous and allogeneic sources and the importance of stringent quality control. The potential synergies of integrating CAR-MΦ with existing cancer therapies like checkpoint inhibitors and conventional chemotherapeutics are examined to highlight possible enhanced treatment outcomes. Furthermore, regulatory pathways for CAR-MΦ therapies are scrutinized alongside established protocols for CAR-T cells, identifying unique considerations essential for clinical trials and market approval. Proposed safety monitoring frameworks aim to manage potential adverse events, such as cytokine release syndrome, crucial for patient safety. Consolidating current research and clinical insights, this review seeks to refine CAR-MΦ therapeutic applications, overcome barriers, and suggest future research directions to transition CAR-MΦ therapies from experimental platforms to standard cancer care options.

Keywords: CAR macrophage (CAR-MΦ); Clinical trials; Combination therapies; Immunotherapy; Tumor Microenvironment (TME).

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Overview of CAR Cell Therapies: Clinical Trials, TME Interaction, and Safety Profiles. (A) Clinical Trials Overview: This panel illustrates the stages of clinical trial progression for CAR cell therapies, from pre-clinical lab research to Phase IV, detailing the evaluation of treatment effects in humans, safety and efficacy assessments, and the long-term impact of treatments. (B) Mechanisms of Action in the TME: Diagram displaying the diverse cellular composition and cytokine environment of the TME. The relationships and influences between different cell types and secreted cytokines are highlighted, showing the dynamic interactions within the TME that impact therapy outcomes. (C) Mechanism Differences between CAR-MΦ, CAR-T, and CAR-NK in Killing Solid Tumors: This segment compares the functional approaches of CAR-MΦ, CAR T-cells, and CAR natural killer cells (CAR-NK in combating solid tumors, emphasizing the unique mechanisms like phagocytosis by CAR-MΦ, antigen-specific T cell activation by CAR-T, and direct cytotoxicity along with antibody-dependent cellular cytotoxicity (ADCC) by CAR-NK. (D) Safety Profile: Outlines the critical safety concerns associated with CAR cell therapies, including CRS, neurotoxicity (ICANS), and macrophage activation syndrome (MAS). The panel describes the progression of CRS symptoms from mild to severe, details the cellular and molecular processes involved in ICANS, and explains the various macrophage polarization states in MAS, along with their associated cytokines
Fig. 2
Fig. 2
Tumor Microenvironment Interaction. This figure illustrates the interactions of various immune cells within the TME and their mechanisms for targeting cancer cells. The top row includes legends for different cell types. The central section depicts a dense network of cancer cells interspersed with various immune cells within the TME, highlighting stimulatory cytokines, including TNF, IL-1, IL-6, IL-12, and IL-18 that enhance immune responses, and inhibitory cytokines such as TGF-β, IL-4, and IL-10 that suppress immune responses. CAR-T cells attack cancer cells by releasing granzymes and perforin, leading to cell death. CAR-NK cells kill cancer cells through direct cytotoxicity using perforin. CAR-MΦ cells, with their dual role, kill cancer cells by secreting pro-inflammatory cytokines and presenting antigens. The death of cancer cells post-interaction with these CAR cells emphasizes their respective mechanisms of action. This figure underscores the complexity of the TME, and the strategies employed by CAR-T, CAR-NK, and CAR-MΦ cells to overcome immunosuppressive barriers and effectively target cancer cells
Fig. 3
Fig. 3
Mechanisms of Action of CAR-MΦ in the TME. This figure illustrates the multifaceted mechanisms through which CAR-MΦ exert their effects within the TME: (A) Antigen Recognition and Activation Pathways: CAR-MΦ are equipped with engineered receptors that target specific tumor antigens and intracellular signaling domains, allowing them to switch from an M0 state to an M1 state, which is pro-inflammatory and antitumor. (B) TME Remodeling: CAR-MΦ can remodel the TME by releasing pro-inflammatory cytokines that activate exhausted CD8+ T cells and other innate immune cells, including NK cells, dendritic cells, eosinophils, and neutrophils. (C) Tumor Phagocytosis: When tumor antigens bind to the CAR receptor on the surface of CAR-MΦ, activation signals are generated, leading to tumor phagocytosis. This process includes recognition, activation, engulfment, and elimination within phagolysosomes. (D) Transcription Factor Activation and Cytokine Release: CAR-MΦ activation involves transcription factors like NF-kB, releasing inflammatory cytokines that can activate T cell-mediated immunity against tumors. (E) Infiltration of CAR-MΦ in Tumor Cells: CAR-MΦ play vital roles in the TME and, through their direct effects, efficiently eliminate tumor cells by phagocytosis and antigen presentation to CD8+ T cells, bridging innate and adaptive immunity. (F) Legend: The legend shows the names of immune and tumor cells
Fig. 4
Fig. 4
Optimization of MΦ Design. (A) Target Selection: CAR-MΦ is engineered to target specific tumor-associated antigens. The ectodomain of the CAR is designed to recognize these tumor antigens, ensuring precise targeting and engagement with tumor cells. (B) CAR Construction Design: Constructing CAR- MΦ involves inserting genes for the CAR into macrophage cells. The CAR structure includes an antigen recognition domain, a spacer, transmembrane domains, co-stimulatory domains (e.g., CD28 or 4-1BB), and CD3 essential signaling domains. These components are crucial for the activation and function of CAR-MΦ. (C) Co-stimulatory Domain and Activation Pathway: Upon activation by IFN-γ and IPS, CAR-MΦ transitions from an M0 (naive) state to an M1 (pro-inflammatory) state. This activation leads to the secretion of inflammatory cytokines such as IL-6, IL-8, IL-12, TNF-α, and TNF-β, which are essential for enhancing the antitumor immune response

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