Hurdles to breakthrough in CAR T cell therapy of solid tumors

Marofi, Faroogh; Achmad, Harun; Bokov, Dmitry Olegovich; Abdelbasset, Walid Kamal; Alsadoon, Zeid; Chupradit, Supat; Suksatan, Wanich; Shariatzadeh, Siavash; Hasanpoor, Zahra; Yazdanifar, Mahboubeh; Shomali, Navid; Khiavi, Farhad Motavalli

doi:10.1186/s13287-022-02819-x

Cited by 25 publications

(19 citation statements)

References 197 publications

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“…CARs have transformed the treatment of blood cancers, but treatment of solid tumors and tumors with low antigen have been less successful due to poor persistence and decreased responsiveness ( 5, 33 ). A major caveat is the inefficient proximal signaling propagated by CARs ( 6, 10, 11 ) compared with TCRs.…”

Section: Discussionmentioning

confidence: 99%

Generation of anti-tumor chimeric antigen receptors incorporating T cell signaling motifs

Balagopalan

Moreno

Qin

et al. 2022

Preprint

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Chimeric antigen receptors (CAR) T cells have been successfully used to treat lymphoma, leukemia, and multiple myeloma, but adverse effects due to cytokine secretion, CAR-T cell exhaustion, and loss of target antigen have limited their potential. Furthermore, while CARs have been designed to harness T Cell Receptor (TCR) signaling, they are significantly less sensitive than TCRs, resulting in suboptimal signaling. We have designed novel Chimeric Adapter Proteins (CAPs) that are designed to trigger signaling downstream of the TCR-zeta chain. CAPs are chimeric molecules that contain adapter domains in tandem with the kinase domain of ZAP70, fused to an extracellular targeting domain. We hypothesized that CAPs would be more potent than CARs because kinetic proofreading steps that define the signaling threshold and the inhibitory regulation of upstream molecules are bypassed. Indeed, CAPs exhibited high anti-tumor efficacy, and significantly enhanced long-term in vivo tumor clearance in leukemia-bearing NSG mice as compared with conventional CD19-28zeta-CAR-T. Mechanistically, CAPs were activated in an Lck-independent manner and displayed slower phosphorylation kinetics and a longer duration of signaling compared with 28zeta-CAR. The unique signaling properties of CAPs may therefore be harnessed to improve the in vivo efficacy of T cells engineered to express an anti-tumor chimeric receptor.

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Section: Discussionmentioning

confidence: 99%

Generation of anti-tumor chimeric antigen receptors incorporating T cell signaling motifs

Balagopalan

Moreno

Qin

et al. 2022

Preprint

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“…Immune checkpoint inhibitors such as CTL4 and PD1 combined with CAR T cells have been used to target immune cells and weaken the role of immune cells in the immune microenvironment [ 85 ]. The T-cell immunoglobulin mucin 3 (Tim3) is an immune checkpoint receptor that plays a dominant role in T-cell depletion in the tumor microenvironment.…”

Section: Challenges Originating From the Tumor Microenvironmentmentioning

confidence: 99%

Current advances and challenges in CAR T-Cell therapy for solid tumors: tumor-associated antigens and the tumor microenvironment

2023

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The past decade has witnessed ongoing progress in immune therapy to ameliorate human health. As an emerging technique, chimeric antigen receptor (CAR) T-cell therapy has the advantages of specific killing of cancer cells, a high remission rate of cancer-induced symptoms, rapid tumor eradication, and long-lasting tumor immunity, opening a new window for tumor treatment. However, challenges remain in CAR T-cell therapy for solid tumors due to target diversity, tumor heterogeneity, and the complex microenvironment. In this review, we have outlined the development of the CAR T-cell technique, summarized the current advances in tumor-associated antigens (TAAs), and highlighted the importance of tumor-specific antigens (TSAs) or neoantigens for solid tumors. We also addressed the challenge of the TAA binding domain in CARs to overcome off-tumor toxicity. Moreover, we illustrated the dominant tumor microenvironment (TME)-induced challenges and new strategies based on TME-associated antigens (TMAs) for solid tumor CAR T-cell therapy.

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“…A major challenge of CAR T cells in solid tumors is the absence of truly tumor-restricted targets, leading to on-target off-tumor toxicity. 149 Therefore, targeting the CD3 (signal 1) and 4–1BB (signal 2) agonists to different crosslinking targets can lead to less on-target-off-tumor-mediated healthy tissue damage and a better safety profile. This can further be enhanced by the possibility to dose and schedule both agonists differently.…”

Section: Combination Therapiesmentioning

confidence: 99%

The emerging landscape of novel 4-1BB (CD137) agonistic drugs for cancer immunotherapy

Claus

Ferrara-Koller

Klein

2023

mAbs

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The clinical development of 4–1BB agonists for cancer immunotherapy has raised substantial interest during the past decade. The first generation of 4–1BB agonistic antibodies entering the clinic, urelumab (BMS-663513) and utomilumab (PF-05082566), failed due to (liver) toxicity or lack of efficacy, respectively. The two antibodies display differences in the affinity and the 4–1BB receptor epitope recognition, as well as the isotype, which determines the Fc-gamma-receptor (FcγR) crosslinking activity. Based on this experience a very diverse landscape of second-generation 4–1BB agonists addressing the liabilities of first-generation agonists has recently been developed, with many entering clinical Phase 1 and 2 studies. This review provides an overview focusing on differences and their scientific rationale, as well as challenges foreseen during the clinical development of these molecules.

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Hurdles to breakthrough in CAR T cell therapy of solid tumors

Cited by 25 publications

References 197 publications

Generation of anti-tumor chimeric antigen receptors incorporating T cell signaling motifs

Generation of anti-tumor chimeric antigen receptors incorporating T cell signaling motifs

Current advances and challenges in CAR T-Cell therapy for solid tumors: tumor-associated antigens and the tumor microenvironment

The emerging landscape of novel 4-1BB (CD137) agonistic drugs for cancer immunotherapy

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