Anand RotteEditorial on the Research Topic
Emerging learnings in cell therapy: novel binding domains, universal CAR-T cells, and more
This recent decade has seen a dramatic improvement in the potential of immunotherapy and cell therapy as options for the treatment of cancer (1–6). Research interest in cell therapy has increased significantly over the past few years, with a focus on improving efficacy and addressing challenges (7) that has resulted in the introduction of novel target binding domains, dual intracellular signaling domains, T cells redirected for universal cytokine-mediated killing (TRUCKs), and allogeneic cell therapies (8). The current Research Topic, “Emerging learnings in cell therapy: novel binding domains, universal CAR-T cells, and more” aimed to attract new innovative research on cell therapy for cancer. Articles published in the Research Topic include two review articles, five preclinical studies, two studies reporting findings from real-world use of CAR-T cells, and one study reporting findings on atypical T-cell receptor (TCR)-T cells.
The review article by Zhang et al. provided a summary of recent developments in CAR-T cell therapy for solid tumors. The authors mainly discussed the strategies developed to increase the efficacy of CAR-T cells in solid tumors through the use of dual-targets, receptor switches, and CARs that are designed to resist the inhibitory signaling molecules in the TME. The second review article by Liu et al. summarized the latest advances and updates from the ASH 2022 annual meeting on anti-CD7 CAR-T cells and their application for treatment of acute myeloid leukemia and T-Lymphocyte Leukemia and Lymphoma.
The importance of intracellular costimulatory domain (4-1-BB) in activating non-canonical NF-κB pathways and thereby reducing T-cell exhaustion and improving T-cell survival has been demonstrated previously (9). Julamanee and colleagues extended the knowledge of intracellular costimulatory domains further and showed in their study that a novel B-cell signaling moiety, CD79A/CD40-based CAR, can stimulate both canonical and non-canonical signaling pathways inside the cell and improve the CAR-T cell function (10). In their current study, Ung et al. further explored the downstream mechanisms in CD79A/CD40 based CAR-T cells. The authors reported enrichment of genes known to be associated with T-cell proliferation, interferon signaling, and memory-cell signatures, upregulation of genes related to glycolysis and fatty acid metabolism, and downregulation of T-cell exhaustion in CD79A/CD40 CAR-T cells.
Zhang et al. advanced the research on targeting gp350, an envelope protein of Epstein Barr Virus (EBV) detected in 25% of biopsies from nasopharyngeal carcinoma (NPC) and developed gp350.CAR-T cells. The authors reported preclinical characterization of gp350.CAR-T cells that were produced under good manufacturing practices and noted the applicability of the product for NPC. In another study, Swan et al. aimed to address multiple challenges of CAR-T cells including improving CAR-T cell persistence, tumor penetration, tumor heterogeneity, and possible inhibition of the endogenous immune system due to lymphodepletion by chemotherapy or radiation. The authors developed CAR-T cells that secreted IL7, a cytokine well known to promote T-cell survival and proliferation alone or along with Fms-like tyrosine kinase receptor 3 ligand (Flt3L), a cytokine known to promote DC differentiation, expansion, and survival. They also characterized the activity of the CAR-T cells in a glioblastoma model.
Potez et al. aimed to address the recurrence or relapse of glioblastoma multiforme (GBM) attributed to glioma stem cells (GSCs) and reported the characterization of CAR-T cells targeting GSMs. In their study, researchers combined two previously identified (11), 7-amino acid length peptides that specifically bind to GSCs using in vitro and in vivo phage display, biopanning through a flexible linker peptide to develop CAR-T cells targeting GSCs. The combined peptide with 29 amino acids was used in place of scFv as an antigen binding domain in the study. Authors reported that the peptide-based CAR-T cells (E-28t28z-tCD34) had significantly higher IFN-Υ secretion when co-cultured with GSCs compared to differentiated glioma cells and showed that N-cadherin was the likely ligand on tumor cells that bound to the CAR.
Solid tumors are considered resistant to CAR-T cells due to the immunosuppressive tumor microenvironment that favors the expression of inhibitory immune checkpoints on effector T-cells such as T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) (12). Yang et al. aimed to address the expression of inhibitory immune checkpoints through anti-mesothelin CAR-T cells that constitutively produce TIGIT-blocking single-chain variable fragments. In their article, authors characterized the activity of anti-mesothelin CAR-T cells that produced anti-TIGIT scFvs constitutively using in vitro and in vivo experiments and reported that the self-delivery of anti-TIGIT scFvs resulted in enhanced infiltration and activity of CAR-T cells in the TME.
Treatment-related adverse events and subsequent hospitalizations are a concern for CAR-T cell therapy. The retrospective observational cohort study by Lipe et al. analyzed the emergency department (ED) visits of patients after receiving CAR-T cell therapy and the association with survival outcomes. Authors reported that patients with ED visits within 14 days of CAR-T cell treatment had significantly better survival outcomes compared to patients with ED visits after 14 days of CAR-T cell treatment; they explained that earlier ED visits were mainly due to an inflammatory response to CAR-T cell therapy possibly resulting in better survival outcomes and the later ED visits were likely due to disease progression resulting in worse survival. In the case report and literature review study by Nogués-Castell et al., authors presented the case history of a patient with plasma cell leukemia (PCL) who achieved complete response after CAR-T cell therapy and later developed orbital tumors consistent with plasmacytoma in both eyes.
Adoptive cell therapy using T-cells expressing transgenic T-cell receptors (TCR-T cells) is an alternative to CAR-T cell therapy and is believed to have advantages over CAR-T cells for solid tumors due to their ability to target intracellular antigens in an MHC-dependent manner. Mercier-Letondal et al. studied engineered TCR-T cells and characterized the phenotype and functional features of atypical TCR-T cells by generating mismatched MHC II-restricted TCR/CD8-expressing T cells and cytotoxic CD4+ T cells against HPV16-derived epitope.
In summary, the articles published as part of the Research Topic covered broad areas of research in cell therapy, ranging from binding domains and intracellular signaling domains and insights into TCR-T cell engineering to real-world outcomes of CAR-T cells. Additional follow-up studies in animal models as well as phase 1 clinical studies may confirm the safety and efficacy of newly developed cell therapies.
Author contributions
AR: Writing – original draft, Writing – review & editing.
Conflict of interest
AR is employed at Arcellx Inc, a biotech company developing CAR T-cell therapies for the treatment of cancer. However, other than the regular employment benefits, author did not receive any additional salary or benefits for drafting this manuscript. Arcellx was not involved in the drafting and did not influence the contents of the manuscript.
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References
1. Pan K, Farrukh H, Chittepu V, Xu H, Pan CX, Zhu Z. CAR race to cancer immunotherapy: from CAR T, CAR NK to CAR macrophage therapy. J Exp Clin Cancer Res. (2022) 41:119. doi: 10.1186/s13046-022-02327-z
2. Lemaire V, Shemesh CS, Rotte A. Pharmacology-based ranking of anti-cancer drugs to guide clinical development of cancer immunotherapy combinations. J Exp Clin Cancer Res. (2021) 40:311. doi: 10.1186/s13046-021-02111-5
3. Rotte A. Predictive models for response and survival in patients treated with anti-PD-1 monotherapy or with anti-PD-1 and ipilimumab combination: editorial commentary. Ann Trans Med. (2023) 11:227. doi: 10.21037/atm-22-6564
4. Rotte A, Frigault MJ, Ansari A, Gliner B, Heery C, Shah B. Dose-response correlation for CAR-T cells: a systematic review of clinical studies. J Immunother Cancer. (2022) 10(12):e005678. doi: 10.1136/jitc-2022-005678
5. Zmievskaya E, Valiullina A, Ganeeva I, Petukhov A, Rizvanov A, Bulatov E. Application of CAR-T cell therapy beyond oncology: autoimmune diseases and viral infections. Biomedicines. (2021) 9(1):59. doi: 10.3390/biomedicines9010059
6. Asmamaw Dejenie T, Tiruneh GMM, Dessie Terefe G, Tadele Admasu F, Wale Tesega W, Chekol Abebe E. Current updates on generations, approvals, and clinical trials of CAR T-cell therapy. Hum Vaccin Immunother. (2022) 18:2114254. doi: 10.1080/21645515.2022.2114254
7. Kandra P, Nandigama R, Eul B, Huber M, Kobold S, Seeger W, et al. Utility and drawbacks of chimeric antigen receptor T cell (CAR-T) therapy in lung cancer. Front Immunol. (2022) 13:903562. doi: 10.3389/fimmu.2022.903562
8. Tomasik J, Jasinski M, Basak GW. Next generations of CAR-T cells - new therapeutic opportunities in hematology? Front Immunol. (2022) 13:1034707. doi: 10.3389/fimmu.2022.1034707
9. Long AH, Haso WM, Shern JF, Wanhainen KM, Murgai M, Ingaramo M, et al. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med. (2015) 21:581–90. doi: 10.1038/nm.3838
10. Julamanee J, Terakura S, Umemura K, Adachi Y, Miyao K, Okuno S, et al. Composite CD79A/CD40 co-stimulatory endodomain enhances CD19CAR-T cell proliferation and survival. Mol Ther. (2021) 29:2677–90. doi: 10.1016/j.ymthe.2021.04.038
11. Kim J, She C, Potez M, Huang P, Wu Q, Prager BC, et al. Phage display targeting identifies EYA1 as a regulator of glioblastoma stem cell maintenance and proliferation. Stem Cells. (2021) 39:853–65. doi: 10.1002/stem.3355
Keywords: CAR-T cells, D-Domains, protein aggregation, Tonic signaling, cell therapy (CT)
Citation: Rotte A (2024) Editorial: Emerging learnings in cell therapy: novel binding domains, universal CAR-T cells, and more. Front. Oncol. 14:1404376. doi: 10.3389/fonc.2024.1404376
Received: 20 March 2024; Accepted: 29 March 2024;
Published: 15 April 2024.
Edited and Reviewed by:
Vassiliki A. Boussiotis, Beth Israel Deaconess Medical Center and Harvard Medical School, United StatesCopyright © 2024 Rotte. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Anand Rotte, arotte@arcellx.com