The Past, Present, and Future of Clinically Applied Chimeric Antigen Receptor-T-Cell Therapy

Fujiwara, Yuki; Kato, Toshiki; Hasegawa, Futoshi; Baghdadi, Muhammad; Tsurumaki, Yoshie

doi:10.3390/ph15020207

Cited by 7 publications

(5 citation statements)

References 150 publications

(160 reference statements)

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“…In addition, higher levels of naïve T cells in the leukapheresis product were also previously associated with higher CAR-T cell expansion and efficacy [ 11 , 26 ]. A recent review also emphasizes timely leukapheresis and cryopreservation as a safe and viable strategy [ 33 ]. After this preliminary analysis focused on T-cells repertoire before Ly-apheresis, correlations between the fitness of collected Ly and CAR-T cells expansion will be performed in the next future.…”

Section: Discussionmentioning

confidence: 99%

Timely Leukapheresis May Interfere with the “Fitness” of Lymphocytes Collected for CAR-T Treatment in High Risk DLBCL Patients

Farina

Chiarini

Almici

et al. 2022

Cancers

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The development of chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment of hematological diseases. However, approximately 60% of patients relapse after CAR-T cell therapy, and no clear cause for this failure has been identified. The objective of the Bio-CAR-T BS study (ClinicalTrials.gov: NCT05366569) is to improve our understanding of the lymphocyte harvest to maximize the quality of the CAR-T cell product. Of the 14 patients enrolled, 11 were diagnosed with DLBCL, 2 with PMBCL, and 1 with ALL. Five of 11 DLBCL patients met the criteria for “pre-emptive” Lymphocytes-apheresis (being at high risk of second relapse), and 6 were included in the standard-of-care Lymphocytes-apheresis group. Previous autologous stem cell transplantation (ASCT) and age were significantly different between the two groups. At the time of Lymphocyte-apheresis, patients in the “pre-emptive” group had more “fit” lymphocytes (higher CD4+/CD8+ ratio; higher naïve T cells levels) compared with standard group, probably due to the impact of ASCT. At the same time, also being older than 60 years results in a more “exhausted” lymphocyte profile. Overall, “pre-emptive” Ly-apheresis in DLBCL patients at high risk of relapse appears to be feasible and may allow the timely collection of “fit” lymphocytes for CAR-T cell manufacturing.

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Section: Discussionmentioning

confidence: 99%

Timely Leukapheresis May Interfere with the “Fitness” of Lymphocytes Collected for CAR-T Treatment in High Risk DLBCL Patients

Farina

Chiarini

Almici

et al. 2022

Cancers

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“…Alkylating agents such as cyclophosphamide, commonly used in MM management, impair proliferation and blunt functional activity of T cells (8). The alkylator bendamustine, used to treat hematological malignancies and solid tumors, is associated with decreased naïve T cell counts and impaired T-cell directed cytotoxicity (23,24). Bendamustine use before immunotherapy negatively affects the clinical outcomes of CAR-T therapy, causing prolonged lymphopenia that can result in serious and fatal infections (25).…”

Section: Negative Impactors Of T-cell Healthmentioning

confidence: 99%

Impacting T-cell fitness in multiple myeloma: potential roles for selinexor and XPO1 inhibitors

Binder,

Walker,

Mark

et al. 2023

Front. Immunol.

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Competent T-cells with sufficient levels of fitness combat cancer formation and progression. In multiple myeloma (MM), T-cell exhaustion is caused by several factors including tumor burden, constant immune activation due to chronic disease, age, nutritional status, and certain MM treatments such as alkylating agents and proteasome inhibitors. Many currently used therapies, including bispecific T-cell engagers, anti-CD38 antibodies, proteasome inhibitors, and CART-cells, directly or indirectly depend on the anti-cancer activity of T-cells. Reduced T-cell fitness not only diminishes immune defenses, increasing patient susceptibility to opportunistic infections, but can impact effectiveness MM therapy effectiveness, bringing into focus sequencing strategies that could modulate T-cell fitness and potentially optimize overall benefit and clinical outcomes. Certain targeted agents used to treat MM, such as selective inhibitors of nuclear export (SINE) compounds, have the potential to mitigate T-cell exhaustion. Herein referred to as XPO1 inhibitors, SINE compounds inhibit the nuclear export protein exportin 1 (XPO1), which leads to nuclear retention and activation of tumor suppressor proteins and downregulation of oncoprotein expression. The XPO1 inhibitors selinexor and eltanexor reduced T-cell exhaustion in cell lines and animal models, suggesting their potential role in revitalizating these key effector cells. Additional clinical studies are needed to understand how T-cell fitness is impacted by diseases and therapeutic factors in MM, to potentially facilitate the optimal use of available treatments that depend on, and impact, T-cell function. This review summarizes the importance of T-cell fitness and the potential to optimize treatment using T-cell engaging therapies with a focus on XPO1 inhibitors.

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“…CAR-T (chimeric antigen receptor T cell) therapy is a type of immunotherapy that manipulates T cells to better recognize and attack tumor cells [11][12][13]. A monoclonal antibody derivative forms the extracellular antigen-binding domain of CAR-T cells, allowing them to recognize specifics antigen and bind to them [14][15][16]. A costimulatory signal is then released, activating the T cells and augmenting their lifespan and functionality.…”

Section: Fig 1 a Schematic Representation Of In Vivo Versus Ex Vivo G...mentioning

confidence: 99%

Gene Therapy: Recent Advancement and Challenges

Aggarwal

Mittal

2022

AJBGMB

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Background: Gene therapy involves delivering therapeutic genomic material to a target tissue to modify expression of a protein or induce other characteristic changes. Recent advancements in the field, including FDA-approval of numerous gene therapies, are paving the way for future technological progress. While gene therapy can be either somatic or germline, most research and drug development has focused on somatic cells. In this article, we discuss the recent advancements and challenges associated with gene therapy. Main Text: There are multiple types of gene therapies, including hematopoietic stem cell therapy, CAR-T cell therapy, and Crispr/Cas9 gene therapy. Rare diseases and cancers are being researched to determine methods of treatment using gene therapy, and several clinical trials have been performed within the last decade to test the efficacy of new therapeutic drugs, many of them at least somewhat successful. However, gene therapy does pose some challenges, including large-scale manufacturing of vectors, precision of gene delivery to target tissue, and, most importantly, the immune responses of patients. Conclusions: The near future is an exciting time for new gene therapy technologies and strategies. Researchers and patients can look forward to new advancements in base editing, prime editing, and RNA-targeted editing technologies. Furthermore, future research can focus on new genetic targets, such as genes whose functions may still be unknown and epigenomic elements.

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The Past, Present, and Future of Clinically Applied Chimeric Antigen Receptor-T-Cell Therapy

Cited by 7 publications

References 150 publications

Timely Leukapheresis May Interfere with the “Fitness” of Lymphocytes Collected for CAR-T Treatment in High Risk DLBCL Patients

Timely Leukapheresis May Interfere with the “Fitness” of Lymphocytes Collected for CAR-T Treatment in High Risk DLBCL Patients

Impacting T-cell fitness in multiple myeloma: potential roles for selinexor and XPO1 inhibitors

Gene Therapy: Recent Advancement and Challenges

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