Failure of CAR-T cell therapy in relapsed and refractory large cell lymphoma and multiple myeloma: An urgent unmet need

Martin, Yasmine St.; Franz, Joseph; Agha, Mounzer; Lazarus, Hillard M.

doi:10.1016/j.blre.2023.101095

Cited by 11 publications

(3 citation statements)

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“…Even in the absence of medical complications during the vein-to-vein time, 4–7% of patients are unable to receive their CAR-T cell products as a result of manufacturing failures ( Bhaskar et al, 2021 ; St Martin et al, 2023 ), with risk factors including reduced fitness of patient T cells following multiple lines of treatment and the lengthy manufacturing process itself ( Jo et al, 2023 ). Therapeutic options following unsuccessful product manufacturing include repeating apheresis or transitioning to alternative therapies, though survival outcomes are poor in both cases ( Jagannath et al, 2021 ; Jo et al, 2023 ; Mateos et al, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

CAR-T cell manufacturing: Major process parameters and next-generation strategies

Ayala Ceja,

Khericha,

Harris

et al. 2024

Journal of Experimental Medicine

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Chimeric antigen receptor (CAR)-T cell therapies have demonstrated strong curative potential and become a critical component in the array of B-cell malignancy treatments. Successful deployment of CAR-T cell therapies to treat hematologic and solid cancers, as well as other indications such as autoimmune diseases, is dependent on effective CAR-T cell manufacturing that impacts not only product safety and efficacy but also overall accessibility to patients in need. In this review, we discuss the major process parameters of autologous CAR-T cell manufacturing, as well as regulatory considerations and ongoing developments that will enable the next generation of CAR-T cell therapies.

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Section: Introductionmentioning

confidence: 99%

CAR-T cell manufacturing: Major process parameters and next-generation strategies

Ayala Ceja,

Khericha,

Harris

et al. 2024

Journal of Experimental Medicine

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“…Furthermore, a subset of patients, particularly those with relapsed and refractory disease, do not respond adequately to CAR-T therapy. 15,16 The underlying mechanisms remains elusive.…”

Section: Introductionmentioning

confidence: 99%

miR‐34a promotes the immunosuppressive function of multiple myeloma‐associated macrophages by dampening the TLR‐9 signaling

Zhang,

Luo

et al. 2024

Cancer Medicine

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BackgroundPromising outcomes have been observed in multiple myeloma (MM) with the use of immunotherapies, specifically chimeric antigen receptor T (CAR‐T) cell therapy. However, a portion of MM patients do not respond to CAR‐T therapy, and the reasons for this lack of response remain unclear. The objective of this study was to investigate the impact of miR‐34a on the immunosuppressive polarization of macrophages obtained from MM patients.MethodsThe levels of miR‐34a and TLR9 (Toll‐like receptor 9) were examined in macrophages obtained from both healthy individuals and patients with MM. ELISA was employed to investigate the cytokine profiles of the macrophage samples. Co‐culture experiments were conducted to evaluate the immunomodulatory impact of MM‐associated macrophages on CAR‐T cells.ResultsThere was an observed suppressed activation of macrophages and CD4+ T lymphocytes in the blood samples of MM patients. Overexpression of miR‐34a in MM‐associated macrophages dampened the TLR9 expression and impaired the inflammatory polarization. In both the co‐culture system and an animal model, MM‐associated macrophages suppressed the activity and tumoricidal effect of CAR‐T cells in a miR‐34a‐dependent manner.ConclusionThe findings imply that targeting the macrophage miR‐34a/TLR9 axis could potentially alleviate the immunosuppression associated with CAR‐T therapy in MM patients.

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“…CAR‐T cells stand at the forefront of immunotherapy, holding promise for extending their impact to a broader spectrum of cancers and transforming the landscape of oncological care. It is now also realized that the frequent failure of CAR‐T treatment [ 7 , 8 ] may be intrinsically linked with suboptimal differentiation and metabolic rewiring, and recent reports suggest ways to address this [ 9 , 10 ]. The review by Taylor et al.…”

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confidence: 99%

Immunometabolism unveiled: Pioneering breakthroughs in cancer therapeutics

Eldering,

Ricci

2024

Molecular Oncology

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The field of immunometabolism cannot be considered ‘emerging’ anymore; it is at the moment one of the most active and rapidly evolving areas of biomedical research. Its hottest zone is cancer immunometabolism. This is partly due to the clinical application of immunotherapy, with either antibodies (checkpoint blockade) or cellular therapies (e.g., CAR‐T cells). In addition, the proliferating tumor cells create a nutrient‐deprived microenvironment that impairs the metabolic fitness and functionality of infiltrating immune cells such as T cells, NK cells, and macrophages. The key concepts are bidirectional metabolic signaling, plus the conviction that a better understanding of these processes will improve current immunotherapies, and foster new tools and targets for treatment. This collection of reviews will address various exciting aspects from junior and established scientists in the field.

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Failure of CAR-T cell therapy in relapsed and refractory large cell lymphoma and multiple myeloma: An urgent unmet need

Cited by 11 publications

References 88 publications

CAR-T cell manufacturing: Major process parameters and next-generation strategies

CAR-T cell manufacturing: Major process parameters and next-generation strategies

miR‐34a promotes the immunosuppressive function of multiple myeloma‐associated macrophages by dampening the TLR‐9 signaling

Immunometabolism unveiled: Pioneering breakthroughs in cancer therapeutics

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