Born to survive: how cancer cells resist CAR T cell therapy

Lemoine, Jean; Ruella, Marco; Houot, Roch

doi:10.1186/s13045-021-01209-9

Cited by 83 publications

(82 citation statements)

References 106 publications

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“…There is widespread appreciation that antigen density and antigen loss in response to therapy are key drivers of successful CAR-19 T cell treatment (30). Low antigen density or antigen loss uncouples the CAR-T cells from targets, leading to loss of response.…”

Section: Discussionmentioning

confidence: 99%

“…For example, CD19 antigen loss was associated with relapse from lymphoma in 62% of patients treated with an anti-CD19 CAR-T therapy, as assessed using quantitative flow cytometric methods (15, 31). Many mechanisms for CD19 antigen loss have been described, including transcriptional downregulation of expression and genetic alterations that prevent expression (13, 30, 39, 40).…”

Section: Discussionmentioning

confidence: 99%

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CAR-T Engager Proteins Optimize Anti-CD19 CAR-T Cell Therapies for Lymphoma

Su¹,

Wu²,

Lobb³

et al. 2022

Preprint

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B cell lymphoma therapy has been transformed by CD19-targeting cellular therapeutics that induce high clinical response rates and impressive remissions in relapsed and refractory patients. However, approximately half of all patients who respond to CD19-directed cell therapy relapse, the majority within six months. One characteristic of relapse is loss or reduction of CD19 expression on malignant B cells. We designed a unique therapeutic to prevent and reverse relapses due to lost or reduced CD19 expression. This novel biologic, a CAR T Engager, binds CD20 and displays the CD19 extracellular domain. This approach increases the apparent CD19 antigen density on CD19-positive/CD20-positive lymphoma cells, and prevents CD19 antigen-loss induced relapse, as CD19 bound to CD20 remains present on the cell surface. We demonstrate that this novel therapeutic prevents and reverses lymphoma relapse in vitro and prevents CD19-negative lymphoma growth and relapse in vivo.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

CAR-T Engager Proteins Optimize Anti-CD19 CAR-T Cell Therapies for Lymphoma

Su¹,

Wu²,

Lobb³

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Indeed, the relapse in B-ALL patients following CD19 CAR-T treatment can affect even half of them, but the cumulative incidence of relapse according to the meta-analysis of available clinical trials’ reports is estimated at 36% [ 90 ]. The most commonly reported causes of tumor resistance to CD19 CAR-T treatment and subsequent relapse concern various tumor cells aberrations, among which the loss of CD19 antigen is the most frequent [ 91 ]. The loss of CD19 is reported even in up to 25% of B-ALL cases [ 12 , 92 , 93 , 94 , 95 ].…”

Section: Mechanisms Of Resistance To the Cd19 Car-t Therapy In B Cell...mentioning

confidence: 99%

“…An inherent resistance of neoplastic B cells for CD19 CAR-T therapy has been also correlated with aberrant expression of genes from the death receptor apoptosis pathway such as BID , FADD , CASP8 , TNFRSF10B , Fas , and TRAIL [ 91 , 120 ]. The crucial role of death receptor signaling in susceptibility to CD19 CAR-T cytotoxicity was demonstrated in a Nalm-6 B-ALL cell line in vitro model and CRISPR-based genome-wide loss-of-function screen [ 121 , 122 ].…”

Section: Mechanisms Of Resistance To the Cd19 Car-t Therapy In B Cell...mentioning

confidence: 99%

CAR-T Cells Shoot for New Targets: Novel Approaches to Boost Adoptive Cell Therapy for B Cell-Derived Malignancies

Marhelava

Krawczyk

Firczuk

et al. 2022

Cells

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Chimeric antigen receptor (CAR)-T cell therapy is undeniably a promising tool in combating various types of hematological malignancies. However, it is not yet optimal and a significant number of patients experience a lack of response or relapse after the treatment. Therapy improvement requires careful analysis of the occurring problems and a deeper understanding of the reasons that stand behind them. In this review, we summarize the recent knowledge about CAR-T products’ clinical performance and discuss diversified approaches taken to improve the major shortcomings of this therapy. Especially, we prioritize the challenges faced by CD19 CAR-T cell-based treatment of B cell-derived malignancies and revise the latest insights about mechanisms mediating therapy resistance. Since the loss of CD19 is one of the major obstacles to the success of CAR-T cell therapy, we present antigens that could be alternatively used for the treatment of various types of B cell-derived cancers.

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“…The remarkable responses of relapsed/refractory patients to CAR-T cell therapy have led to broad testing of this strategy in clinical trials and increasing research within the field [ 1 ]. However, more than 50% of patients experience inferior efficacy or disease progression due to loss of antigen density, tumor microenvironment suppression and/or intrinsic CAR-T cell exhaustion [ 2 – 5 ]. CAR-T cell exhaustion is a vital barrier to adoptive cell therapy (ACT) and is characterized by the gradual loss of induced cytotoxicity and proliferation, sustained expression of inhibitory receptors, an increased apoptosis rate and metabolic dysfunction [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Rewiring mitochondrial metabolism to counteract exhaustion of CAR-T cells

Huang

Shao

et al. 2022

J Hematol Oncol

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Short persistence and early exhaustion of T cells are major limits to the efficacy and broad application of immunotherapy. Exhausted T and chimeric antigen receptor (CAR)-T cells upregulate expression of genes associated with terminated T cell differentiation, aerobic glycolysis and apoptosis. Among cell exhaustion characteristics, impaired mitochondrial function and dynamics are considered hallmarks. Here, we review the mitochondrial characteristics of exhausted T cells and particularly discuss different aspects of mitochondrial metabolism and plasticity. Furthermore, we propose a novel strategy of rewiring mitochondrial metabolism to emancipate T cells from exhaustion and of targeting mitochondrial plasticity to boost CAR-T cell therapy efficacy.

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Born to survive: how cancer cells resist CAR T cell therapy

Cited by 83 publications

References 106 publications

CAR-T Engager Proteins Optimize Anti-CD19 CAR-T Cell Therapies for Lymphoma

CAR-T Engager Proteins Optimize Anti-CD19 CAR-T Cell Therapies for Lymphoma

CAR-T Cells Shoot for New Targets: Novel Approaches to Boost Adoptive Cell Therapy for B Cell-Derived Malignancies

Rewiring mitochondrial metabolism to counteract exhaustion of CAR-T cells

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