CAR T Cell Therapy for Chronic Lymphocytic Leukemia: Successes and Shortcomings

Todorović, Zoran; Todorović, Dušan; Markovic, V.M.; Ladjevac, Nevena; Zdravković, Nataša; Djurdjević, Predrag; Arsenijević, Nebojša; Milovanovic, Marija; Arsenijević, Aleksandar; Milovanović, Jelena

doi:10.3390/curroncol29050293

Cited by 22 publications

(19 citation statements)

References 75 publications

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“…CARs consist of the fusion of an antigen-binding extracellular domain, a signaling CD3ζ subunit and one or more costimulatory intracellular domains [152,154]. Surprisingly, anti-CD19 CAR-T cell treatment has not reached the expected outcomes in CLL, with an average complete remission rate of ~30%, significantly lower compared to that obtained in acute lymphoblastic leukemia and diffuse large B cell lymphoma [155][156][157][158]. Several mechanisms of resistance to the treatment with anti-CD19 CAR-T cells in CLL have been proposed, principally due to T cell exhaustion promoted by the neoplastic clone [155].…”

Section: Potential Biomarkers Of Refractoriness To Car-t Cellsmentioning

confidence: 99%

Treatment Refractoriness in Chronic Lymphocytic Leukemia: Old and New Molecular Biomarkers

Maher

Mouhssine

Matti

et al. 2023

IJMS

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Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. Despite its indolent clinical course, therapy refractoriness and disease progression still represent an unmet clinical need. Before the advent of pathway inhibitors, chemoimmunotherapy (CIT) was the commonest option for CLL treatment and is still widely used in areas with limited access to pathway inhibitors. Several biomarkers of refractoriness to CIT have been highlighted, including the unmutated status of immunoglobulin heavy chain variable genes and genetic lesions of TP53, BIRC3 and NOTCH1. In order to overcome resistance to CIT, targeted pathway inhibitors have become the standard of care for the treatment of CLL, with practice-changing results obtained through the inhibitors of Bruton tyrosine kinase (BTK) and BCL2. However, several acquired genetic lesions causing resistance to covalent and noncovalent BTK inhibitors have been reported, including point mutations of both BTK (e.g., C481S and L528W) and PLCG2 (e.g., R665W). Multiple mechanisms are involved in resistance to the BCL2 inhibitor venetoclax, including point mutations that impair drug binding, the upregulation of BCL2-related anti-apoptotic family members, and microenvironmental alterations. Recently, immune checkpoint inhibitors and CAR-T cells have been tested for CLL treatment, obtaining conflicting results. Potential refractoriness biomarkers to immunotherapy were identified, including abnormal levels of circulating IL-10 and IL-6 and the reduced presence of CD27+CD45RO− CD8+ T cells.

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Section: Potential Biomarkers Of Refractoriness To Car-t Cellsmentioning

confidence: 99%

Treatment Refractoriness in Chronic Lymphocytic Leukemia: Old and New Molecular Biomarkers

Maher

Mouhssine

Matti

et al. 2023

IJMS

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“…Although the first experimental use of CAR-T cells was reported as the treatment of CLL in 2011, 121 further development was outpaced by other hematological malignancies and CAR-T therapies are still in the investigational stage for CLL. 122 The phase 1/2 TRANSCEND CLL004 trial has recently reported the preliminary data on lisocabtagene maraleucel (liso-cel), an autologous CD19-targeting CAR-T cell product, with 118 RR-CLL/SLL patients. All patients had received a previous BTKi.…”

Section: Chimeric Antigen Receptor T Cell Therapiesmentioning

confidence: 99%

Taking the Next Step in Double Refractory Disease: Current and Future Treatment Strategies for Chronic Lymphocytic Leukemia

Hayama,

Riches

2024

OTT

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Chronic lymphocytic leukemia (CLL) is a monoclonal B-cell lymphoproliferative disease with a high annual incidence in Western countries. As B-cell receptor (BCR) signaling and intrinsic apoptotic resistance play critical roles in the development and survival of CLL cells, therapeutic approaches targeting these pathways have been extensively investigated to tackle this incurable disease. Over the last decade, several Phase 3 trials have confirmed the superior efficacy of covalent Bruton tyrosine kinase inhibitors (cBTKis) and venetoclax, a selective B-cell lymphoma 2 (BCL2) inhibitor, over chemoimmunotherapy. This has been demonstrated in both the treatment-naïve and relapsed/refractory (RR) settings and includes patients with high-risk molecular features. However, these drugs are not curative, with patients continuing to relapse after treatment with both cBTKis and BCL2is, and the optimal treatment strategy for these patients has not been defined. Several novel agents with distinct mechanisms have recently been developed for CLL which have demonstrated efficacy in patients who have previously received cBTKis and BCL2i. In particular, novel BCR-signaling targeting agents have shown promising efficacy in early-phase clinical trials for RR-CLL. Furthermore, cancer immunotherapies such as bispecific antibodies and chimeric antigen receptor T-cells have also shown anti-tumor activity in patients with heavily pretreated RR-CLL. Personalised approaches with these novel agents and combination strategies based on the understanding of resistance mechanisms have the potential to overcome the clinical challenge of what to do next for a patient who has already had a cBTKi and venetoclax.

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“…Finally, chimeric antigen receptor (CAR) T-cell therapy represents the most novel strategy that is being investigated in R/R CLL [82][83][84][85][86]. The first studies have provided promising results on the effectiveness of CD19-directed CAR-T in CLL [70,[82][83][84][85].…”

Section: Overcoming Resistance To Btkimentioning

confidence: 99%

A Review of Resistance Mechanisms to Bruton’s Kinase Inhibitors in Chronic Lymphocytic Leukemia

Wiśniewski,

Puła

2024

IJMS

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Bruton’s Tyrosine Kinase (BTK) inhibitors have become one of the most vital drugs in the therapy of chronic lymphocytic leukemia (CLL). Inactivation of BTK disrupts the B-cell antigen receptor (BCR) signaling pathway, which leads to the inhibition of the proliferation and survival of CLL cells. BTK inhibitors (BTKi) are established as leading drugs in the treatment of both treatment-naïve (TN) and relapsed or refractory (R/R) CLL. Furthermore, BTKi demonstrate outstanding efficacy in high-risk CLL, including patients with chromosome 17p deletion, TP53 mutations, and unmutated status of the immunoglobulin heavy-chain variable region (IGHV) gene. Ibrutinib is the first-in-class BTKi which has changed the treatment landscape of CLL. Over the last few years, novel, covalent (acalabrutinib, zanubrutinib), and non-covalent (pirtobrutinib) BTKi have been approved for the treatment of CLL. Unfortunately, continuous therapy with BTKi contributes to the acquisition of secondary resistance leading to clinical relapse. In recent years, it has been demonstrated that the predominant mechanisms of resistance to BTKi are mutations in BTK or phospholipase Cγ2 (PLCG2). Some differences in the mechanisms of resistance to covalent BTKi have been identified despite their similar mechanism of action. Moreover, novel mutations resulting in resistance to non-covalent BTKi have been recently suggested. This article summarizes the clinical efficacy and the latest data regarding resistance to all of the registered BTKi.

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CAR T Cell Therapy for Chronic Lymphocytic Leukemia: Successes and Shortcomings

Cited by 22 publications

References 75 publications

Treatment Refractoriness in Chronic Lymphocytic Leukemia: Old and New Molecular Biomarkers

Treatment Refractoriness in Chronic Lymphocytic Leukemia: Old and New Molecular Biomarkers

Taking the Next Step in Double Refractory Disease: Current and Future Treatment Strategies for Chronic Lymphocytic Leukemia

A Review of Resistance Mechanisms to Bruton’s Kinase Inhibitors in Chronic Lymphocytic Leukemia

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