Second-Line Tisagenlecleucel or Standard Care in Aggressive B-Cell Lymphoma

Bishop, Michael; Dickinson, Michael; Purtill, Duncan; Barba, Pere; Santoro, Armando; Hamad, Nada; Kato, Koji; Sureda, Anna; Greil, Richard; Thiéblemont, Catherine; Morschhauser, Franck; Janz, Martin; Flinn, Ian W.; Rabitsch, Werner; Kwong, Yok–Lam; Kersten, Marie José; Minnema, Monique C.; Holte, Harald; Chan, Esther Hian Li; Martínez‐López, Joaquín; Müller, Antonia; Maziarz, Richard T.; McGuirk, Joseph P.; Bachy, Emmanuel; Gouill, Steven Le; Dreyling, Martin; Harigae, Hideo; Bond, David A.; Andreadis, Charalambos; McSweeney, Peter A.; Kharfan‐Dabaja, Mohamed A.; Newsome, Simon; Degtyarev, Evgeny; Awasthi, Rakesh; Corral, Christopher del; Andreola, Giovanna; Masood, Aisha; Schuster, Stephen J.; Jäger, Ulrich; Borchmann, Peter; Westin, Jason R.

doi:10.1056/nejmoa2116596

Cited by 348 publications

(309 citation statements)

References 16 publications

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“…An additional 7% did not receive an infusion due to manufacturing failures ( 3 ). Similar data was reported from 2 nd -line auto-CAR studies in which bridging was permitted ( 6 , 12 ). The need for bridging chemotherapy likely reflects more aggressive disease biology, as retrospective analyses have shown that patients who receive bridging have higher Eastern Cooperative Oncology Group Performance Status and International Prognostic Index scores, disease stage, bulky disease (> 10 cm), and higher lactate dehydrogenase levels at the start of therapy ( 13 ).…”

Section: Introductionsupporting

confidence: 81%

Custom CARs: Leveraging the Adaptability of Allogeneic CAR Therapies to Address Current Challenges in Relapsed/Refractory DLBCL

Jeyakumar

Smith

2022

Front. Immunol.

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Cellular therapies have transformed the treatment of relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL), which typically does not respond well to salvage chemotherapy. Recently, approximately 40% of r/r DLBCL patients across three different trials achieved a complete remission at 1 year after receiving treatment with autologous chimeric antigen receptor (CAR) T cells (auto-CARs). These successes have prompted studies of auto-CARs in second-line settings, in which axicabtagene ciloleucel and lisocabtagene maraleucel both showed improved event-free survival over autologous hematopoietic cell transplantation (AHCT). While encouraging, this data also highlights that 60% of patients relapse or progress following treatment with auto-CARs. Individual disease characteristics and logistical challenges of cell engineering also limit patients’ eligibility for auto-CARs. Allogeneic CAR T cells (allo-CARs) may address some of these limitations as they may mitigate delays associated with auto-CARs, thereby reducing the need for bridging chemotherapies and increasing availability of cellular products for patients with aggressive lymphomas. By being sourced from healthy donors who have never been exposed to cytotoxic chemotherapy, allo-CARs can be created from T cells with better fitness. Allo-CARs made from specific cellular subsets (e.g., stem cell memory or naïve/early memory T cells) may also have increased efficacy and long-term persistence. Additionally, allo-CARs have been successfully created from other cell types, including natural killer cells, gamma-delta T-cells and induced pluripotent stem cells. These cell types can be engineered to target viral antigens, enabling precision targeting of virally driven DLBCL. As allogeneic donor cells can be banked and cryopreserved in batches, they can be made more readily available, potentially reducing logistical hurdles and costs compared to engineering auto-CARs. This may ultimately create a more sustainable platform for cell therapies. Challenges with allo-CARs that will need to be addressed include graft versus host disease, alloimmunization, potentially decreased persistence relative to auto-CARs, and antigen escape. In short, the adaptability of allo-CARs makes them ideal for treating patients with r/r DLBCL who have progressed through standard chemotherapy, AHCT, or auto-CARs. Here, we review the published literature on patients with r/r DLBCL treated with allogeneic CAR products manufactured from various cell types as well as forthcoming allogeneic CAR technologies.

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Section: Introductionsupporting

confidence: 81%

Custom CARs: Leveraging the Adaptability of Allogeneic CAR Therapies to Address Current Challenges in Relapsed/Refractory DLBCL

Jeyakumar

Smith

2022

Front. Immunol.

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“…Moreover, patients with early relapse following first-line therapy have a poor prognosis, with a 50% rate of overall survival when treated with the currently available therapies [ 46 ]. Based on results of trials comparing CAR-T cell with SOC, investigators from TRANSFORM and ZUMA-7 studies support the respective CAR-T cell products as potential second-line (2L) treatment for patients with R/R DLBCL [ 47 , 48 ]. On the other hand, investigators of the BELINDA study state that insights from a longer follow-up and additional studies of this randomized Phase 3 trial will inform the possible use of tisagenlecleucel in the 2L R/R DLBCL setting [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

Systematic Review of Available CAR-T Cell Trials around the World

Barros

Couto

Santurio

et al. 2022

Cancers

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In this systematic review, we foresee what could be the approved scenario in the next few years for CAR-T cell therapies directed against hematological and solid tumor malignancies. China and the USA are the leading regions in numbers of clinical studies involving CAR-T. Hematological antigens CD19 and BCMA are the most targeted, followed by mesothelin, GPC3, CEA, MUC1, HER2, and EGFR for solid tumors. Most CAR constructs are second-generation, although third and fourth generations are being largely explored. Moreover, the benefit of combining CAR-T treatment with immune checkpoint inhibitors and other drugs is also being assessed. Data regarding product formulation and administration, such as cell phenotype, transfection technique, and cell dosage, are scarce and could not be retrieved. Better tracking of trials’ status and results on the ClinicalTrials.gov database should aid in a more concise and general view of the ongoing clinical trials involving CAR-T cell therapy.

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“…In the interim analysis of the TRANSFORM trial, median EFS in the 92 patients who received lisocabtagene maraleucel was 10.1 compared to 2.3 months among the 92 patients treated with standard of care. These data were contrasted by the BELINDA ( 24 ) study (NCT03570892), using tisagenlecleucel, which showed no difference in outcomes.…”

Section: Introductionmentioning

confidence: 90%

Novel Immune-Based treatments for Diffuse Large B-Cell Lymphoma: The Post-CAR T Cell Era

et al. 2022

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Prognosis for patients with refractory/relapsed (R/R) diffuse large B-cell lymphoma (DLBCL) is poor. Immune-based therapeutic treatments such as CD19 Chimeric Antigen Receptor (CAR) T cell therapies have dramatically changed the treatment landscape for R/R DLBCL leading to durable remissions in ~ 50% of patients. However, there remains an unmet need for developing novel therapies to improve clinical outcomes of patients not responding or relapsing after CAR T cell therapies. Lack of suitable immunotherapeutic targets and disease heterogeneity represent the foremost challenges in this emerging field. In this review, we discuss the recently approved and emerging novel immunotherapies for patients with R/R DLBCL in the post-CAR T era and the cell surface targets currently used.

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Second-Line Tisagenlecleucel or Standard Care in Aggressive B-Cell Lymphoma

Cited by 348 publications

References 16 publications

Custom CARs: Leveraging the Adaptability of Allogeneic CAR Therapies to Address Current Challenges in Relapsed/Refractory DLBCL

Custom CARs: Leveraging the Adaptability of Allogeneic CAR Therapies to Address Current Challenges in Relapsed/Refractory DLBCL

Systematic Review of Available CAR-T Cell Trials around the World

Novel Immune-Based treatments for Diffuse Large B-Cell Lymphoma: The Post-CAR T Cell Era

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