Mechanisms of Resistance and Treatment of Relapse after CAR T-cell Therapy for Large B-cell Lymphoma and Multiple Myeloma

Rejeski, Kai; Jain, Michael D.; Smith, Eric L.

doi:10.1016/j.jtct.2023.04.007

Cited by 24 publications

(11 citation statements)

References 178 publications

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“…While commercial scFv-based anti-BCMA CAR T cell products have achieved excellent clinical results in pivotal studies, therapeutic failure and relapse are still observed [ 6 ]. CAR T cell therapy has evolved in recent years due to continuous improvements in CAR vector design [ 7 , 8 ].…”

Section: Discussionmentioning

confidence: 99%

“…In terms of efficacy, only 33% of the patients treated with ide-cel exhibited a complete remission and 26% of all patients achieved MRD negativity [ 4 ]. ScFv-based anti-BCMA CAR T cell therapy remains a promising treatment approach, although coming with limitations including therapeutic resistance and toxicity [ 2 , 4 – 6 ]. Besides the disease and patient’s characteristics, the CAR design influences its functionality [ 7 – 10 ].…”

Section: Introductionmentioning

confidence: 99%

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Comparative performance of scFv-based anti-BCMA CAR formats for improved T cell therapy in multiple myeloma

Stock,

Fertig,

Gottschlich

et al. 2024

Cancer Immunol Immunother

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In multiple myeloma (MM), B cell maturation antigen (BCMA)-directed CAR T cells have emerged as a novel therapy with potential for long-term disease control. Anti-BCMA CAR T cells with a CD8-based transmembrane (TM) and CD137 (41BB) as intracellular costimulatory domain are in routine clinical use. As the CAR construct architecture can differentially impact performance and efficacy, the optimal construction of a BCMA-targeting CAR remains to be elucidated. Here, we hypothesized that varying the constituents of the CAR structure known to impact performance could shed light on how to improve established anti-BCMA CAR constructs. CD8TM.41BBIC-based anti-BCMA CAR vectors with either a long linker or a short linker between the light and heavy scFv chain, CD28TM.41BBIC-based and CD28TM.CD28IC-based anti-BCMA CAR vector systems were used in primary human T cells. MM cell lines were used as target cells. The short linker anti-BCMA CAR demonstrated higher cytokine production, whereas in vitro cytotoxicity, T cell differentiation upon activation and proliferation were superior for the CD28TM.CD28IC-based CAR. While CD28TM.CD28IC-based CAR T cells killed MM cells faster, the persistence of 41BBIC-based constructs was superior in vivo. While CD28 and 41BB costimulation come with different in vitro and in vivo advantages, this did not translate into a superior outcome for either tested model. In conclusion, this study showcases the need to study the influence of different CAR architectures based on an identical scFv individually. It indicates that current scFv-based anti-BCMA CAR with clinical utility may already be at their functional optimum regarding the known structural variations of the scFv linker.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Comparative performance of scFv-based anti-BCMA CAR formats for improved T cell therapy in multiple myeloma

Stock,

Fertig,

Gottschlich

et al. 2024

Cancer Immunol Immunother

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“…Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a powerful treatment modality for a range of advanced B-cell malignancies but is associated with a unique toxicity profile. 1 , 2 , 3 , 4 , 5 , 6 Next to cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) as prototypical side effects, hematological toxicity represents the most common side effect of CAR-T therapy. 7 , 8 Cytopenias are qualitatively unique because of their biphasic trajectory and can be long-lasting in nature.…”

Section: Introductionmentioning

confidence: 99%

Applying the EHA/EBMT grading for ICAHT after CAR-T: comparative incidence and association with infections and mortality

Rejeski,

Wang,

Hansen

et al. 2024

Blood Advances

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Cytopenias represent the most common side effect of CAR T-cell therapy and can predispose for severe infectious complications. Current grading systems such as the CTCAE neither reflect the unique quality of post CAR-T neutrophil recovery, nor do they reflect the inherent risk of infections due to protracted neutropenia. For this reason, a novel EHA/EBMT consensus grading was recently developed for Immune Effector Cell-Associated HematoToxicity (ICAHT). In this multicenter observational study, we applied the grading system to a large real-world cohort of 549 patients treated with BCMA- or CD19 CAR-T for refractory B-cell malignancies (112 MM, 334 LBCL, 103 MCL) and examined the clinical sequelae of severe (≥3°) ICAHT. The ICAHT grading was strongly associated with the cumulative duration of severe neutropenia (r=0.92, p<0.0001), presence of multilineage cytopenias, and the use of platelet and red blood cell transfusions. We noted an increased rate of severe ICAHT in MCL vs. LBCL and MM patients (28% vs. 23% vs. 15%). Severe ICAHT was associated with a higher rate of severe infections (49% vs. 13%, p<0.0001), increased NRM (14% vs. 4%, p<0.0001), and inferior survival outcomes (1-year PFS 35% vs. 51%, 1-year OS 52% vs. 73%, both p<0.0001). Importantly, the ICAHT grading demonstrated superior capacity to predict severe infections compared to CTCAE grading (c-index 0.73 vs. 0.55, p<0.0001 vs. non-signficant). Taken together, these data highlight the clinical relevance of the novel grading system and support the reporting of ICAHT severity in clinical trials evaluating CAR-T therapies.

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“…Recently, CD19‐directed chimeric antigen receptor (CAR) T‐cell therapy with brexucabtagene autoleucel (brexu‐cel) has broadened the armamentarium for r/r MCL patients with promising response rates both in clinical studies and the real‐world setting 5–8 . Even though a substantial number of patients achieve long‐term remissions, CAR T‐cell therapy is accompanied by a unique spectrum of side effects including cytokine release syndrome (CRS) and immune effector cell‐associated neurotoxicity syndrome (ICANS) 9–11 . However, the most frequent grade ≥3 side effect is hematological toxicity, which may present in the form of profound and/or long‐lasting cytopenias 12–15 .…”

Section: Introductionmentioning

confidence: 99%

“…[5][6][7][8] Even though a substantial number of patients achieve long-term remissions, CAR T-cell therapy is accompanied by a unique spectrum of side effects including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). [9][10][11] However, the most frequent grade ≥3 side effect is hematological toxicity, which may present in the form of profound and/or long-lasting cytopenias. [12][13][14][15] Importantly, such sustained cellular immunosuppression predisposes for severe infectious complications.…”

Section: Introductionmentioning

confidence: 99%

The CAR‐HEMATOTOX score identifies patients at high risk for hematological toxicity, infectious complications, and poor treatment outcomes following brexucabtagene autoleucel for relapsed or refractory MCL

et al. 2023

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CD19‐directed CAR T‐cell therapy with brexucabtagene autoleucel (brexu‐cel) has substantially improved treatment outcomes for patients with relapsed/refractory mantle cell lymphoma (r/r MCL). Prolonged cytopenias and infections represent common and clinically relevant side effects. In this multicenter observational study, we describe cytopenias and infections in 103 r/r MCL patients receiving brexu‐cel. Furthermore, we report associations between the baseline CAR‐HEMATOTOX (HT) score and toxicity events, non‐relapse mortality (NRM), and progression‐free/overall survival (PFS/OS). At lymphodepletion, 56 patients were HTlow (score 0–1) while 47 patients were HThigh (score ≥2). The HThigh cohort exhibited prolonged neutropenia (median 14 vs. 6 days, p < .001) and an increased rate of severe infections (30% vs. 5%, p = .001). Overall, 1‐year NRM was 10.4%, primarily attributed to infections, and differed by baseline HT score (high vs. low: 17% vs. 4.6%, p = .04). HThigh patients experienced inferior 90‐day complete response rate (68% vs. 93%, p = .002), PFS (median 9 months vs. not‐reached, p < .0001), and OS (median 26 months vs. not‐reached, p < .0001). Multivariable analyses showed that high HT scores were independently associated with severe hematotoxicity, infections, and poor PFS/OS. In conclusion, infections and hematotoxicity are common after brexu‐cel and contribute to NRM. The baseline HT score identified patients at increased risk of poor treatment outcomes.

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Mechanisms of Resistance and Treatment of Relapse after CAR T-cell Therapy for Large B-cell Lymphoma and Multiple Myeloma

Cited by 24 publications

References 178 publications

Comparative performance of scFv-based anti-BCMA CAR formats for improved T cell therapy in multiple myeloma

Comparative performance of scFv-based anti-BCMA CAR formats for improved T cell therapy in multiple myeloma

Applying the EHA/EBMT grading for ICAHT after CAR-T: comparative incidence and association with infections and mortality

The CAR‐HEMATOTOX score identifies patients at high risk for hematological toxicity, infectious complications, and poor treatment outcomes following brexucabtagene autoleucel for relapsed or refractory MCL

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