Tumor burden, inflammation, and product attributes determine outcomes of axicabtagene ciloleucel in large B-cell lymphoma

Locke, Frederick L.; Rossi, John M.; Neelapu, Sattva S.; Jacobson, Caron A.; Miklos, David B.; Ghobadi, Armin; Oluwole, Olalekan O.; Reagan, Patrick M.; Lekakis, Lazaros J.; Lin, Yi; Sherman, Marika; Better, Marc; Go, William Y.; Wiezorek, Jeffrey S.; Xue, Allen; Bot, Adrian

doi:10.1182/bloodadvances.2020002394

Cited by 336 publications

(375 citation statements)

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“…Patients with high LDH levels had a worse outcome after treatment with tisa‐cel. Other studies also identified LDH 11 and high tumor volume, measured on CT 29 or PET scan, 14,30 as clear prognostic factors for disease response after CAR T‐cell therapy. Patients with primary refractory disease also had a lower PFS and OS.…”

Section: Discussionmentioning

confidence: 99%

Real‐world evidence of tisagenlecleucel for the treatment of relapsed or refractory large B‐cell lymphoma

Iacoboni

Villacampa²,

Martínez-Cibrián

et al. 2021

Cancer Medicine

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Tisagenlecleucel (tisa‐cel) is a second‐generation autologous CD19‐targeted chimeric antigen receptor (CAR) T‐cell therapy approved for relapsed/refractory (R/R) large B‐cell lymphoma (LBCL). The approval was based on the results of phase II JULIET trial, with a best overall response rate (ORR) and complete response (CR) rate in infused patients of 52% and 40%, respectively. We report outcomes with tisa‐cel in the standard‐of‐care (SOC) setting for R/R LBCL. Data from all patients with R/R LBCL who underwent leukapheresis from December 2018 until June 2020 with the intent to receive SOC tisa‐cel were retrospectively collected at 10 Spanish institutions. Toxicities were graded according to ASTCT criteria and responses were assessed as per Lugano 2014 classification. Of 91 patients who underwent leukapheresis, 75 (82%) received tisa‐cel therapy. Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 5% and 1%, respectively; non‐relapse mortality was 4%. Among the infused patients, best ORR and CR were 60% and 32%, respectively, with a median duration of response of 8.9 months. With a median follow‐up of 14.1 months from CAR T‐cell infusion, median progression‐free survival and overall survival were 3 months and 10.7 months, respectively. At 12 months, patients in CR at first disease evaluation had a PFS of 87% and OS of 93%. Patients with an elevated lactate dehydrogenase showed a shorter PFS and OS on multivariate analysis. Treatment with tisa‐cel for patients with relapsed/refractory LBCL in a European SOC setting showed a manageable safety profile and durable complete responses.

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Section: Discussionmentioning

confidence: 99%

Real‐world evidence of tisagenlecleucel for the treatment of relapsed or refractory large B‐cell lymphoma

Iacoboni

Villacampa²,

Martínez-Cibrián

et al. 2021

Cancer Medicine

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“…on their surface in order to recognize tumor-associated antigens, expanded, and transferred into patients(100,101). CAR-T therapy showed tremendous results for relapsed/refractory B cell hematological malignancies, and CD19-targeted CAR-T therapies have been approved by the FDA (102)(103)(104)(105)(106). Compared to hematological malignancies, the efficacy of CAR-T therapy for solid tumors is limited because of tumorassociated antigen heterogeneity in these, and immunosuppressive factors derived from the tumor microenvironment.…”

Section: Therapy Targeting Emtmentioning

confidence: 99%

Tumor Immune Microenvironment during Epithelial–Mesenchymal Transition

Taki

Abiko

Ukita

et al. 2021

Clinical Cancer Research

202

137

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Epithelial-mesenchymal transition (EMT) has been shown to play a critical role in tumor development from initiation to metastasis. EMT could be regarded as a continuum, with intermediate hybrid epithelial and mesenchymal phenotypes having high plasticity. Classical EMT is characterized by the phenotype change of epithelial cells to cells with mesenchymal properties, but EMT is also associated with multiple other molecular processes, including tumor immune evasion. Some previous studies have shown that EMT is associated with the cell number of immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs), and the expression of immune checkpoints, such as programmed cell death-ligand 1, in several cancer types. At the molecular level, EMT transcriptional factors, including Snail, Zeb1, and Twist1, produce or attract immunosuppressive cells or promote the expression of immunosuppressive checkpoint molecules via chemokine production, leading to a tumor immunosuppressive microenvironment. In turn, immunosuppressive factors induce EMT in tumor cells. This feedback loop between EMT and immunosuppression promotes tumor progression. For therapy directly targeting EMT has been challenging, the elucidation of the interactive regulation of EMT and immunosuppression is desirable for developing new therapeutic approaches in cancer. The combination of immune checkpoint inhibitors (ICIs) and immunotherapy targeting immunosuppressive cells could be a promising therapy for EMT.Research.

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“…Decreased tumor burden prior to CAR T-cell infusion is associated with improved efficacy and decreased toxicity in R/R DLBCL ( 10 ). The overall response rate to axi-cel in ZUMA-1, as well as durability of response at 1 year, has been directly associated with lower tumor burden ( 10 , 14 , 41 ). Additionally, there was an association between decreased tumor burden and lower rates of treatment-related toxicity (Grade 3 or higher neurologic events and CRS).…”

Section: Radiation As Bridging Therapy Between Apheresis and Car T Imentioning

confidence: 99%

Radiation and CAR T-cell Therapy in Lymphoma: Future Frontiers and Potential Opportunities for Synergy

Fang

Gunther

et al. 2021

Front. Oncol.

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CAR T-cell therapy has revolutionized the treatment approach to patients with relapsed/refractory hematologic malignancies; however, there continues to be opportunity for improvement in treatment toxicity as well as response durability. Radiation therapy can play an important role in combined modality treatments for some patients undergoing CAR T-cell therapy in various clinical settings. In this review, we discuss the current evidence for RT in the setting of CAR T-cell therapy for patients with hematologic malignancies and propose potential opportunities for future investigation of RT and CAR T-cell treatment synergy. Future research frontiers include investigation of hypotheses including radiation priming of CAR T-cell mediated death, pre-CAR T-cell tumor debulking with radiation therapy, and selection of high risk patients for early radiation salvage after CAR T cell therapy.

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Tumor burden, inflammation, and product attributes determine outcomes of axicabtagene ciloleucel in large B-cell lymphoma

Cited by 336 publications

References 50 publications

Real‐world evidence of tisagenlecleucel for the treatment of relapsed or refractory large B‐cell lymphoma

Real‐world evidence of tisagenlecleucel for the treatment of relapsed or refractory large B‐cell lymphoma

Tumor Immune Microenvironment during Epithelial–Mesenchymal Transition

Radiation and CAR T-cell Therapy in Lymphoma: Future Frontiers and Potential Opportunities for Synergy

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