Use of Chimeric Antigen Receptor T Cell Therapy in Clinical Practice for Relapsed/Refractory Aggressive B Cell Non-Hodgkin Lymphoma: An Expert Panel Opinion from the American Society for Transplantation and Cellular Therapy

Jain, Tania; Bar, Merav; Kansagra, Ankit; Chong, Elise A.; Hashmi, Shahrukh K.; Neelapu, Sattva S.; Byrne, Michael; Jacoby, Elad; Lazaryan, Aleksandr; Jacobson, Caron A.; Ansell, Stephen M.; Awan, Farrukh T.; Burns, Linda J.; Bachanová, Veronika; Bollard, Catherine M.; Carpenter, Paul A.; DiPersio, John F.; Hamadani, Mehdi; Heslop, Helen E.; Hill, Joshua A.; Komanduri, Krishna V.; Kovitz, Craig A.; Lazarus, Hillard M.; Serrette, Justin M.; Mohty, Mohamad; Miklos, David B.; Nagler, Arnon; Pavletić, Steven Z.; Savani, Bipin N.; Schuster, Stephen J.; Kharfan‐Dabaja, Mohamed A.; Perales, Miguel Angel; Lin, Yi

doi:10.1016/j.bbmt.2019.08.015

Cited by 155 publications

(141 citation statements)

References 101 publications

(206 reference statements)

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“…These findings extend beyond published results of older patients in ZUMA-1 and JULIET trials, and provide novel insights and the entry point for large scale investigation of geriatric vulnerabilities in CAR T. We contend that older patients should not be automatically excluded from CAR T consideration based solely on chronological age, multi-morbidity, functional limitation, or cognitive impairment; rather, their care should be individualized including greater attention to non-oncologic geriatric issues. It is likely that detailed GA in combination with organ function evaluation will allow better selection of older patients who could benefit from this curative treatment 15 .…”

Section: Letter To the Editormentioning

confidence: 99%

Impact and safety of chimeric antigen receptor T-cell therapy in older, vulnerable patients with relapsed/refractory large B-cell lymphoma

et al. 2020

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Section: Letter To the Editormentioning

confidence: 99%

Impact and safety of chimeric antigen receptor T-cell therapy in older, vulnerable patients with relapsed/refractory large B-cell lymphoma

et al. 2020

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“…Two anti-CD19 chimeric antigen receptor (CAR) T-cell products are approved by the US Food and Drug Administration (FDA): axicabtagene-ciloleucel (axi-cel; Yescarta, Kite/Gilead) for the treatment of adult relapsed/refractory (R/R) diffuse large B-cell lymphomas (DLBCL), based on results of the ZUMA-1 trial (clinicaltrials.gov #NCT02348216), 1 and tisagenlecleucel (Kymriah, Novartis Pharmaceuticals), both for adult R/R DLBCL (JULIET trial; #NCT02445248) 2 and pediatric R/R B-cell acute lymphoblastic leukemias (B-ALL; ELIANA trial; #NCT02435849). 3 These therapies have been associated with specific toxicities, including cytokine release syndrome (CRS) and neurotoxicity, 4,5 for which investigators involved in the pivotal clinical trials developed different grading systems. For CRS, they include (1) consensus-based score by Lee et al (referred to herein as Lee), 6 used in the ZUMA-1 trial 1 ; (2) University of Pennsylvania's score (referred herein to as Penn), 7 used in the JULIET and ELIANA trials 2,3 ; (3) National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 (CTCAEv5.0) 8 ; (4) the Memorial Sloan Kettering Cancer Center (MSKCC) grading used in trial #NCT01044069 9 ; and (5) a score developed by the multiinstitutional CAR T-Cell Therapy-Associated Toxicity (CARTOX) working group.…”

Section: Introductionmentioning

confidence: 99%

Comparing CAR T-cell toxicity grading systems: application of the ASTCT grading system and implications for management

et al. 2020

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Key Points• Use of different grading systems leads to inconsistent CAR T-cell toxicity rates, with possible implications for disease management.• A unified grading system should be used in clinical practice and trials, and related management guidelines should be developed. Various grading systems are currently used for chimeric antigen receptor (CAR) T-cell-related toxicity, cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS). We compared the recently proposed American Society for Transplantation and Cellular Therapy (ASTCT) grading system to other grading scores in 2 populations of adults: patients (n 5 53) with B-cell acute lymphoblastic leukemia (B-ALL) treated with 1928z CAR T-cells (clinicaltrials.gov #NCT01044069), and patients (n 5 49) with diffuse large B-cell lymphoma (DLBCL) treated with axicabtagene-ciloleucel (axi-cel) or tisagenlecleucel after US Food and Drug Administration approval. According to ASTCT grading, 82% of patients had CRS, 87% in the B-ALL and 77% in the DLBCL groups (axi-cel: 86%, tisagenlecleucel: 54%), whereas 50% of patients experienced ICANS, 55% in the B-ALL and 45% in the DLBCL groups (axi-cel: 55%, tisagenlecleucel: 15%). All grading systems agreed on CRS and ICANS diagnosis in 99%and 91% of cases, respectively. However, when analyzed grade by grade, only 25% and 54% of patients had the same grade in each system for CRS and ICANS, respectively, as different systems score symptoms differently (upgrading or downgrading their severity), leading to inconsistent final grades. Investigation of possible management implications in DLBCL patients showed that different recommendations on tocilizumab and steroids across current guidelines potentially result in either overtreating or delaying treatment. Moreover, because these guidelines are based on single products and different grading systems, they cannot be universally applied. To avoid discrepancies in assessing and managing toxicities of different products, we propose that unified grading be used across clinical trials and in practice and that paired management guidelines with product-specific indications be developed.

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“…The remarkable potency, specificity, and additivity of keyhole repressors enable engineering of highly pure and potentially safer T cell products. The epigenetic durability of repression (>4 weeks in vivo) parallels the clinical effectiveness windows of recently described engineered cell therapies targeting lymphoid malignancies 35 , opening the door for creation of epigenetically engineered therapeutic cell products with defined kinetics or natural 'off switches'. As proof of concept, multiplex repression of the immune checkpoint genes PD-1, LAG3, and TIM3 in anti CD19 CAR-T cells resulted in enhanced efficacy compared with any individual repressor in a tumor re-challenge experiment, suggesting that this combination confers enhanced persistence and/or resistance to exhaustion.…”

Section: Discussionmentioning

confidence: 97%

Quantitative dialing of gene expression via precision targeting of KRAB repressor

Wilken

Ciarlo

Pearl

et al. 2020

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Non-invasive epigenome editing is a promising strategy for engineering gene expression programs, yet potency, specificity, and persistence remain challenging. Here we show that effective epigenome editing is gated at single-base precision via 'keyhole' sites in endogenous regulatory DNA. Synthetic repressors targeting promoter keyholes can ablate gene expression in up to 99% of primary cells with single-gene specificity and can seamlessly repress multiple genes in combination. Transient exposure of primary T cells to keyhole repressors confers mitotically heritable silencing that persists to the limit of primary cultures in vitro and for at least 4 weeks in vivo, enabling manufacturing of cell products with enhanced therapeutic efficacy. DNA recognition and effector domains can be encoded as separate proteins that reassemble at keyhole sites and function with the same efficiency as single chain effectors, enabling gated control and rapid screening for novel functional domains that modulate endogenous gene expression patterns. Our results provide a powerful and exponentially flexible system for programming gene expression and therapeutic cell products.Here we report that the potency and specificity of epigenetic transcriptional repression are linked through promoter keyhole sites, the targeting of which triggers nearcomplete repression with single-gene accuracy. Potent repression, in turn, enables durable programming via reliable induction of mitotically heritable expression programs, offering new potential for engineered cell therapies. 7

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Use of Chimeric Antigen Receptor T Cell Therapy in Clinical Practice for Relapsed/Refractory Aggressive B Cell Non-Hodgkin Lymphoma: An Expert Panel Opinion from the American Society for Transplantation and Cellular Therapy

Cited by 155 publications

References 101 publications

Impact and safety of chimeric antigen receptor T-cell therapy in older, vulnerable patients with relapsed/refractory large B-cell lymphoma

Impact and safety of chimeric antigen receptor T-cell therapy in older, vulnerable patients with relapsed/refractory large B-cell lymphoma

Comparing CAR T-cell toxicity grading systems: application of the ASTCT grading system and implications for management

Quantitative dialing of gene expression via precision targeting of KRAB repressor

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