IACH CAR-T News
IACH CAR-T News - April 2024
Chimeric antigen receptor (CAR)-T cells are transforming the care of patients with hematologic and solid malignancies. The forthcoming applications for autoimmune and infectious diseases are at the forefront of translational research that may affect clinical practice. As part of our effort to promote good clinical practice and acquaint clinicians with these innovative therapy options, we are delighted to launch the first issue of IACH CAR-T News. Each month we will highlight exciting developments and publications related to CAR-T cell therapy. Our focus will be on findings that have potential clinical applications and will bring hematologists and oncologists up-to-date with changes in the field.
Minson A, Hamad N, Cheah CY, Tam C, Blombery P, Westerman D, Ritchie D, Morgan H, Holzwart N, Lade S, Anderson MA, Khot A, Seymour JF, Robertson M, Caldwell I, Ryland G, Saghebi J, Sabahi Z, Xie J, Koldej R, Dickinson M.Blood. 2024 Feb 22;143(8):673-684. doi: 10.1182/blood.2023021306.PMID: 37883795
In this phase 2 study entitled TARMAC , Minson et al. studied the combination of CD19-CAR-T (CLT019 – the investigational form of tisagenlecleucel) and ibrutinib for treating relapsed/refractory mantle cell lymphoma (MCL), demonstrating promising efficacy and safety. In a cohort of 20 patients with MCL, the research revealed an 80% 4-month post infusion complete response rate, with notable measurable residual disease negativity by flow cytometry and molecular methods. Despite a cytokine release syndrome occurrence in 75% of patients, predominantly grade 1 to 2, and reversible neurotoxicity in 10%, the combination therapy was delivered safely with manageable side effects. Further insights into CAR-T cellular kinetics indicated a correlation between deep responses and robust CAR-T expansion, alongside a less exhausted baseline T-cell phenotype, suggesting the potential for patient selection and pretreatment optimization to enhance outcomes. Overall, these early data provide a promising signal for the combination of CAR-T with ibrutinib in MCL, but warrant larger prospective studies.
CD19 CAR T-Cell Therapy in Autoimmune Disease – A Case Series with Follow-up.
Müller F, Taubmann J, Bucci L, Wilhelm A, Bergmann C, Völkl S, Aigner M, Rothe T, Minopoulou I, Tur C, Knitza J, Kharboutli S, Kretschmann S, Vasova I, Spoerl S, Reimann H, Munoz L, Gerlach RG, Schäfer S, Grieshaber-Bouyer R, Korganow AS, Farge-Bancel D, Mougiakakos D, Bozec A, Winkler T, Krönke G, Mackensen A, Schett G.N Engl J Med. 2024 Feb 22;390(8):687-700. doi: 10.1056/NEJMoa2308917.PMID: 38381673
Müller et al. report their experience in treating 15 patients with refractory autoimmune disorders (systemic lupus erythematosus, idiopathic inflammatory myositis, and systemic sclerosis) using autologous CD19-directed CAR-T cells (MB-CART19.1, Miltenyi Biotec). CAR-T administration resulted in the attainment of durable complete response criteria across autoimmune diseases, with patients ceasing all immunosuppressive treatments. The intervention had a low toxicity profile, with 10 patients developing grade 1 CRS. Following infusion, there was an expected period of B-cell aplasia. Interestingly, B-cell reconstitution was characterized by the emergence of a naive B-cell phenotype, significantly devoid of CD19+CD27+ memory B cells. This shift in the B-cell repertoire indicates a resetting of the B-cell compartment, potentially conducive to the remission of autoimmune activity observed clinically. Notably, the response to treatment persisted. Overall, CD19 CAR T-cell transfer appeared to be feasible, safe, and efficacious in three different autoimmune diseases, providing a rationale for further controlled clinical trials.
Zou H, Liu W, Wang X, Wang Y, Wang C, Qiu C, Liu H, Shan D, Xie T, Huang W, Sui W, Yi S, An G, Xu Y, Ma T, Wang J, Qiu L, Zou D.J Immunother Cancer. 2024 Mar 4;12(3):e008450. doi: 10.1136/jitc-2023-008450.PMID: 38443094
In the study by Zou et al., dynamic monitoring of circulating tumor DNA (ctDNA) was employed to evaluate outcomes and identify genomic alterations in patients with relapsed or refractory large B-cell lymphoma undergoing CD19-targeted chimeric antigen receptor (CAR19) T-cell therapy. The research, conducted on an Asian population, highlighted the prognostic value of ctDNA in predicting treatment response and survival outcomes. Higher pretreatment ctDNA levels were found to correlate with poorer progression-free survival (PFS) and overall survival (OS). Additionally, the study observed a rapid decline in ctDNA levels post-CAR19 T-cell infusion, with ctDNA negativity at day 14 and day 28 post-infusion being indicative of better clinical outcomes. The analysis also revealed that shorter ctDNA fragments were significantly associated with inferior PFS and OS. Genomic analysis of serial ctDNA monitoring further identified specific mutations, such as in the TP53 and IGLL5 genes, that were associated with resistance to CAR T-cell therapy. This research underscores the potential of ctDNA monitoring as a non-invasive method for early prediction of treatment efficacy and survival in patients receiving CAR T-cell therapy for large B-cell lymphoma.
Intraventricular CARv3-TEAM-E T Cells in Recurrent Glioblastoma.
Choi BD, Gerstner ER, Frigault MJ, Leick MB, Mount CW, Balaj L, Nikiforow S, Carter BS, Curry WT, Gallagher K, Maus MV.N Engl J Med. 2024 Mar 13. doi: 10.1056/NEJMoa2314390. Online ahead of print.PMID: 38477966
In the first-in-human, open-label study, three participants with recurrent glioblastoma were treated with autologous CARv3-TEAM-E T cells, targeting both the epidermal growth factor receptor (EGFR) variant III and the wild-type EGFR through a T-cell–engaging antibody molecule (TEAM). No severe adverse events were noted. Remarkably, rapid tumor regression was observed post-single intraventricular infusion, although the responses were transient in two participants. This study underscores the potential of CARv3-TEAM-E T cells in treating recurrent glioblastoma, indicating a promising, though short-lived, response without significant toxicity.
Hamilton MP, Craig E, Gentille Sanchez C, Mina A, Tamaresis J, Kirmani N, Ehlinger Z, Syal S, Good Z, Sworder B, Schroers-Martin J, Lu Y, Muffly L, Negrin RS, Arai S, Lowsky R, Meyer E, Rezvani AR, Shizuru JA, Weng WK, Shiraz P, Sidana S, Bharadwaj S, Smith M, Dahiya S, Sahaf B, Kurtz DM, Mackall CL, Tibshirani R, Alizadeh AA, Frank MJ, Miklos DB.Blood Adv. 2024 Mar 18:bloodadvances.2024012637. doi: 10.1182/bloodadvances.2024012637. Online ahead of print.
In the study by Hamilton et al., an analysis of CD19-directed CAR T-cell expansion and its clinical implications across various B-cell lymphomas revealed histology-specific differences in CAR19 expansion, with mantle cell lymphoma (MCL) patients exhibiting higher levels of expansion and associated toxicity than those with large B-cell lymphoma (LBCL) or follicular lymphoma (FL). This expansion correlated with increased instances of toxicity, notably CRS and ICANS, yet did not uniformly predict treatment efficacy across lymphoma subtypes. Particularly in LBCL, CAR19 expansion showed no direct association with treatment response. However, lower CAR19 expansion in conjunction with a lower tumor burden, as indicated by lactate dehydrogenase (LDH) levels, was linked to improved outcomes, underscoring the nuanced relationship between CAR19 expansion, toxicity, and therapeutic response, and suggesting the potential for tailored treatment approaches based on individual patient and disease characteristics.
The intervention showcased significant therapeutic success, further evidenced by safety assessments that highlighted manageable adverse effects, predominantly low-grade cytokine release syndrome. Interestingly,
In this exploratory analysis by Müller et al., titled “CD19 CAR T-Cell Therapy in Autoimmune Disease — A Case Series with Follow-up,” the efficacy and safety of CD19 chimeric antigen receptor (CAR) T-cell therapy in treating refractory autoimmune diseases such as systemic lupus erythematosus (SLE), idiopathic inflammatory myositis, and systemic sclerosis were meticulously evaluated. The study, engaging a cohort of 15 patients, employed a one-time administration of CD19 CAR T cells following preconditioning with fludarabine and cyclophosphamidels.
IACH CAR-T News - February 2024
Chimeric antigen receptor (CAR)-T cells are transforming the care of patients with hematologic and solid malignancies. The forthcoming applications for autoimmune and infectious diseases are at the forefront of translational research that may affect clinical practice. As part of our effort to promote good clinical practice and acquaint clinicians with these innovative therapy options, we are delighted to launch the first issue of IACH CAR-T News. Each month we will highlight exciting developments and publications related to CAR-T cell therapy. Our focus will be on findings that have potential clinical applications and will bring hematologists and oncologists up-to-date with changes in the field.
Haradhvala NJ, Maus MV.Blood Cancer Discov. 2024 Feb 7:OF1-OF4. doi: 10.1158/2643-3230.BCD-23-0212. Online ahead of print.PMID: 38324393
Understanding Mechanisms of Response to CAR T-cell Therapy through Single-Cell Sequencing: Insights and Challenges. Haradhvala et al, Blood Cancer Discov . 2024 Feb 7:OF1-OF4.
This review encapsulates the role of single-cell RNA sequencing (scRNA-seq) in understanding chimeric antigen receptor (CAR) T-cell therapy for B-cell malignancies. It delves into how scRNA-seq enables a deeper exploration of treatment failure and resistance mechanisms, shedding light on the phenotypic characteristics of CAR T cells.
Cheok KPL, Farrow A, Springell D, O’Reilly M, Morley S, Stone N, Roddie C.Lancet Infect Dis. 2024 Feb 1:S1473-3099(23)00563-7. doi: 10.1016/S1473-3099(23)00563-7. Online ahead of print.PMID: 38310904
This review examines the clinical burden of mucormycosis in patients undergoing chimeric antigen receptor (CAR) T-cell therapy for relapsed B-cell cancers. While CAR T-cell therapy can induce durable remissions, it also poses a risk of treatment-associated immunocompromise, leading to increased susceptibility to opportunistic infections such as mucormycosis. The report presents a case study of mucormycosis in a 54-year-old patient undergoing CAR T-cell therapy, highlighting the challenges and complexities of managing this invasive fungal infection. The review incorporates an analysis of adverse events reported to the US Food and Drug Administration and a literature review to provide broader context on the epidemiology, clinical features, diagnostic tools, and treatment strategies for mucormycosis in CAR T-cell therapy patients. The analysis underscores the importance of increased vigilance among physicians and microbiologists specializing in CAR T-cell therapy, advocating for early initiation of therapy and targeted surveillance to improve outcomes in this patient population.
Naturally occurring T cell mutations enhance engineered T cell therapies.
Garcia J, Daniels J, Lee Y, Zhu I, Cheng K, Liu Q, Goodman D, Burnett C, Law C, Thienpont C, Alavi J, Azimi C, Montgomery G, Roybal KT, Choi J.Nature. 2024 Feb 7. doi: 10.1038/s41586-024-07018-7. Online ahead of print.PMID: 38326614
The paper investigates the potential of utilizing mutations found in human T cell cancers to enhance the efficacy of adoptive T cell therapies in cancer treatment. Through a systematic screening process involving 71 mutations from T cell neoplasms, the study identifies a specific gene fusion, CARD11–PIK3R3, which enhances signaling within the CARD11–BCL10–MALT1 complex. This augmentation leads to improved anti-tumour efficacy of therapeutic T cells in various immunotherapy-refractory models, particularly in an antigen-dependent manner. Importantly, the study demonstrates that CARD11–PIK3R3-expressing cells exhibit prolonged in vivo persistence without evidence of malignant transformation for up to 418 days post-T cell transfer, suggesting a potential safe deployment of this approach. Overall, the findings suggest that leveraging naturally occurring mutations from malignant T cells holds promise in advancing T cell therapies by tapping into evolutionary solutions that enhance T cell biology.
Locke FL, Filosto S, Chou J, Vardhanabhuti S, Perbost R, Dreger P, Hill BT, Lee C, Zinzani PL, Kröger N, López-Guillermo A, Greinix H, Zhang W, Tiwari G, Budka J, Marincola FM, To C, Mattie M, Schupp M, Cheng P, Bot A, Shen R, Bedognetti D, Miao H, Galon J.Nat Med. 2024 Jan 17. doi: 10.1038/s41591-023-02754-1. Online ahead of print.PMID: 38233586
The ZUMA-7 trial investigated the comparative efficacy of axicabtagene ciloleucel (axi-cel) and salvage chemotherapy followed by hematopoietic transplantation in second-line treatment for large B cell lymphoma. In this work, through an exploratory analysis, notable associations were observed between pretreatment tumor characteristics and treatment outcomes, particularly within the tumor microenvironment (TME). Notably, B cell gene expression signature (GES) and CD19 expression were found to significantly impact event-free survival with axi-cel but not with standard therapy. Axi-cel consistently demonstrated superior efficacy irrespective of varying levels of these characteristics. Of significance, low CD19 expression correlated with a tumor GES indicative of immune suppression, underscoring the instrumental role of the TME in modulating treatment response. Moreover, factors such as tumor burden and cell-of-origin exhibited differential impacts on standard therapy versus axi-cel outcomes, suggesting potential therapeutic advantages of targeting the TME earlier in the treatment paradigm.
Rejeski K, Wang Y, Hansen DK, Iacoboni G, Bachy E, Bansal R, Penack O, Müller F, Bethge WA, Munoz J, Mohty R, Bücklein VL, Barba P, Locke FL, Lin Y, Jain MD, Subklewe M.Blood Adv. 2024 Jan 4:bloodadvances.2023011767. doi: 10.1182/bloodadvances.2023011767. Online ahead of print.PMID: 38181508
This multicenter observational study evaluated the Immune Effector Cell-Associated HematoToxicity (ICAHT) grading system in 549 patients treated with BCMA- or CD19-directed CAR-T therapy for refractory B-cell malignancies. Severe ICAHT, as defined by the recently developed EHA/EBMT grading system, was strongly associated with prolonged severe neutropenia, multilineage cytopenias, and the need for transfusions. Patients with severe ICAHT experienced higher rates of severe infections, increased non-relapse mortality (NRM), and inferior survival outcomes compared to those without severe ICAHT. Importantly, the ICAHT grading system demonstrated superior predictive ability for severe infections compared to the commonly used CTCAE grading. These findings underscore the clinical significance of ICAHT severity in CAR-T therapy and advocate for its incorporation into clinical trial reporting standards.
Hill LC, Rouce RH, Wu M, Wang T, Ma R, Zhang H, Mehta B, Lapteva N, Mei Z, Smith TS, Yang L, Srinivasan M, Burkhardt PM, Ramos CA, Lulla PD, Arredondo M, Grilley B, Heslop HE, Brenner MK, Mamonkin M.Blood. 2023 Dec 25:blood.2023022204. doi: 10.1182/blood.2023022204. Online ahead of print.PMID: 38145560
In a phase 1 study, a CD5-directed CAR-T cell therapy was tested in patients with relapsed T-cell lymphoma (TCL). The therapy, designed to minimize fratricide and preserve endogenous T-cells, showed promise in inducing clinical responses, with an overall response rate of 44% and complete responses in two patients. The treatment was well-tolerated, with cytopenias being the most common adverse events. No severe cytokine release syndrome or neurologic events occurred. These findings suggest that CD5.CAR-T cells are safe and effective in treating relapsed TCL, though further validation with larger cohorts and longer follow-up is necessary.
IACH CAR-T News - October 2023
Chimeric antigen receptor (CAR)-T cells are transforming the care of patients with hematologic and solid malignancies. The forthcoming applications for autoimmune and infectious diseases are at the forefront of translational research that may affect clinical practice. As part of our effort to promote good clinical practice and acquaint clinicians with these innovative therapy options, we are delighted to launch the first issue of IACH CAR-T News. Each month we will highlight exciting developments and publications related to CAR-T cell therapy. Our focus will be on findings that have potential clinical applications and will bring hematologists and oncologists up-to-date with changes in the field.
A single-cell atlas of CD19 chimeric antigen receptor T cells.
Li X, Henderson J, Gordon MJ, Sheikh I, Nastoupil LJ, Westin J, Flowers C, Ahmed S, Wang L, Neelapu SS, Strati P, Deng Q, Green MR.Cancer Cell. 2023 Sep 15:S1535-6108(23)00316-1. doi: 10.1016/j.ccell.2023.08.015. Online ahead of print.PMID: 37738975
The authors employ single-cell RNA sequencing to examine infusion products from 59 relapse/refractory (rr) LBCL patients treated with axicabtagene ciloleucel and publicly share the resulting dataset. They identify distinct gene expression patterns, particularly an overexpression of glycolysis-related genes in T cells from patients who achieved complete responses, suggesting a link between T cell metabolic profile and treatment success. While further experimental validation is needed, this dataset highlights the potential of large single-cell datasets in understanding and improving CAR T cell therapy for rrLBCL patients. The data are available in multiple repositories to facilitate future research in the field.
IACH CAR-T News - October 2023
Three-Year Follow-Up Analysis of Axicabtagene Ciloleucel in Relapsed/Refractory Indolent Non-Hodgkin Lymphoma (ZUMA-5).
Neelapu SS, Chavez JC, Sehgal A, Epperla N, Ulrickson ML, Bachy E, Munshi P, Casulo C, Maloney DG, de Vos S, Reshef R, Leslie LA, Oluwole OO Dr, Yakoubagha I, Khanal R, Rosenblatt JD, Korn R, Peng W, Lui C, Wullf J, Shen RR, Poddar S, Jung AS, Miao H, Beygi S, Jacobson CA.Blood. 2023 Oct 25:blood.2023021243. doi: 10.1182/blood.2023021243. Online ahead of print.PMID: 37879047
The ZUMA-5 study investigated the long-term outcomes of Axicabtagene ciloleucel (axi-cel), a CAR T-cell therapy, in patients with relapsed/refractory indolent non-Hodgkin lymphoma (iNHL), which includes follicular lymphoma (FL) and marginal zone lymphoma (MZL). In the initial analysis, axi-cel showed a remarkable 92% overall response rate (74% complete response rate) after a median follow-up of 17.5 months. In this follow-up study, with extended median follow-up times of 41.7 months in FL and 31.8 months in MZL, the overall response rates remained high at 94% in FL and 77% in MZL. Median progression-free survival was 40.2 months in FL and not yet reached in MZL, and overall survival had not reached a median in either disease type. The study also noted manageable safety profiles, especially in patients with limited adverse events beyond 2 years, and found correlations between clinical outcomes and prior exposure to certain treatments. Axi-cel demonstrated continued durable responses, making it a promising therapeutic option for R/R iNHL patients.
Iacoboni G, Navarro V, Martín-López AÁ, Rejeski K, Kwon M, Jalowiec KA, Amat P, Reguera-Ortega JL, Gallur L, Blumenberg V, Gutiérrez-Herrero S, Roddie C, Benzaquén A, Delgado-Serrano J, Sánchez-Salinas MA, Bailén R, Carpio C, López-Corral L, Hernani R, Bastos M, O’Reilly M, Martín-Martín L, Subklewe M, Barba P.J Clin Oncol. 2023 Oct 24:JCO2301097. doi: 10.1200/JCO.23.01097. Online ahead of print.PMID: 37874957
This study investigated the influence of recent bendamustine treatment on the treatment outcomes of patients with relapsed/refractory large B-cell lymphoma (LBCL) undergoing chimeric antigen receptor (CAR) T-cell therapy. The research included 439 patients with LBCL who received CD19-targeted CAR T cells, and among them, 80 patients had previously undergone bendamustine treatment before apheresis. Patients with prior bendamustine exposure showed lower CD3+ cell and platelet counts at apheresis and experienced significantly poorer outcomes. This included a reduced overall response rate (53% vs. 72%), shorter progression-free survival (3.1 vs. 6.2 months), and overall survival (10.3 vs. 23.5 months) compared to those who hadn’t received bendamustine. These differences were somewhat mitigated after accounting for baseline variables. Notably, patients with recent (<9 months) bendamustine exposure fared even worse, with significant differences in outcomes that remained after various adjustment methods. Importantly, the cumulative bendamustine dose before apheresis did not appear to affect CAR T-cell efficacy. In conclusion, recent bendamustine exposure before apheresis was associated with negative treatment outcomes in CD19-targeted CAR T-cell therapy for patients with large B-cell lymphoma, emphasizing the importance of avoiding bendamustine in CAR T-cell candidates.
Probiotic-guided CAR-T cells for solid tumor targeting.
Vincent RL, Gurbatri CR, Li F, Vardoshvili A, Coker C, Im J, Ballister ER, Rouanne M, Savage T, de Los Santos-Alexis K, Redenti A, Brockmann L, Komaranchath M, Arpaia N, Danino T.Science. 2023 Oct 13;382(6667):211-218. doi: 10.1126/science.add7034. Epub 2023 Oct 12.PMID: 37824640
In this study, authors devised a unique strategy involving probiotics engineered to colonize solid tumors and deliver synthetic antigens, effectively “tagging” the tumor tissue for targeted destruction by chimeric antigen receptor (CAR) T cells. This innovative approach, known as probiotic-guided CAR-T cells (ProCARs), demonstrated remarkable results in multiple xenograft and syngeneic models of both human and mouse cancers. The use of nonpathogenic Escherichia coli strains as carriers for synthetic antigens in the tumor microenvironment allowed for the precise homing of CAR T cells to solid tumors, leading to efficient tumor cell killing in experimental models of breast and colon cancer. By combining probiotics and CAR-T cells, this study offers a promising and safe approach to enhance the effectiveness of immunotherapy for solid tumors, potentially opening up new avenues for the treatment of heterogeneous and challenging cancer types.
Genetic Basis of Relapse after GPRC5D-Targeted CAR T Cells.
Mi X, Penson A, Abdel-Wahab O, Mailankody S.N Engl J Med. 2023 Oct 12;389(15):1435-1437. doi: 10.1056/NEJMc2308544.PMID: 37819961 No abstract available.
In this study, the authors report a mechanism of relapse following GPRC5D-targeted CAR-T cell therapy in patients with relapsed or refractory multiple myeloma. The research involved a phase 1 study of the MCARH109 CAR T-cell therapy, which showed positive responses in 12 out of 17 patients. However, six patients experienced relapse after an initial response lasting 3 to 9 months. Immunohistochemical analysis revealed a loss of GPRC5D protein expression in all six patients with relapse. All the patients who had a relapse showed reduced or absent GPRC5D mRNA and protein expression at the time of disease progression. In one patient’s case, a thorough genetic analysis revealed biallelic loss of GPRC5D, a result of structural chromosome alterations, leading to relapse despite an initially robust response. Importantly, subclonal genetic alterations in GPRC5D were not seen at baseline. In summary, antigen escape after GPRC5D-directed CAR T-cell therapy can be mediated by structural chromosome alterations resulting in biallelic loss of GPRC5D.
IACH CAR-T News - September 2023
Chimeric antigen receptor (CAR)-T cells are transforming the care of patients with hematologic and solid malignancies. The forthcoming applications for autoimmune and infectious diseases are at the forefront of translational research that may affect clinical practice. As part of our effort to promote good clinical practice and acquaint clinicians with these innovative therapy options, we are delighted to launch the first issue of IACH CAR-T News. Each month we will highlight exciting developments and publications related to CAR-T cell therapy. Our focus will be on findings that have potential clinical applications and will bring hematologists and oncologists up-to-date with changes in the field.
Mechanisms of antigen escape from BCMA- or GPRC5D-targeted immunotherapies in multiple myeloma.
Lee H, Ahn S, Maity R, Leblay N, Ziccheddu B, Truger M, Chojnacka M, Cirrincione A, Durante M, Tilmont R, Barakat E, Poorebrahim M, Sinha S, McIntyre J, M Y Chan A, Wilson H, Kyman S, Krishnan A, Landgren O, Walter W, Meggendorfer M, Haferlach C, Haferlach T, Einsele H, Kortüm MK, Knop S, Alberge JB, Rosenwald A, Keats JJ, Rasche L, Maura F, Neri P, Bahlis NJ.Nat Med. 2023 Aug 31. doi: 10.1038/s41591-023-02491-5. Online ahead of print.PMID: 37653344
This study investigates the mechanisms of resistance to anti-B cell maturation antigen (BCMA) therapies in multiple myeloma (MM). Researchers performed bulk and single-cell whole-genome sequencing and copy number variation analysis on 30 MM patients treated with anti-BCMA and/or anti-GPRC5D CAR T/TCE therapies. They found that resistance to these therapies can arise from various factors, including BCMA-negative clones with deletions at the TNFRSF17 locus and mutations in the extracellular domain of BCMA. Additionally, biallelic mutations in GPRC5D were observed after anti-GPRC5D TCE therapy. These findings shed light on the tumor-intrinsic drivers of relapse post-targeted therapies in MM.
Mechanisms of antigen escape from BCMA- or GPRC5D-targeted immunotherapies in multiple myeloma.
Lee H, Ahn S, Maity R, Leblay N, Ziccheddu B, Truger M, Chojnacka M, Cirrincione A, Durante M, Tilmont R, Barakat E, Poorebrahim M, Sinha S, McIntyre J, M Y Chan A, Wilson H, Kyman S, Krishnan A, Landgren O, Walter W, Meggendorfer M, Haferlach C, Haferlach T, Einsele H, Kortüm MK, Knop S, Alberge JB, Rosenwald A, Keats JJ, Rasche L, Maura F, Neri P, Bahlis NJ.Nat Med. 2023 Aug 31. doi: 10.1038/s41591-023-02491-5. Online ahead of print.PMID: 37653344
This study investigates the mechanisms of resistance to anti-B cell maturation antigen (BCMA) therapies in multiple myeloma (MM). Researchers performed bulk and single-cell whole-genome sequencing and copy number variation analysis on 30 MM patients treated with anti-BCMA and/or anti-GPRC5D CAR T/TCE therapies. They found that resistance to these therapies can arise from various factors, including BCMA-negative clones with deletions at the TNFRSF17 locus and mutations in the extracellular domain of BCMA. Additionally, biallelic mutations in GPRC5D were observed after anti-GPRC5D TCE therapy. These findings shed light on the tumor-intrinsic drivers of relapse post-targeted therapies in MM.
Ram R, Amit O, Adler A, Bar-On Y, Beyar-Katz O, Avivi I, Shasha D, Ben-Ami R.Transplant Cell Ther. 2023 Aug 15:S2666-6367(23)01471-9. doi: 10.1016/j.jtct.2023.08.013. Online ahead of print.PMID: 37591446
This study investigated early antibiotic deescalation in patients receiving cellular therapy for febrile neutropenia. The results showed that early deescalation is safe and led to more antibiotic-free days compared to standard treatment. This benefit was observed in various cellular therapy subgroups, including allogeneic HCT, autologous HCT, and CAR-T therapy. Overall, early deescalation reduced broad-spectrum antibiotic use without affecting cellular therapy outcomes, suggesting its potential as a safer and more efficient approach.
Scordo M, Flynn JR, Gonen M, Devlin SM, Parascondola A, Alarcon Tomas A, Shouval R, Brower J, Porter DL, Schuster SJ, Bachanova V, Maakaron J, Maziarz RT, Chen AI, Nastoupil LJ, McGuirk JP, Oluwole OO, Ip A, Leslie LA, Bishop MR, Riedell PA, Perales MA.Blood Adv. 2023 Jul 31:bloodadvances.2023010302. doi: 10.1182/bloodadvances.2023010302. Online ahead of print.PMID: 37522731
This study explored the use of fludarabine as a lymphodepletion agent before CD19 CAR T cell therapy in 199 adult patients with aggressive B cell non-Hodgkin lymphomas. Fludarabine exposure was estimated using a pharmacokinetic model, categorizing patients into low, optimal, and high AUC groups. Patients with optimal AUC had the highest 6-month cumulative PFS (66%) and the lowest relapse/progression risk, with no increased CRS or ICANS risk compared to the low AUC group. High AUC was associated with a higher risk of any-grade ICANS and more non-relapse-related deaths, including ICANS-related fatalities. The findings suggest that personalized, PK-directed fludarabine dosing to achieve an optimal AUC can improve outcomes in Axi-cel-treated patients.
Neurologic toxicities following adoptive immunotherapy with BCMA-directed CAR T-cells.
Karschnia P, Miller KC, Yee AJ, Rejeski K, Johnson PCC, Raje N, Frigault MJ, Dietrich J.Blood. 2023 Jul 20:blood.2023020571. doi: 10.1182/blood.2023020571. Online ahead of print.PMID: 37471607 No abstract available.
This study examines the neurotoxicity associated with BCMA-directed CAR T-cell therapy in multiple myeloma patients. The authors retrospectively analyzed data from 76 heavily pre-treated patients who received this therapy between 2016-2023. They found that 41% of patients developed neurologic symptoms post-treatment, with 8% experiencing severe symptoms. Mild neurotoxicity manifested as headaches, expressive aphasia, and confusion, while severe cases involved profound encephalopathy. There was a strong association between neurotoxicity and cytokine release syndrome (CRS). Parkinsonism-like symptoms were observed in a small subset of patients and appeared reversible with various treatments. Overall, BCMA-directed CAR T-cell therapy demonstrated manageable neurotoxicity, with potential avenues for further research into treatment algorithms and risk factors.
Granit V, Benatar M, Kurtoglu M, Miljković MD, Chahin N, Sahagian G, Feinberg MH, Slansky A, Vu T, Jewell CM, Singer MS, Kalayoglu MV, Howard JF Jr, Mozaffar T; MG-001 Study Team.Lancet Neurol. 2023 Jul;22(7):578-590. doi: 10.1016/S1474-4422(23)00194-1.
This study explores the use of RNA-engineered CAR T cells (rCAR-T) targeting B-cell maturation antigen (BCMA) for the treatment of individuals with myasthenia gravis (MG), an autoimmune disease. The trial, known as MG-001, involved 14 participants with generalized MG. The primary aim was to assess the safety and tolerability of Descartes-08, an autologous anti-BCMA rCAR-T therapy. Results showed no dose-limiting toxicity, cytokine release syndrome, or neurotoxicity. Common adverse events were mild and transient, and participants experienced clinically meaningful improvements in MG severity scales. This study suggests that rCAR-T therapy may be a safe and promising treatment option for autoimmune diseases like myasthenia gravis, warranting further investigation.
IACH CAR-T News - August 2023
Chimeric antigen receptor (CAR)-T cells are transforming the care of patients with hematologic and solid malignancies. The forthcoming applications for autoimmune and infectious diseases are at the forefront of translational research that may affect clinical practice. As part of our effort to promote good clinical practice and acquaint clinicians with these innovative therapy options, we are delighted to launch the first issue of IACH CAR-T News. Each month we will highlight exciting developments and publications related to CAR-T cell therapy. Our focus will be on findings that have potential clinical applications and will bring hematologists and oncologists up-to-date with changes in the field.
Cowan AJ, Pont MJ, Sather BD, Turtle CJ, Till BG, Libby EN 3rd, Coffey DG, Tuazon SA, Wood B, Gooley T, Wu VQ, Voutsinas J, Song X, Shadman M, Gauthier J, Chapuis AG, Milano F, Maloney DG, Riddell SR, Green DJ.Lancet Oncol. 2023 Jul;24(7):811-822. doi: 10.1016/S1470-2045(23)00246-2.PMID: 37414012 Clinical Trial.
This first-in-human phase 1 trial (n=18) of a BCMA-directed CAR-T in combination with a γ-secretase inhibitor (GSI -crenigacestat) shows that the combination is both feasible and well tolerated in individuals with relapsed or refractory multiple myeloma. Crenigacestat led to substantial increases in BCMA surface density on malignant plasma cells, decreased soluble BCMA concentrations, and deep responses (including a combined complete response and stringent complete response rate of 91% for participants who were naive to previous BCMA-targeted treatment) in study participants, many of whom had high-risk multiple myeloma and had been heavily pretreated. The findings support further investigation of GSIs in combination with BCMA-targeted therapies in clinical trials.
Park JH, Nath K, Devlin SM, Sauter CS, Palomba ML, Shah G, Dahi P, Lin RJ, Scordo M, Perales MA, Shouval R, Tomas AA, Cathcart E, Mead E, Santomasso B, Holodny A, Brentjens RJ, Riviere I, Sadelain M.Nat Med. 2023 Jul;29(7):1710-1717. doi: 10.1038/s41591-023-02404-6. Epub 2023 Jul 3.
In a phase 2 clinical trial, the use of the IL-1 receptor antagonist, anakinra, was investigated as a prophylactic measure to reduce immune effector cell-associated neurotoxicity syndrome (ICANS) in patients (n=31) with relapsed or refractory large B-cell lymphoma and mantle cell lymphoma treated with commercial anti-CD19 CAR T-cell therapy. The study included 31 patients, with 74% receiving axicabtagene ciloleucel, 13% brexucabtagene ciloleucel, and 4% tisagenlecleucel. Results showed that the prophylactic administration of subcutaneous anakinra significantly reduced the rates of severe ICANS, with only 9.7% of patients experiencing severe ICANS. There were no grade 4 or 5 ICANS events. All-grade cytokine release syndrome (CRS) occurred in 74%, and severe CRS occurred in 6.4% of patients. The overall disease response rate was 77%, with a 65% complete response rate. The study demonstrated that anakinra administration did not compromise the efficacy of CAR T cells. These promising results suggest that prophylactic anakinra can effectively reduce the incidence of severe ICANS in patients receiving CD19-directed CAR T-cell therapy and support further investigation of anakinra in immune-related neurotoxicity syndromes.
This study is featured in the IACH news podcast
https://soundcloud.com/cme-congresses/jordan-gauthier-cd19-car-t-cell-therapy-prophylactic-anakinra-in-relapsed-or-refractory-lymphoma
Shouse G, Kaempf A, Gordon MJ, Artz A, Yashar D, Sigmund AM, Smilnak G, Bair SM, Mian A, Fitzgerald LA, Bajwa A, Jaglowski S, Bailey N, Shadman M, Patel K, Stephens DM, Kamdar M, Hill BT, Gauthier J, Karmali R, Nastoupil LJ, Kittai AS, Danilov AV.Blood Adv. 2023 Jul 25;7(14):3516-3529. doi: 10.1182/bloodadvances.2022009309.
Shouse et al conducted a large retrospective study of 577 patients with relapsed or refractory lymphoma who received CAR-T therapy. They developed a model to predict survival outcomes after CAR-T treatment, and confirmed their findings with an additional cohort of over 200 patients. The researchers investigated the cumulative illness rating score (CIRS), which assesses comorbidities in 14 organ systems, along with other prognostic factors in lymphoma. They used advanced machine learning techniques to identify that patients with at least one severe comorbidity (score ≥3) in the respiratory, upper gastrointestinal, hepatic, or renal organ systems (referred to as “Severe4”) had independently poorer outcomes. In the learning cohort, 9% of patients had Severe4 comorbidities, which led to inferior progression-free survival (HR 2.15; P < .001) and overall survival (HR 1.94; P < .001). The validation cohort confirmed these results, with 16% of patients having Severe4 comorbidities, resulting in independently worse progression-free survival (HR 1.85; P = .003) and overall survival (HR 1.70; P = .019). These findings highlight the importance of considering comorbidities in CAR-T therapy outcomes for lymphoma patients.
Survival with Axicabtagene Ciloleucel in Large B-Cell Lymphoma.
Westin JR, Oluwole OO, Kersten MJ, Miklos DB, Perales MA, Ghobadi A, Rapoport AP, Sureda A, Jacobson CA, Farooq U, van Meerten T, Ulrickson M, Elsawy M, Leslie LA, Chaganti S, Dickinson M, Dorritie K, Reagan PM, McGuirk J, Song KW, Riedell PA, Minnema MC, Yang Y, Vardhanabhuti S, Filosto S, Cheng P, Shahani SA, Schupp M, To C, Locke FL; ZUMA-7 Investigators and Kite Members.N Engl J Med. 2023 Jul 13;389(2):148-157. doi: 10.1056/NEJMoa2301665. Epub 2023 Jun 5.PMID: 37272527 Clinical Trial.
The Phase III ZUMA-7 trial examined the outcomes of patients with early relapsed or refractory large B-cell lymphoma treated with axicabtagene ciloleucel (axi-cel) as a second-line treatment compared to standard care. A total of 359 patients were included in the study, with 180 receiving axi-cel and 179 receiving standard care, which consisted of two to three cycles of chemoimmunotherapy followed by high-dose chemotherapy with autologous stem-cell transplantation for responding patients.
At a median follow-up of 47.2 months, the median overall survival (OS) had not yet been reached in the axi-cel group, while the standard care group had a median OS of 31.1 months. The estimated 4-year overall survival rates were 54.6% for the axi-cel group and 46.0% for the standard care group, indicating a 27.4% reduction in death with axi-cel therapy. Regarding progression-free survival (PFS), the axi-cel group had a median PFS of 14.7 months, compared to 3.7 months in the standard care group. The estimated 4-year PFS rates were 41.8% and 24.4% for the axi-cel and standard care groups, respectively. The study’s findings suggest that axicabtagene ciloleucel should be the standard of care as second-line treatment for patients with early relapsed or refractory large B-cell lymphoma.
Patterson MT, Khan SM, Nunes NS, Fletcher RE, Bian J, Hadjis AD, Eckhaus MA, Mendu SK, de Paula Pohl A, Venzon DJ, Choo-Wosoba H, Ishii K, Qin H, Fry TJ, Cam M, Kanakry CG.Blood. 2023 Feb 9;141(6):659-672. doi: 10.1182/blood.2022016660.
The study investigates the integration of chimeric antigen receptor (CAR) T cell therapy and allogeneic hematopoietic cell transplantation (allo-HCT) in murine models to address the limitations of relapse. Previous concerns regarding potential graft-versus-host disease (GVHD) induced by allogeneic CAR T cells have discouraged direct integration of these therapies. However, the authors demonstrate in murine T-cell-replete MHC-haploidentical allo-HCT that posttransplant cyclophosphamide (PTCy) suppressive mechanisms prevent GVHD induction by alloreactive T cells. Building on this, the study explores the safety and efficacy of integrating allogeneic CAR T cells early after PTCy or even before PTCy in their murine model. Results reveal that CAR T cells given early after PTCy or on day 0 effectively clear leukemia without exacerbating cytokine release syndrome or interfering with PTCy-mediated GVHD prevention. While CAR T cell infusion on day +9 or day +14 is safe, its therapeutic efficacy is limited, suggesting a specific treatment window. Infusing CAR T cells before PTCy allows for continued expansion and proliferation despite PTCy. Compared to day +5 infusion, day 0 CAR T cell infusion demonstrates superior clinical efficacy, linked to earlier CAR T-cell expansion, higher phenotypic activation, and increased cytotoxicity. This study provides mechanistic insight into PTCy’s impact on graft-versus-tumor immunity and presents novel approaches for CAR T cell and allo-HCT integration, specifically in murine models, addressing individual approach deficiencies.
IACH CAR-T News - June 2023
Chimeric antigen receptor (CAR)-T cells are transforming the care of patients with hematologic and solid malignancies. The forthcoming applications for autoimmune and infectious diseases are at the forefront of translational research that may affect clinical practice. As part of our effort to promote good clinical practice and acquaint clinicians with these innovative therapy options, we are delighted to launch the first issue of IACH CAR-T News. Each month we will highlight exciting developments and publications related to CAR-T cell therapy. Our focus will be on findings that have potential clinical applications and will bring hematologists and oncologists up-to-date with changes in the field.
Base-Edited CAR7 T Cells for Relapsed T-Cell Acute Lymphoblastic Leukemia.
Chiesa R, Georgiadis C, Syed F, Zhan H, Etuk A, Gkazi SA, Preece R, Ottaviano G, Braybrook T, Chu J, Kubat A, Adams S, Thomas R, Gilmour K, O’Connor D, Vora A, Qasim W; Base-Edited CAR T Group.N Engl J Med. 2023 Jun 14. doi: 10.1056/NEJMoa2300709. Online ahead of print.PMID: 37314354
The study investigated the use of base-edited CAR7 T cells in relapsed T-cell acute lymphoblastic leukemia. Researchers employed CRISPR technology to precisely convert cytosine to thymine without DNA breaks. They generated universal CAR T cells targeting CD7 and inactivated genes to overcome therapy challenges. In three patients, the treatment showed promising results, achieving molecular remission and successful stem-cell transplants. Adverse events included cytokine release syndrome and infections. The study supports further investigation of base-edited T cells for relapsed leukemia patients
Major A, Yu J, Shukla N, Che Y, Karrison TG, Treitman R, Kamdar M, Haverkos BM, Godfrey J, Babcook MA, Voorhees TJ, Carlson SG, Gaut D, Oliai C, Romancik JT, Winter AM, Hill BT, Bansal R, Villasboas JC, Nizamuddin IA, Karmali R, Fitzgerald LA, Stephens DM, Pophali PA, Trabolsi A, Schatz JH, Hu M, Bachanova V, Slade M, Singh N, Ahmed N, McGuirk JP, Bishop MR, Riedell PA, Kline J.Blood Adv. 2023 Apr 7:bloodadvances.2023010016. doi: 10.1182/bloodadvances.2023010016. Online ahead of print.PMID: 37026796
This retrospective study evaluated checkpoint inhibitor (CPI) therapy in 96 patients with aggressive B-cell lymphomas after CAR T-cell therapy failure. CPI therapy showed limited efficacy, with an overall response rate of 19% and a complete response rate of 10%. Median progression-free survival was 54 days, and overall survival was 159 days. Patients with late relapse (>180 days) after CAR-T had better outcomes. Grade ≥3 adverse events occurred in 19% of patients, and the majority died due to progressive disease. Only 5% had durable responses to CPI therapy. These findings indicate that CPI therapy is not an effective salvage strategy for the majority of patients after CAR-T, suggesting the need for alternative approaches to improve post-CAR-T outcomes.
Treatment of a patient with severe systemic sclerosis (SSc) using CD19-targeted CAR T cells.
Bergmann C, Müller F, Distler JHW, Györfi AH, Völkl S, Aigner M, Kretschmann S, Reimann H, Harrer T, Bayerl N, Boeltz S, Wirsching A, Taubmann J, Rösler W, Spriewald B, Wacker J, Atzinger A, Uder M, Kuwert T, Mackensen A, Schett G.Ann Rheum Dis. 2023 May 5:ard-2023-223952. doi: 10.1136/ard-2023-223952. Online ahead of print.
This case study represents the first reported use of CD19-targeting CAR T-cell therapy in a patient with severe, treatment refractory systemic sclerosis (SSc). Remarkably, the patient exhibited improvements in heart, joint, and skin manifestations, along with seroconversion, highlighting the potential effectiveness of this therapy for SSc. These findings provide support for the involvement of B cell-mediated autoimmunity in SSc and suggest CD19-CAR T cells as a promising treatment approach for the disease.
Costimulatory domains direct distinct fates of CAR-driven T-cell dysfunction.
Selli ME, Landmann JH, Terekhova M, Lattin J, Heard A, Hsu YS, Chang TC, Chang J, Warrington J, Ha H, Kingston N, Hogg G, Slade M, Berrien-Elliott MM, Foster M, Kersting-Schadek S, Gruszczynska A, DeNardo D, Fehniger TA, Artyomov M, Singh N.Blood. 2023 Jun 29;141(26):3153-3165. doi: 10.1182/blood.2023020100.
Selli et al conducted a study to explore the differences in dysfunctional CAR T cells with various costimulation domains at the transcriptional, epigenetic, and phenotypic levels. They observed that CD28-based CAR T cells exhibited classic T-cell exhaustion markers, while 4-1BB-based CAR T cells showed unique phenotypic characteristics. By analyzing gene expression and chromatin accessibility, they identified a distinct gene signature, TBBD, in dysfunctional 4-1BB CAR T cells, which was also observed in a patient with persistent CAR T cells despite disease progression. They discovered that reactivation of the transcription factor FOXO3 played a crucial role in driving dysfunction in 4-1BB CAR T cells. Manipulating FOXO3 levels confirmed its impact on CAR T cell dysfunction and expansion. These findings provide valuable insights into the molecular mechanisms underlying CAR T cell dysfunction and suggest the potential of targeting FOXO3 to enhance CAR T cell therapy effectiveness.
Siddiqi T, Maloney DG, Kenderian SS, Brander DM, Dorritie K, Soumerai J, Riedell PA, Shah NN, Nath R, Fakhri B, Stephens DM, Ma S, Feldman T, Solomon SR, Schuster SJ, Perna SK, Tuazon SA, Ou SS, Papp E, Peiser L, Chen Y, Wierda WG.Lancet. 2023 Jun 5:S0140-6736(23)01052-8. doi: 10.1016/S0140-6736(23)01052-8. Online ahead of print.PMID: 37295445
The study evaluated the effectiveness and safety of lisocabtagene maraleucel (liso-cel) in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma who had failed treatment with Bruton tyrosine kinase (BTK) inhibitors and venetoclax. In a single-arm, open-label phase 1-2 trial, patients received an intravenous infusion of liso-cel at two different dose levels. The primary endpoint was the rate of complete response or remission in patients with previous BTK inhibitor progression and venetoclax failure. Of the 117 participants treated with liso-cel, 18% achieved complete response or remission, which was statistically significant. Adverse events included cytokine release syndrome and neurological events, but the safety profile was manageable. The study demonstrates that liso-cel infusion can induce favorable responses in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma, even after treatment failure with BTK inhibitors and venetoclax. However, response rates are lower than those typically observer with CD19-CAR-T in large B-cell lymphoma,
Cilta-cel or Standard Care in Lenalidomide-Refractory Multiple Myeloma.
San-Miguel J, Dhakal B, Yong K, Spencer A, Anguille S, Mateos MV, Fernández de Larrea C, Martínez-López J, Moreau P, Touzeau C, Leleu X, Avivi I, Cavo M, Ishida T, Kim SJ, Roeloffzen W, van de Donk NWCJ, Dytfeld D, Sidana S, Costa LJ, Oriol A, Popat R, Khan AM, Cohen YC, Ho PJ, Griffin J, Lendvai N, Lonardi C, Slaughter A, Schecter JM, Jackson CC, Connors K, Li K, Zudaire E, Chen D, Gilbert J, Yeh TM, Nagle S, Florendo E, Pacaud L, Patel N, Harrison SJ, Einsele H.N Engl J Med. 2023 Jun 5. doi: 10.1056/NEJMoa2303379. Online ahead of print.
In a phase 3 randomized trial, the effectiveness of ciltacabtagene autoleucel (cilta-cel), a CAR-T cell therapy targeting B-cell maturation antigen (BCMA), was evaluated in patients with lenalidomide-refractory multiple myeloma. The study included 419 patients who received either cilta-cel or standard care. At a median follow-up of 15.9 months, the cilta-cel group showed significantly improved progression-free survival compared to the standard-care group (hazard ratio of 0.26). Cilta-cel-treated patients also exhibited higher overall response rates, complete responses or better, and absence of minimal residual disease. Adverse events were observed, including cytokine release syndrome and neurotoxicity, but were generally manageable. The findings demonstrate that a single infusion of cilta-cel is more effective than standard care in lenalidomide-refractory multiple myeloma patients who have received one to three previous therapies.
IACH CAR-T News - May 2023
Chimeric antigen receptor (CAR)-T cells are transforming the care of patients with hematologic and solid malignancies. The forthcoming applications for autoimmune and infectious diseases are at the forefront of translational research that may affect clinical practice. As part of our effort to promote good clinical practice and acquaint clinicians with these innovative therapy options, we are delighted to launch the first issue of IACH CAR-T News. Each month we will highlight exciting developments and publications related to CAR-T cell therapy. Our focus will be on findings that have potential clinical applications and will bring hematologists and oncologists up-to-date with changes in the field.
Rejeski K, Cordas Dos Santos DM, Parker NH, Bücklein VL, Winkelmann M, Jhaveri KS, Liu L, Trinkner P, Günther S, Karschnia P, Blumenberg V, Schmidt C, Kunz WG, von Bergwelt-Baildon M, Jain MD, Theurich S, Subklewe M.Cancer Immunol Res. 2023 Apr 11:CIR-22-0487. doi: 10.1158/2326-6066.CIR-22-0487. Online ahead of print.PMID: 37040425
The study analyzed the impact of immunometabolic host features and body composition measurements on post-CD19-directed chimeric antigen receptor T-cell therapy. clinical outcomes in 106 relapsed/refractory large B-cell lymphoma patients. The results showed that patients with increased abdominal fat and muscle mass had particularly favorable treatment outcomes. Additionally, patients with a low skeletal muscle index and poor immuno-nutritional scores had poor clinical outcomes. The study suggests that body composition and immuno-nutritional status play a role in CAR-T treatment responses and that the obesity paradox extends to T-cell based immunotherapies.
Dubnikov Sharon T, Assayag M, Avni B, Kfir-Erenfeld S, Lebel E, Gatt ME, Goldschmidt N, Stepensky P, Asherie N, Grisariu S.Br J Haematol. 2023 Apr 18. doi: 10.1111/bjh.18816. Online ahead of print.PMID: 37070396
The study evaluated the potential benefits of performing lymphopheresis at an earlier stage for patients with relapsed/refractory DLBCL treated with CD19 CAR-T cells. Early lymphopheresis resulted in improved T-cell functionality and a lower exhaustion profile, without compromising CAR T-cell quality. Although the improved T-cell phenotype and function did not significantly improve clinical outcomes, there was a trend towards better overall survival and progression-free survival.
Kim AB, Chou SY, Kang S, Kwon E, Inkman M, Szymanski J, Andruska N, Colgan C, Zhang J, Yang JC, Singh N, DeSelm C.Blood Adv. 2023 Apr 24:bloodadvances.2022009543. doi: 10.1182/bloodadvances.2022009543. Online ahead of print.PMID: 37093643
The authors demonstrate that low-dose total body irradiation (TBI) sensitizes acute lymphoblastic leukemia in mice treated with CD19-CAR-T. The beneficial effects of radiation are transient (<7 days), suggesting that CAR-T cells should be infused shortly after TBI exposure. Interestingly, the sensitization occurs via transcriptional activation of the death-receptor pathway and is independent of p53 status. Overall, these findings suggest that TBI could be an actionable method for improving CAR-T outcomes, but further validation in humans is needed.
GD2-CART01 for Relapsed or Refractory High-Risk Neuroblastoma.
Del Bufalo F, De Angelis B, Caruana I, Del Baldo G, De Ioris MA, Serra A, Mastronuzzi A, Cefalo MG, Pagliara D, Amicucci M, Li Pira G, Leone G, Bertaina V, Sinibaldi M, Di Cecca S, Guercio M, Abbaszadeh Z, Iaffaldano L, Gunetti M, Iacovelli S, Bugianesi R, Macchia S, Algeri M, Merli P, Galaverna F, Abbas R, Garganese MC, Villani MF, Colafati GS, Bonetti F, Rabusin M, Perruccio K, Folsi V, Quintarelli C, Locatelli F; Precision Medicine Team–IRCCS Ospedale Pediatrico Bambino Gesù. N Engl J Med. 2023 Apr 6;388(14):1284-1295. doi: 10.1056/NEJMoa2210859.PMID: 37018492
A phase 1-2 clinical trial to evaluate the use of autologous, third-generation GD2-CAR T cells expressing the inducible caspase 9 suicide gene (GD2-CART01) as a therapeutic option for patients (1 to 25 years of age) with relapsed or refractory, high-risk neuroblastoma. A total of 27 children were enrolled, and GD2-CART01 showed feasibility and safety with mild cytokine release syndrome reported in 74% of patients. GD2-targeted CAR T cells persisted for up to 30 months after infusion, and 63% of patients showed an overall response to the treatment, including 9 complete responses and 8 partial responses. The use of GD2-CART01 may have a sustained antitumor effect, making it a potential therapeutic option for high-risk
IACH CAR-T News - April 2023
Chimeric antigen receptor (CAR)-T cells are transforming the care of patients with hematologic and solid malignancies. The forthcoming applications for autoimmune and infectious diseases are at the forefront of translational research that may affect clinical practice. As part of our effort to promote good clinical practice and acquaint clinicians with these innovative therapy options, we are delighted to launch the first issue of IACH CAR-T News. Each month we will highlight exciting developments and publications related to CAR-T cell therapy. Our focus will be on findings that have potential clinical applications and will bring hematologists and oncologists up-to-date with changes in the field.
Stein-Thoeringer CK, Saini NY, Zamir E, Blumenberg V, Schubert ML, Mor U, Fante MA, Schmidt S, Hayase E, Hayase T, Rohrbach R, Chang CC, McDaniel L, Flores I, Gaiser R, Edinger M, Wolff D, Heidenreich M, Strati P, Nair R, Chihara D, Fayad LE, Ahmed S, Iyer SP, Steiner RE, Jain P, Nastoupil LJ, Westin J, Arora R, Wang ML, Turner J, Menges M, Hidalgo-Vargas M, Reid K, Dreger P, Schmitt A, Müller-Tidow C, Locke FL, Davila ML, Champlin RE, Flowers CR, Shpall EJ, Poeck H, Neelapu SS, Schmitt M, Subklewe M, Jain MD, Jenq RR, Elinav E.Nat Med. 2023 Mar 13. doi: 10.1038/s41591-023-02234-6. Online ahead of print.PMID: 36914893
In a study spanning multiple centers in Germany and the US, researchers discovered that administering certain antibiotics, such as piperacillin-tazobactam, meropenem, or cefepime, before infusing commercial CD19-directed CAR T cell therapy in large B-cell lymphoma patients was linked to an increase in the progression of the disease and a decrease in overall survival. The researchers found that early exposure to antibiotics was correlated with higher tumor burden and systemic inflammation in the lymphoma patient population prior to CAR-T therapy initiation. To account for this confounding factor and better understand the impact of the microbiome on CAR-T efficacy, the authors examined the relationship between the fecal microbiome and CAR-T outcomes in lymphoma patients who had not been exposed to antibiotics. The study revealed that Bacteroides, Ruminococcus, Eubacterium, and Akkermansia were significant factors in determining CAR-T responsiveness. Collectively, this study suggests that the microbiome is an important determinant of CAR T cell therapy success.
Immune Effector Cell associated Hemophagocytic Lymphohistiocytosis-like Syndrome (IEC-HS).
Hines MR, Knight TE, McNerney KO, Leick MB, Jain T, Ahmed S, Frigault MJ, Hill JA, Jain MD, Johnson WT, Lin Y, Mahadeo KM, Maron GM, Marsh RA, Neelapu SS, Nikiforow S, Ombrello AK, Shah NN, Talleur AC, Turicek D, Vatsayan A, Wong SW, Maus MV, Komanduri KV, Berliner N, Henter JI, Perales MA, Frey NV, Teachey DT, Frank MJ, Shah NN.Transplant Cell Ther. 2023 Mar 9:S2666-6367(23)01164-8. doi: 10.1016/j.jtct.2023.03.006. Online ahead of print.PMID: 36906275
An American Society for Transplantation and Cellular Therapy (ASTCT) multidisciplinary panel developed a framework for identifying and grading the severity of immune effector cell (IEC) associated HLH-like syndrome (IEC-HS). This article also discusses the pathophysiology of IEC-HS and suggests potential treatment approaches and strategies for optimizing supportive care for patients with this syndrome.
How I treat unique and difficult to manage cases of CAR T-cell therapy associated neurotoxicity.
Santomasso BD, Gust J, Perna F.Blood. 2023 Mar 6:blood.2022017604. doi: 10.1182/blood.2022017604. Online ahead of print.PMID: 36877916
Gutierrez C, Neilan T, Grover NS.Blood. 2023 Feb 24:blood.2022017579. doi: 10.1182/blood.2022017579. Online ahead of print.PMID: 36827628
How I Treat Cytopenias after CAR T-cell Therapy.
Jain T, Olson TS, Locke FL.Blood. 2023 Feb 17:blood.2022017415. doi: 10.1182/blood.2022017415. Online ahead of print.PMID: 36800563
A series of “How I Treat” manuscripts on CAR T cell-related toxicities.
Biomarkers and cardiovascular outcomes in chimeric antigen receptor T-cell therapy recipients.
Mahmood SS, Riedell PA, Feldman S, George G, Sansoterra SA, Althaus T, Rehman M, Mead E, Liu JE, Devereux RB, Weinsaft JW, Kim J, Balkan L, Barbar T, Lee Chuy K, Harchandani B, Perales MA, Geyer MB, Park JH, Palomba ML, Shouval R, Tomas AA, Shah GL, Yang EH, Gaut DL, Rothberg MV, Horn EM, Leonard JP, Van Besien K, Frigault MJ, Chen Z, Mehrotra B, Neilan TG, Steingart RM.Eur Heart J. 2023 Mar 20:ehad117. doi: 10.1093/eurheartj/ehad117. Online ahead of print.PMID: 36939851
This retrospective multicenter study examines the association between severe cardiovascular events (SCE) following CAR T cell threapy and mortality. Investigators found that those who experienced SCE had higher levels of IL-6, CRP, ferritin, and troponin and were at higher risk of mortality. The study highlights the importance of monitoring and managing cardiovascular events in CAR-T recipients.
Hematopoietic stem cell boost for persistent neutropenia after CAR T-cell therapy: a GLA/DRST study.
Gagelmann N, Wulf GG, Duell J, Glass B, van Heteren P, von Tresckow B, Fischer M, Penack O, Ayuk F, Einsele H, Holtick U, Thomson J, Dreger P, Kröger N.Blood Adv. 2023 Feb 28;7(4):555-559. doi: 10.1182/bloodadvances.2022008042.PMID: 35696759 .
This study examines the use of hematopoietic stem cell boost (HSCB) in 31 patients who experienced sustained severe or moderate neutropenia following chimeric antigen receptor (CAR) T-cell therapy. Investigators found that HSCB resulted in an overall neutrophil response rate of 84% within a median of 9 days. Patients with a shorter duration of neutropenia had significantly better one-year overall survival compared to those with a longer duration of neutropenia. The study suggests that early or prophylactic HSCB may improve outcomes for sustained moderate to severe neutropenia after CAR-T therapy.
Read JA, Rouce RH, Mo F, Mamonkin M, King KY.Transplant Cell Ther. 2023 Mar;29(3):165.e1-165.e7. doi: 10.1016/j.jtct.2022.12.020. Epub 2022 Dec 31.PMID: 36592718 Free.
A murine study providing evidence that the elevation of proinflammatory cytokines following CAR-T therapy impacts the bone marrow through a combined mechanism: pluripotent HSCs that are exposed to elevated levels of IFN-γ and IL-6 undergo increased cell death, while more committed progenitor cells become more proliferative in response to elevated IFN-γ. These combined effects lead to depleted stores of repopulating HSCs and ultimately cytopenia.
Preinfusion factors impacting relapse immunophenotype following CD19 CAR T cells.
Lamble AJ, Myers RM, Taraseviciute A, John S, Yates B, Steinberg SM, Sheppard J, Kovach AE, Wood B, Borowitz MJ, Stetler-Stevenson M, Yuan CM, Pillai V, Foley T, Chung P, Chen L, Lee DW, Annesley C, DiNofia A, Grupp SA, Verneris MR, Gore L, Laetsch TW, Bhojwani D, Brown PA, Pulsipher MA, Rheingold SR, Gardner RA, Shah NN.Blood Adv. 2023 Feb 28;7(4):575-585. doi: 10.1182/bloodadvances.2022007423.
The authors conducted a retrospective review of 420 acute lymphoblastic leukemia patients treated with a CD19-CAR construct and identified risk factors associated with each relapse pattern. A greater cumulative number of prior complete remissions was associated with CD19pos relapses, whereas high preinfusion disease burden, prior blinatumomab nonresponse, older age, and 4-1BB CAR construct were associated with CD19neg relapses. The presence of a KMT2A rearrangement was the only preinfusion risk factor associated with lineage switch.
IACH CAR-T News - March 2023
Chimeric antigen receptor (CAR)-T cells are transforming the care of patients with hematologic and solid malignancies. The forthcoming applications for autoimmune and infectious diseases are at the forefront of translational research that may affect clinical practice. As part of our effort to promote good clinical practice and acquaint clinicians with these innovative therapy options, we are delighted to launch the first issue of IACH CAR-T News. Each month we will highlight exciting developments and publications related to CAR-T cell therapy. Our focus will be on findings that have potential clinical applications and will bring hematologists and oncologists up-to-date with changes in the field.
Wang Y, Jain P, Locke FL, Maurer MJ, Frank MJ, Munoz JL, Dahiya S, Beitinjaneh AM, Jacobs MT, Mcguirk JP, Vose JM, Goy A, Andreadis C, Hill BT, Dorritie KA, Oluwole OO, Deol A, Paludo J, Shah B, Wang T, Banerjee R, Miklos DB, Rapoport AP, Lekakis L, Ghobadi A, Neelapu SS, Lin Y, Wang ML, Jain MD.J Clin Oncol. 2023 Feb 8:JCO2201797. doi: 10.1200/JCO.22.01797. Online ahead of print.PMID: 36753699
The study reported “real-world” data on the efficacy and safety of brexucabtagene autoleucel (brexu-cel) in patients with relapsed or refractory mantle cell lymphoma (MCL). Interestingly, of leukapheresed patients, 79% would not have met ZUMA-2 (the pivotal trial leading to brexu-cel FDA approval) eligibility criteria. Best overall and complete response rates were 90% and 82%, respectively, comparable to ZUMA-2. Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 8% and 32%, respectively. Additional notable findings are a relatively high rate of 1-year non-relapse mortality, primarily due to infections, and that recent bendamustine exposure may contribute to inferior outcomes.
Shouse G, Kaempf A, Gordon MJ, Artz AS, Yashar D, Sigmund AM, Smilnak G, Bair SM, Mian A, Fitzgerald LA, Bajwa A, Jaglowski SM, Bailey N, Shadman M, Patel K, Stephens DM, Kamdar M, Hill BT, Gauthier J, Karmali R, Nastoupil LJ, Kittai AS, Danilov AV.Blood Adv. 2023 Feb 3:bloodadvances.2022009309. doi: 10.1182/bloodadvances.2022009309. Online ahead of print.PMID: 36735393
Authors developed a comorbidity score (Severe4) in a multicenter cohort including 577 lymphoma patients treated with CD19-directed CAR-T. Comorbidities comprising the score were selected using a random forest approach. The score was associated with overall survival and progression-free survival both in the development cohort as well as an independent validation cohort.
Bader P, Rossig C, Hutter M, Ayuk FA, Baldus CD, Bücklein VL, Bonig H, Cario G, Einsele H, Holtick U, Koenecke C, Bakhtiar S, Künkele A, Meisel R, Mueller F, Müller I, Penack O, Rettinger E, Sauer MG, Schlegel PG, Soerensen J, von Stackelberg A, Strahm B, Feuchtinger T, Hauer J, Jarisch A.Blood Adv. 2023 Jan 6:bloodadvances.2022008981. doi: 10.1182/bloodadvances.2022008981. Online ahead of print.PMID: 36607834
A retrospective multicenter study from Germany reporting outcomes on pediatric and young adult patients (n=81) with B-acute lymphoblastic leukemia (ALL), who had received Tisagenlecleucel (Tisa-cel) for relapsed/refractory B-acute lymphoblastic leukemia (ALL) as standard of care. Sixty five patients (80%) were previously treated with an allogeneic hematopoietic cell transplantation (allo-HCT).
Severe CRS and ICANS were infrequent. Day 28 CR rate was high (71/81; 88%); of note 54% of patients were in morphological CR at time of lymphodepleting chemotherapy. Notably, all patients in CR and with available MRD testing were MRD negative. The vast majority of CR patients (70/71) did not receive any consolidation treatment after CAR-T. NRM rates were low. Event-free survival (EFS) and overall survival probability at 2 years were 45.3% and 53.2%, respectively. EFS was not different in patients without (n=16, 55.0%) vs. with prior alloHSCT (n=65, 43.4%). However, early relapse (<6 months) following the pre-CAR-T allo-HCT was a poor prognostic factor. Overall, this study provides real-world experience and suggests the potential benefit of Tisa-cel for B-ALL patients post-allo-HCT.
Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma.
Rodriguez-Otero P, Ailawadhi S, Arnulf B, Patel K, Cavo M, Nooka AK, Manier S, Callander N, Costa LJ, Vij R, Bahlis NJ, Moreau P, Solomon SR, Delforge M, Berdeja J, Truppel-Hartmann A, Yang Z, Favre-Kontula L, Wu F, Piasecki J, Cook M, Giralt S.N Engl J Med. 2023 Feb 10. doi: 10.1056/NEJMoa2213614. Online ahead of print.PMID: 36762851
This international, open-label, phase 3 trial (KarMMa-3), randomized patients with relapsed and refractory multiple myeloma who had received two to four regimens previously to idecabtagene vicleucel (ide-cel) and standard anti-myeloma regimens (2:1 randomization). The results showed that ide-cel had a higher overall response rate and longer duration of response compared to standard regimens. However, ide-cel was also associated with more adverse events, including cytokine release syndrome and neurotoxicity. The study suggests that ide-cel could be an effective treatment option for patients with relapsed and refractory multiple myeloma, but its safety profile should be carefully monitored.
Zhang M, Wei G, Zhou L, Zhou J, Chen S, Zhang W, Wang D, Luo X, Cui J, Huang S, Fu S, Zhou X, Tang Y, Ding X, Kuang J, He XP, Hu Y, Huang H.Lancet Haematol. 2023 Feb;10(2):e107-e116. doi: 10.1016/S2352-3026(22)00372-6.PMID: 36725117 Clinical Trial.
POLARIS is a phase 1 clinical trial that evaluated the safety and efficacy of GPRC5D CAR T cells (OriCAR-017) in patients with relapsed or refractory multiple myeloma. The trial recruited 13 patients, of which 10 patients received the CAR T product. Nine patients were assigned to the dose escalation phase. The maximum tolerated dose was not identified, because no dose-limiting toxic effects were observed. On the basis of safety and preliminary activity, the recommended phase 2 dose was set at 3 × 106 CAR T cells per kg, which was received by one additional patient in the dose expansion phase. There were no serious adverse events and no treatment-related deaths, but grade 3 neutropenia and thrombocytopenia occurred in 90-100% of patients. Ten (100%) had an overall response, of whom 6 (60%) had a stringent complete response, and 4 (40%) had very good partial response. These results and other previously published studies suggest that GPRC5D is an active target for immunotherapy in multiple myeloma.
Battram AM, Oliver-Caldés A, Suárez-Lledó M, Lozano M, Bosch I Crespo M, Martínez-Cibrián N, Cid J, Moreno DF, Rodríguez-Lobato LG, Urbano-Ispizua A, Fernández de Larrea C.Mol Ther Methods Clin Dev. 2022 Jun 22;26:207-223. doi: 10.1016/j.omtm.2022.06.010. eCollection 2022 Sep 8.PMID: 35859694
An interesting analysis indicating the use of G-CSF to mobilize hematopoietic progenitor cells before autologous hematopoietic cell transplantation has a minimal impact on T-cell phenotype and is not deleterious for anti-BCMA CAR-T cells. The authors conclude that ASCT apheresis products are a suitable source of T cells for anti-BCMA CAR-T cell manufacture.
CD19-targeted CAR T cells in refractory antisynthetase syndrome
Fabian Müller, Sebastian Boeltz, Johannes Knitza, Michael Aigner, Simon Völkl Soraya Kharboutli, Hannah Reimann, Jule Taubmann, Sascha Kretschmann, Wolf Rösler, Bernhard Manger, Jochen Wacker, Dimitrios Mougiakakos, Samir Jabari, Rolf Schröder, Michael Uder, Frank Roemer, Gerhard Krönke, Andreas Mackensen, Georg Schet.
The Lancet, Published:February 15, 2023DOI:https://doi.org/10.1016/S0140-6736(23)00023-5.
A case report of a patient with refractory antisynthetase syndrome and related refractory idiopathic inflammatory myopathy treated with CD19-directed autologous CAR-T cells (Miltenyi Biotech; Bergisch Gladbach, Germany). Remarkably CAR-T cell infusion led to the complete resolution of the antisynthetase syndrome despite the cessation of all immunosuppressive drugs. This resolution was sustained even after the reconstitution of B cells. Long-term follow-up will be needed to assess whether CAR T-cell treatment might have permanently resolved antisynthetase syndrome in this patient.
IACH CAR-T News - February 2023
Chimeric antigen receptor (CAR)-T cells are transforming the care of patients with hematologic and solid malignancies. The forthcoming applications for autoimmune and infectious diseases are at the forefront of translational research that may affect clinical practice. As part of our effort to promote good clinical practice and acquaint clinicians with these innovative therapy options, we are delighted to launch the first issue of IACH CAR-T News. Each month we will highlight exciting developments and publications related to CAR-T cell therapy. Our focus will be on findings that have potential clinical applications and will bring hematologists and oncologists up-to-date with changes in the field.
Idecabtagene Vicleucel for Relapsed/Refractory Multiple Myeloma: Real-World Experience From the Myeloma CAR T Consortium.
Hansen DK, Sidana S, Peres LC, Colin Leitzinger C, Shune L, Shrewsbury A, Gonzalez R, Sborov DW, Wagner C, Dima D, Hashmi H, Kocoglu MH, Atrash S, Simmons G, Kalariya N, Ferreri C, Afrough A, Kansagra A, Voorhees P, Baz R, Khouri J, Alsina M, McGuirk J, Locke FL, Patel KK.J Clin Oncol. 2023 Jan 9:JCO2201365. doi: 10.1200/JCO.22.01365. Online ahead of print.PMID: 36623248
The first report of real world experience with Idecabtagene Vicleucel for refractory multiple myeloma. See also Dr. Doris Hansen related report in IACH News.
Allogeneic BCMA-targeting CAR T cells in relapsed/refractory multiple myeloma: phase 1 UNIVERSAL trial interim results.
Mailankody S, Matous JV, Chhabra S, Liedtke M, Sidana S, Oluwole OO, Malik S, Nath R, Anwer F, Cruz JC, Htut M, Karski EE, Lovelace W, Dillon M, Butz E, Ying W, Balakumaran A, Kumar SK.Nat Med. 2023 Jan 23. doi: 10.1038/s41591-022-02182-7. Online ahead of print.PMID: 36690811
A first-in-human phase 1 trial in patients with heavily pretreated multiple myeloma, that demonstrates feasibility, acceptable safety and preliminary evidence of anti-myeloma efficacy for ALLO-715, the first allogeneic BCMA-targeted CAR T therapy.
Impact of poverty and neighborhood opportunity on outcomes for children treated with CD19-directed CAR T-cell therapy.
Newman H, Li Y, Liu H, Myers RM, Tam V, DiNofia A, Wray L, Rheingold SR, Callahan C, White C, Baniewicz D, Winestone LE, Kadauke S, Diorio C, June CH, Getz K, Aplenc R, Teachey DT, Maude SL, Grupp SA, Bona K, Barz Leahy
A retrospective study exploring the influence of socioeconomic status on outcomes of CD19-directed CAR T-cell therapy in children with acute lymphoblastic leukemia (ALL). CAR T produced equivalent remission and survival for children with relapsed/refractory ALL, regardless of household-poverty or neighborhood-opportunity.
Bridging Radiation Rapidly and Effectively Cytoreduces High-Risk Relapsed/Refractory Aggressive B Cell Lymphomas Prior to Chimeric Antigen Receptor T Cell Therapy.
Hubbeling H, Silverman EA, Michaud L, Tomas AA, Shouval R, Flynn J, Devlin S, Wijetunga NA, Tringale KR, Batlevi C, Dahi P, Giralt S, Lin R, Park J, Scordo M, Sauter C, Shah G, Hajj C, Salles G, Schoder H, Palomba ML, Perales MA, Yahalom J, Imber BS.Transplant Cell Ther. 2022 Dec 30:S2666-6367(22)01870-X. doi: 10.1016/j.jtct.2022.12.021. Online ahead of print.PMID: 36587744
A retrospective study demonstrating that bridging with radiation therapy before CAR-T cells in large B-cell lymphoma may “convert” poor-risk patients to better risk.
Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of phase 3 TRANSFORM study.
Abramson JS, Solomon SR, Arnason JE, Johnston PB, Glass B, Bachanova V, Ibrahimi S, Mielke S, Mutsaers PGNJ, Hernandez-Ilizaliturri FJ, Izutsu K, Morschhauser F, Lunning MA, Crotta A, Montheard S, Previtali A, Ogasawara K, Kamdar M.Blood. 2022 Dec 21:blood.2022018730. doi: 10.1182/blood.2022018730. Online ahead of print.PMID: 36542826
This global, phase 3 study compared lisocabtagene maraleucel (liso-cel) with standard of care (SOC) as second-line therapy for primary refractory or early relapsed (≤12 months) large B-cell lymphoma (LBCL). The study demonstrates significant improvements in EFS, CR rate, and PFS for liso-cel over SOC and support liso-cel as a preferred second-line treatment compared with SOC in patients with primary refractory or early relapsed LBCL.
Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas.
Sworder BJ, Kurtz DM, Alig SK, Frank MJ, Shukla N, Garofalo A, Macaulay CW, Shahrokh Esfahani M, Olsen MN, Hamilton J, Hosoya H, Hamilton M, Spiegel JY, Baird JH, Sugio T, Carleton M, Craig AFM, Younes SF, Sahaf B, Sheybani ND, Schroers-Martin JG, Liu CL, Oak JS, Jin MC, Beygi S, Hüttmann A, Hanoun C, Dührsen U, Westin JR, Khodadoust MS, Natkunam Y, Majzner RG, Mackall CL, Diehn M, Miklos DB, Alizadeh AA.Cancer Cell. 2023 Jan 9;41(1):210-225.e5. doi: 10.1016/j.ccell.2022.12.005. Epub 2022 Dec 29.PMID: 36584673
Longitudinal concurrent profiling of tumor-derived circulating tumor DNA as well as CAR19-derived cell-free DNA in large B-cell lymphoma patients undergoing treatment with axicabtagene ciloleucel. This combined strategy allowed for the simultaneous characterization of molecular response, identification of genomic alterations associated with treatment failure, and profiling of CAR19 activity, thus facilitating integrative analyses of how these factors work in concert to lead to CAR19 resistance.