Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas

Sworder, Brian; Kurtz, David M.; Alig, Stefan; Frank, Matthew J.; Shukla, Navika; Garofalo, Andrea; Macaulay, Charles; Esfahani, Mohammad Shahrokh; Olsen, Mari; Hamilton, James N.; Hosoya, Hitomi; Hamilton, Mark; Spiegel, Jay Y.; Baird, John H.; Sugio, Takeshi; Carleton, Mia; Craig, Alexander; Younes, Sheren; Sahaf, Bita; Sheybani, Natasha D.; Schroers‐Martin, Joseph; Liu, Chih Long; Oak, Jean; Jin, Michael C.; Beygi, Sara; Hüttmann, Andreas; Hanoun, Christine; Dührsen, Ulrich; Westin, Jason R.; Khodadoust, Michael S.; Natkunam, Yasodha; Majzner, Robbie G.; Mackall, Crystal L.; Diehn, Maximilian; Miklos, David B.; Alizadeh, Ash A.

doi:10.1016/j.ccell.2022.12.005

Cited by 55 publications

(65 citation statements)

References 66 publications

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“…Consistent with prior reports, 6 Sworder et al. 1 found higher levels of pre-treatment ctDNA were associated with worse event-free survival (EFS) post CD19-CAR T cell therapy. Measurement of cfCAR19 allowed for tracking of CAR T cells post-infusion, similar to FACS analysis.…”

Section: Main Textsupporting

confidence: 86%

“…In the article “Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas,” recently published in Cancer Cell , Sworder et al. 1 developed a comprehensive approach for simultaneous tumor and effector profiling (STEP) to characterize the different cellular compartments involved in treatment response and/or development of resistance ( Figure 1 ). They profiled over 700 longitudinal peripheral blood samples from two independent cohorts (discovery, n = 65; validation, n = 73) of patients with lymphoma, who had received the FDA-approved CD19-CAR T cell product axicabtagene ciloleucel (axi-cel).…”

Section: Main Textmentioning

confidence: 99%

“…Finally, Sworder et al. 1 conducted a multivariable analysis to assess the prognostic impact of tumor, CD19-CAR T cell, and non-engineered immune cell features and patient outcomes. Higher levels of ctDNA pre- and post-treatment (weeks 1 and 4) maintained clinical significance, predicting worse EFS and overall survival (OS).…”

Section: Main Textmentioning

confidence: 99%

“… Sworder et al. 1 developed an integrated simultaneous tumor and effector profiling (STEP) approach to study resistance mechanisms to CD19-CAR T cell therapy in large B-cell lymphomas. Their study provides novel biological insights and paves the way for future interventions.…”

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confidence: 99%

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A tour de force provides novel insights into CD19-CAR T cell resistance mechanisms

Talleur

2023

Cell Reports Medicine

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confidence: 86%

Section: Main Textmentioning

confidence: 99%

Section: Main Textmentioning

confidence: 99%

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confidence: 99%

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A tour de force provides novel insights into CD19-CAR T cell resistance mechanisms

Talleur

2023

Cell Reports Medicine

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“…Still, using xCell, we did not detect significant changes in T-regs in IRF8 mutant primary DLBCL (Supplemental Figure 7A), which were consistently detected in the A20 BalbC models (Tfh cells are not uniquely identified with xCell). This result was somewhat surprising because recently IRF8 mutation in DLBCL was identified as a putative marker for poor response to CD19-CART cells 61 . Moreover, in that study it was postulated that this worse outcome could be related to an increase in T-regs in the microenvironment of IRF8 mutant DLBCL, which therein was detected by deconvolution of bulk RNA-seq signatures using another algorithm, CIBERSORTx 62 .…”

Section: Resultsmentioning

confidence: 96%

IRF8-mutant B cell lymphoma evades immunity through a CD74-dependent deregulation of antigen processing and presentation in MHC CII complexes

Qiu,

Khalife,

Lin

et al. 2023

Preprint

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In diffuse large B-cell lymphoma (DLBCL), the transcription factor IRF8 is the target of a series of potentially oncogenic events, including, chromosomal translocation, focal amplification, and super-enhancer perturbations. IRF8 is also frequently mutant in DLBCL, but how these variants contribute to lymphomagenesis is unknown. We modeled IRF8 mutations in DLBCL and found that they did not meaningfully impact cell fitness. Instead, IRF8 mutants, mapping either to the DNA-binding domain (DBD) or c-terminal tail, displayed diminished transcription activity towards CIITA, a direct IRF8 target. In primary DLBCL, IRF8 mutations were mutually exclusive with mutations in genes involved in antigen presentation. Concordantly, expression of IRF8 mutants in murine B cell lymphomas uniformly suppressed CD4, but not CD8, activation elicited by antigen presentation. Unexpectedly, IRF8 mutation did not modify MHC CII expression on the cell surface, rather it downmodulated CD74 and HLA-DM, intracellular regulators of antigen peptide processing/loading in the MHC CII complex. These changes were functionally relevant as, in comparison to IRF8 WT, mice harboring IRF8 mutant lymphomas displayed a significantly higher tumor burden, in association with a substantial remodeling of the tumor microenvironment (TME), typified by depletion of CD4, CD8, Th1 and NK cells, and increase in T-regs and Tfh cells. Importantly, the clinical and immune phenotypes of IRF8-mutant lymphomas were rescued in vivo by ectopic expression of CD74. Deconvolution of bulk RNAseq data from primary human DLBCL recapitulated part of the immune remodeling detected in mice and pointed to depletion of dendritic cells as another feature of IRF8 mutant TME. We concluded that IRF8 mutations contribute to DLBCL biology by facilitating immune escape.

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2024 Update: Advances in the risk stratification and management of large B‐cell lymphoma

Tavakkoli,

Barta

2023

American J Hematol

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Diffuse large B‐cell lymphoma (DLBCL) is a heterogeneous disease with varying clinical outcomes. Our understanding of its molecular makeup continues to improve risk stratification, and artificial‐intelligence and ctDNA‐based analyses have the potential to enhance risk assessment and disease monitoring. R‐CHOP and Pola‐R‐CHP are used in the frontline setting; chimeric antigen receptor therapy (CART) is now the new standard‐of‐care for most with primary refractory disease; both CART and autologous stem cell transplantation are utilized in the relapsed and refractory setting. In this review, we summarize the classification and management of DLBCL with an emphasis on recent advances in the field.

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Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas

Cited by 55 publications

References 66 publications

A tour de force provides novel insights into CD19-CAR T cell resistance mechanisms

A tour de force provides novel insights into CD19-CAR T cell resistance mechanisms

IRF8-mutant B cell lymphoma evades immunity through a CD74-dependent deregulation of antigen processing and presentation in MHC CII complexes

2024 Update: Advances in the risk stratification and management of large B‐cell lymphoma

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