Tazemetostat-mediated immune remodeling in B-cell lymphomas receiving cart
Authors
Samuel Yamshon¹, Caitlin Gribbin¹, Yusuke Isshiki¹, Ioannis Karagiannidis¹, Sunjae Lee¹, Jizhi Yan¹, Gwynne Ozkan¹, Anna Alperovich¹, Barbara Ma¹, Christopher Hackett¹, Mateo Mejia Saldarriaga¹, Daniel Choi¹, Selina Chen‑Kiang¹, John Leonard¹, Ari Melnick¹, Anastasiia Bolshakova², Alina Mulyukina², Ivan Zubarev², Aleksei Tishchenko², Nathan Fowler², Juliet Barker¹, Giorgio Inghirami¹, Wendy Béguelin³, Peter Martin¹
- Weill Cornell Medicine, New York, NY, USA
- BostonGene Corporation, Waltham, MA,USA
- NYU Langone Health, New York, NY, USA
Abstract
Background:
Chimeric antigen receptor (CAR) T cell therapy has transformed outcomes in B cell lymphoma; however, relapse relapse remains prevalent. Preclinical data suggest EZH2 inhibition may mitigate T-cell exhaustion, promote a T-cell memory phenotype, and enhance response to immune-based approaches.
Aims: Here, we evaluated whether priming with the oral EZH2 inhibitor tazemetostat could favorably modulate host immunity and improve outcomes in patients receiving standard-of-care CART therapy.
Methods:
Thirteen pts with diffuse large B cell (DLBCL, n = 7), follicular (FL, n = 5), or mantle cell lymphoma (MCL, n = 1) received the EZH2 inhibitor tazemetostat for ≥7 days prior to apheresis and continued to lymphodepletion. Following CART infusion, tazemetostat was resumed at hematologic count recovery and continued for up to 12 mo (6 mo in pts with complete remission [CR]). Peripheral blood mononuclear cells were collected Day -24 and Day -5. Immune modulation was evaluated with multiparametric flow cytometry, transcriptomics, cell deconvolution, differential gene expression patterning, and ssGSEA.
Results:
The median number of prior lines of therapy was 2 (range: 1-4), and 85% were refractory to the most recent therapy. EZH2 mutations were present in 2 pts. Features included TP53 mutation or deletion (n = 4), MYC translocation (4 of 7 DLBCL pts), and transformed disease (n = 3). Patients received axicabtagene ciloleucel (n = 5), lisocabtagene maraleucel (n = 5), tisagenlecleucel (n = 2), or brexucabtagene autoleucel (n = 1).
The overall response rate was 100%, with 77% achieving CR (DLBCL 71%, FL 100%). At a median follow up of 18 months, 54% remain progression-free, and 77% remain alive. Cytokine release syndrome (CRS) occurred in 10 pts (77%), with 1 grade 3 CRS. Six pts developed transient grade 1-2 ICANS. Grade 3+ neutropenia was seen in 77%, and 3 pts experienced grade 3 infections. Gastrointestinal adverse events were the most common, predominantly grade 1-2.
Immunoprofiling demonstrated an increase in NK cells (14%) and CD16+ monocytes (20%, p < 0.03) with a concurrent decrease in Tregs (14%) and CD14+ monocytes (53%,p < 0.02) when comparing baseline and pre-CART samples. Gene signature analysis uncovered upregulation of signatures associated with MHC-I antigen presentation (p = 0.010), antigen-specific T cell activation (p = 0.019), and cellular cytotoxicity (p = 0.043), while signatures associated with tolerogenic dendritic cells (p = 0.011), myeloid suppression (p = 0.043), and coagulation (p = 0.030) were downregulated. No detrimental effects on CART transduction efficiency, activation, or expansion were observed.
Summary/Conclusion:
EZH2 inhibition with tazemetostat for immune priming ahead of CART is associated with high clinical efficacy and peripheral immune remodeling. Enhanced lymphocyte activation and cytotoxicity paired with decreased myeloid tolerogenicity and immunosuppression may facilitate CART expansion and persistence. Ongoing immune correlates and planned randomized studies will further define the clinical benefits of this approach.
Chimeric antigen receptor (CAR) T cell therapy has transformed outcomes in B cell lymphoma; however, relapse relapse remains prevalent. Preclinical data suggest EZH2 inhibition may mitigate T-cell exhaustion, promote a T-cell memory phenotype, and enhance response to immune-based approaches.
Aims: Here, we evaluated whether priming with the oral EZH2 inhibitor tazemetostat could favorably modulate host immunity and improve outcomes in patients receiving standard-of-care CART therapy.
Methods:
Thirteen pts with diffuse large B cell (DLBCL, n = 7), follicular (FL, n = 5), or mantle cell lymphoma (MCL, n = 1) received the EZH2 inhibitor tazemetostat for ≥7 days prior to apheresis and continued to lymphodepletion. Following CART infusion, tazemetostat was resumed at hematologic count recovery and continued for up to 12 mo (6 mo in pts with complete remission [CR]). Peripheral blood mononuclear cells were collected Day -24 and Day -5. Immune modulation was evaluated with multiparametric flow cytometry, transcriptomics, cell deconvolution, differential gene expression patterning, and ssGSEA.
Results:
The median number of prior lines of therapy was 2 (range: 1-4), and 85% were refractory to the most recent therapy. EZH2 mutations were present in 2 pts. Features included TP53 mutation or deletion (n = 4), MYC translocation (4 of 7 DLBCL pts), and transformed disease (n = 3). Patients received axicabtagene ciloleucel (n = 5), lisocabtagene maraleucel (n = 5), tisagenlecleucel (n = 2), or brexucabtagene autoleucel (n = 1).
The overall response rate was 100%, with 77% achieving CR (DLBCL 71%, FL 100%). At a median follow up of 18 months, 54% remain progression-free, and 77% remain alive. Cytokine release syndrome (CRS) occurred in 10 pts (77%), with 1 grade 3 CRS. Six pts developed transient grade 1-2 ICANS. Grade 3+ neutropenia was seen in 77%, and 3 pts experienced grade 3 infections. Gastrointestinal adverse events were the most common, predominantly grade 1-2.
Immunoprofiling demonstrated an increase in NK cells (14%) and CD16+ monocytes (20%, p < 0.03) with a concurrent decrease in Tregs (14%) and CD14+ monocytes (53%,p < 0.02) when comparing baseline and pre-CART samples. Gene signature analysis uncovered upregulation of signatures associated with MHC-I antigen presentation (p = 0.010), antigen-specific T cell activation (p = 0.019), and cellular cytotoxicity (p = 0.043), while signatures associated with tolerogenic dendritic cells (p = 0.011), myeloid suppression (p = 0.043), and coagulation (p = 0.030) were downregulated. No detrimental effects on CART transduction efficiency, activation, or expansion were observed.
Summary/Conclusion:
EZH2 inhibition with tazemetostat for immune priming ahead of CART is associated with high clinical efficacy and peripheral immune remodeling. Enhanced lymphocyte activation and cytotoxicity paired with decreased myeloid tolerogenicity and immunosuppression may facilitate CART expansion and persistence. Ongoing immune correlates and planned randomized studies will further define the clinical benefits of this approach.
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