- |||||||||| Multiplexed Cytokine Assessment of T- and NK-Cell Responses to Tumor Cells: Parallel Assessment of Biomarkers Associated with Efficacy, Safety, and Persistence (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_3746;
However, characterization of IP and BD suggest more favourable characteristics of EA material further highlighting the impact of prior therapies before APH. Multiple CAR T therapies (eg Kymriah, Yescarta, and Breyanzi) have been approved by the FDA since 2017...Secreted biomarkers associated with efficacy and persistence (e.g. IFN?, Granzyme B, IL7, IL15) were also detected in co-cultures of HEK293 with TALL104 further indicating that the TALL104 cell is facilitating a cytolytic mechanism and persisting due to T cell receptor / HLA engagement with target HEK293 cells...Here, we have demonstrated the utility of Meso Scale
- |||||||||| Kymriah (tisagenlecleucel-T) / Novartis
Obesity Attenuates CAR T-Cell Function in Pediatric B-Cell Acute Lymphoblastic Leukemia (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_3708;
These results may explain our previously reported retrospective results, where pediatric and young adult patients with obesity and relapsed/refractory B-ALL experienced significant reductions in progression-free survival and overall survival when treated with commercially manufactured Tisagenlecleucel (Ross et al., 2022 ASH Conference)...Overall, our clinical and pre-clinical findings demonstrate that obesity impairs CD19-directed CAR T-cell therapy in pediatric B-ALL largely due to cell autonomous defects in T-cells which cannot by overcome by the Introduction of CD3/CD28-expressing CARs. Furthermore, the efficacy of CAR T-cell therapy is negatively impacted by adipocyte-mediated downregulation of CD19 on bone marrow-derived human B-ALL cells.
- |||||||||| Secondary Myeloid Neoplasms after CD19 CAR-T Cell Therapy: Real-Life Multicenter Data from the Clonhema Study (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_3698;
Methods SMN development was assessed in patients (pts) treated with commercial anti-CD19 CAR-T cells (axicabtagene ciloleucel, axi-cel; tisagenlecleucel, tisa-cel; and brexucabtagene autoleucel, brexu-cel) for Large B-cells Lymphomas, Mantle cell lymphomas (MCL), Follicular lymphoma (FL) and Acute Lymphoblastic Leukemia across 16 Italian Centers from November 2019 to May 2024...The AML pts was treated with HMA and Venetoclax, achieving CR, and underwent allo-SCT...Two pts already had del7, but only a few pts were tested for CH prior to CAR-T. The evaluation of CH and karyotype not only at SMN onset, but also before CAR-T therapy, as prospectively outlined in the ClonHema trial, can be crucial to identify potential alterations predicting SMN and to assess whether pts harboring HR-mutations should receive CAR-T cells, given the dismal outcomes of high-risk SMN.
- |||||||||| EZH1/2 Inhibition Improves the Anti-Tumor Efficacy of CAR and TCR T-Cell Based Therapies Against Multiple Liquid and Solid Tumors (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_3693;
We observed that CART22 and CART79b co-cultured with tazemetostat showed enhanced cytotoxicity (72 hs, CART22-taz vs -DMSO p<0.001; CART79b-taz vs -DMSO p<0.01)...Pretreating an array of MM (e.g. RPMI-8226) and AML (e.g. THP-1, KG-1) cell lines with tazemetostat before exposure to anti-BCMA (CARTBCMA) or anti-CD33 CART (CART33) significantly increased killing efficacy at multiple E : T ratio and even with ineffective single-agent CART doses (72 hs; CARTBCMA-taz vs -DMSO p<0.01; CART33-taz vs -DMSO p<0.001)...Furthermore, we show that the novel EZH2/1 inhibitor valemetostat lead to an increased improvement of tumor killing as compared to EZH2i alone. Mechanistically, we demonstrate that EZH1/EZH2 modulation can unlock the full potential of adoptive T-cell immunotherapy.
- |||||||||| Kymriah (tisagenlecleucel-T) / Novartis
The Role of Gut Microbiota in Modulating Efficacy and Adverse Effects of CAR T-Cell Therapy in the Pediatric Population (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_3676;
Methods Patients aged 6 months to 18 years old with B-lymphoblastic leukemia who met clinical criteria to receive tisagenlecleucel (anti CD19 CAR T-cell therapy) were enrolled in this investigator-initiated non-randomized case control study at Childrens Medical Center in Dallas...Enterococcus has been shown to promote anti-tumor (Th1) immunity in other studies (Viaud et al 2013, Laute?-Caly et al 2018, and Griffin et al 2021), consistent with our ex vivo functional immune cell data. Collectively these data suggest that Enterococcus could be a potential biomarker for CAR-T efficacy and might be leveraged as a CAR-T immune enhancer, but additional studies are merited to confirm these observations and to provide more mechanistic insight.
- |||||||||| CART123 / University of Pennsylvania
CAR T Cells Accelerate Disease Progression in AMLs Harboring an Inflammatory Transcriptional Signature (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_3637;
P1
In particular, we find evidence of inflammatory signaling in AML progresses upon exposure to CART, and we have developed a tool that can identify such AMLs in pre-CART samples. This may be used to refine patient selection, or to highlight those patients who will require additional combination therapy, such as ruxolitinib, to improve outcomes with AML-directed CART.
- |||||||||| Patterns of Immune Reconstitution and Their Clinical Significance in Aggressive Lymphoma Treated with CAR-T Therapy (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_3631;
Cyclophosphamide and fludarabine lymphodepletion was used in 86.7% of patients...Notably, neither CD4+ nor CD8+ T cell recovery was influenced by lymphodepletion regimen or exposure to tocilizumab or corticosteroids...Among immune subsets considered, NK cell recovery emerges as a robust predictor of favorable clinical outcomes. In summary, this novel biomarker may serve as an important prognostic marker of disease outcome following CAR-T and also provide insights into the biology of post-CAR-T relapse.
- |||||||||| Kymriah (tisagenlecleucel-T) / Novartis, Yescarta (axicabtagene ciloleucel) / Gilead, Rituxan (rituximab) / Roche
Inferior Survival in Double Refractory Large B-Cell Lymphoma Eligible for Third-Line CD19 Chimeric Antigen T-Cell Therapy (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_3041;
Anthracycline-refractoriness was defined as pts progressing/stable disease (PD/SD) on therapy or relapsing <3 months of completing treatment (typically R-CHOP)...CAR-T product : axicabtagene ciloleucel 76%, tisagenlecleucel 24%...Identifying DR status at time of referral as a determinate of outcome would be clinically beneficial. Approaches to bridge DR pts to CAR-T therapy and assessing outcomes of DR pts (those progressing on platinum-based BT) in second line CAR-T therapy need to be prospectively investigated.
- |||||||||| Breyanzi (lisocabtagene maraleucel) / BMS, Kymriah (tisagenlecleucel-T) / Novartis, Yescarta (axicabtagene ciloleucel) / Gilead
CAR T-Cell Therapy for DLBCL with CNS Involvement: Overall Safe and Effective with Limited Efficacy in Patients with Leptomeningeal Disease (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_3036;
Pts received CAR-T cell therapy with axicabtagene ciloleucel (31%), tisagenlecleucel (29%), lisocabtagene maraleucel (24%), or point-of-care anti-CD19 therapy (16%) (Kedmi et al, Tansplant Cell Ther 2022)...Conclusions : In pts with S/PCNSL treated with CAR-T cell, we observed a safety and efficacy profile of CAR-T cell therapy comparable to that seen in recent CNSL series. Furthermore, we confirmed inferior PFS and OS in pts with isolated LEPT disease compared to those with PARE disease, suggesting the need for novel therapeutic to better control LEPT disease pre-CAR-T cell or consolidation approaches tailored specifically for pts with LEPT involvement.
- |||||||||| Impact of Pre-Existing Mental Health Disorders (MHD) on CAR T-Cell Therapy Outcomes in Patients with Large B-Cell Lymphoma (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_3035;
380 (86%) received axicabtagene ciloleucel, 42 (10%) received lisocabtagene maraleucel, 19 (4%) received tisagenlecleucel...Patients with MHD had a higher incidence of grade ?3 CRS (19% vs. 9.4%, p=0.0040) and grade ?3 ICANS (51% vs. 26%, p<0.0001), as well as higher use of anakinra (14% vs. 5%, p=0.0019) and corticosteroids (65% vs. 46%, p=0.0001) for CAR-T related toxicity...This data supports access to CAR-T for patients with MHD and underscore the need for integrated psychiatric care and close monitoring to reduce adverse events. Future research should assess if targeted interventions can mitigate CAR-T related toxicity in patients with MHD.
- |||||||||| Breyanzi (lisocabtagene maraleucel) / BMS, Kymriah (tisagenlecleucel-T) / Novartis, Yescarta (axicabtagene ciloleucel) / Gilead
Impact of Pre-Treatment Liver-Related Factors on Clinical Outcomes after CAR T-Cell Therapy for Lymphoma (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_3033;
However, the presence of either lymphomatous lesions or ascites on baseline imaging prior to CAR-T were both poor prognostic factors for disease progression and for overall survival. Further studies are needed to elucidate the underlying mechanisms for these findings which have implications for counselling prior to CAR-T and monitoring after therapy.
- |||||||||| Breyanzi (lisocabtagene maraleucel) / BMS, Kymriah (tisagenlecleucel-T) / Novartis, Yescarta (axicabtagene ciloleucel) / Gilead
CD19 CAR-T Cell Therapy Is Effective in Richter Transformation: A Multicenter Retrospective Analysis By the European Research Initiative on Chronic Lymphocytic Leukemia (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_3031;
Results : The study included 54 patients with RT treated with anti-CD19 CAR-T cells (investigational products : n=29, 54%; tisagenlecleucel : n=20, 37%; axicabtagene ciloleucel : n=4, 7%; lisocabtagene maraleucel : n=1, 2%)...Lymphodepletion consisted of fludarabine with cyclophosphamide in 46/52(85%) and bendamustine in 8 (15%) patients...Conclusions : The current study demonstrates clinically significant response rates and manageable toxicity in patients with RT treated with investigational as well as commercially available CAR-T cell products. These findings could potentially pave the way for new treatment paradigms in the management of this high-risk and challenging patient population.
- |||||||||| Breyanzi (lisocabtagene maraleucel) / BMS, Kymriah (tisagenlecleucel-T) / Novartis, Yescarta (axicabtagene ciloleucel) / Gilead
CAR T Cell Therapy in Early Relapsed/Refractory Large B-Cell Lymphoma: Real World Analysis from the Cell Therapy Consortium (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_3030;
Among 53 (34%) pts receiving CAR T in 2L, 74% received axi-cel and 26% liso-cel, and among 102 (66%) pts receiving CAR T in 3L+, 48% received axi-cel, 24% tisa-cel and 28% liso-cel...Fludarabine/cyclophosphamide LDc was received by 76% of pts and bendamustine by 23%...While our analysis is limited by short follow-up and limited subgroup cohort size, our data suggest similar outcomes for early R/R LBCL pts treated with CAR T in 2L vs 3L+. Selection of more fit pts and efforts to reduce disease burden prior to infusion may improve survival outcomes for early R/R LBCL pts treated with CAR T regardless of line of therapy.
- |||||||||| Breyanzi (lisocabtagene maraleucel) / BMS, Kymriah (tisagenlecleucel-T) / Novartis, Yescarta (axicabtagene ciloleucel) / Gilead
Impact of Broad-Spectrum Antibiotic Exposure on CAR-T Therapy Outcomes in B-Cell Lymphoma: A Multicenter International Study (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_3014;
Background : Previous studies by us and others have shown that broad-spectrum antibiotic exposure, particularly with PIM (piperacillin-tazobactam, imipenem, and meropenem), before CD19-chimeric antigen receptor T-cell (CAR-T) therapy is associated with poor outcomes in B-cell malignancies...This study aims to elucidate the influence of commonly used broad-spectrum antibiotics, including 4th generation cephalosporins (CS, e.g., Cefepime) and PIM, on the efficacy of CAR-T therapy...Axi-cel was the most common CAR-T product (40%), followed by tisa-cel (35%), liso-cel (12%), and a CD19-point-of-care academic product (13%)...Importantly, initiation of broad-spectrum antibiotics after CAR-T infusion with an exposure of less than 10 days did not appear to compromise anti-lymphoma treatment efficacy. These findings may help guide antibiotic use in patients undergoing CAR-T therapy.
- |||||||||| CART123 / University of Pennsylvania
Serum-Based Proteomic Analysis of Cytokine Release Syndrome in Pediatric AML Patients Receiving CART123 (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_2749;
P1, P1/2
Unique protein signatures identified in this study suggest potential lineage specific differences in immune response to CAR-T therapy. Together, these results warrant further exploration to identify clinically targetable regulators of CRS to decrease toxicity and increase efficacy in AML patients, where efficacy has not been observed to the extent of B-cell malignancies.
- |||||||||| Resistance to FLT3 Inhibitors in FLT3-Mutated AML Is Associated with CD45RA+CD200- leukemic Cells and Can be Overcome By Combination with SMAC Mimetics (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_2707;
Our data shows specific differences in myeloid maturation and LSC (Leukemic Stem Cell) phenotype between midostaurin responders and non-responders, together with a potential functional shift in cell signaling in immune signaling and anti-apoptotic pathways. Moreover, ex vivo drug testing data demonstrates that while there is less overall sensitivity to drug treatment in non-responders, combination therapies including apoptotic modulators such as the SMAC mimetics could overcome FLT3i resistance and improve FLT3mut patient outcomes.
- |||||||||| Kymriah (tisagenlecleucel-T) / Novartis, Besponsa (inotuzumab ozogamicin) / Pfizer, UCB
Bridging Pediatric B-Cell Acute Lymphoblastic Leukemia (ALL) Patients to CAR-T Cell Therapy: A National Perspective (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_2663;
All received systemic BT and 140 (97%) received a CAR-T cell product (tisagenlecleucel : 118 patients, anti-CD19 academic product : 10, anti-CD19 and CD22 dual targeting product : 12)...Of a total of 198 bridging courses, escalating intravenous methotrexate with Vincristine (per Capizzi interim maintenance but omitting asparaginase) was the most commonly used [n = 60 (30%)], followed by maintenance [n = 47 (24%)], vincristine and dexamethasone [n = 22 (11%)], Inotuzumab [n = 22 (11%)], high-dose cytarabine [n = 13 (6.5%)], and tyrosine-kinase inhibitor-based therapy [n = 11 (5.5%)]...These additional data will be shared at the congress. Calculating the impact of DB before and after BT and linking it to CAR-T outcomes will aid in dissecting the relative contributions of disease biology and BT choice in outcomes post CAR-T cell therapy.
- |||||||||| puqilunsai (pCAR-19B) / Chongqing Precision Biotech
A Phase 2 Clinical Trial of Anti-CD19 CAR-T (pCAR-19B) in Chinese Pediatric and Young Adult with Relapsed/Refractory (R/R) CD19+ B-ALL: The First Pivotal Study in an Asian Population (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_2662;
P2
pCAR-19B is an autologous CAR-T cell product with an optimized humanized CD19-specific single-chain variable fragment (scFv) designed to address safety concerns...Conclusions : Despite a heavy burden of BM blasts and a high risk of genetic variations, pCAR-19B demonstrated high remission rates, achieved a high rate of MRD-negative remission, durable responses, and a tolerable safety profile. This study represents the first pivotal clinical trial of childhood B-ALL in an Asian population, offering a new treatment option for Chinese pediatric and young adult patients with R/R B-ALL.
- |||||||||| Kymriah (tisagenlecleucel-T) / Novartis, Tecartus (brexucabtagene autoleucel) / Gilead
Allogeneic Hematopoietic Stem Cell Transplantation Following CAR T Therapy in Relapsed/Refractory Acute Lymphoblastic Leukemia (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_2629;
Standard approach regarding sequencing of therapies still remains with a critical knowledge gap. Further larger trials are needed to determine if consolidation with transplant can ultimately cure patients who remain MRD positive after CAR T therapy, and to identify patient subsets who may benefit from HSCT following CAR T therapy.
- |||||||||| Kymriah (tisagenlecleucel-T) / Novartis, Yescarta (axicabtagene ciloleucel) / Gilead
Temporal Association and Risk Window for Secondary Malignancies Post CAR-T (Marriott Grand Ballroom 2-4 (Marriott Marquis San Diego Marina)) - Nov 6, 2024 - Abstract #ASH2024ASH_2320;
The clustering of cases within specific time windows (1-3 months for tisagenleucel; <1 month and 3-6 months for axicabtagene ciloleucel) warrants further investigation into potential mechanisms underlying these temporal patterns. These insights can serve to inform efforts to optimize long-term patient management strategies and refine risk assessment protocols in CAR-T therapy and appropriate follow-up protocols for patients undergoing CAR-T cell therapy.
- |||||||||| Kymriah (tisagenlecleucel-T) / Novartis, Yescarta (axicabtagene ciloleucel) / Gilead
Site-Specific Analysis of Extranodal Involvement Reveals Distinct Efficacy Outcomes with CAR T-Cell Therapy in Large B-Cell Lymphoma Patients (Marriott Grand Ballroom 8-9 (Marriott Marquis San Diego Marina)) - Nov 6, 2024 - Abstract #ASH2024ASH_1418;
Conclusions : Leveraging longitudinal lesion-level data of extranodal involvement from a large international cohort, we uncovered site-specific patterns of response and relapse to CAR T-cells. Both a progressively higher number of extranodal sites and certain disease locations, such as liver and adrenal glands, were associated to reduced efficacy after infusion.
- |||||||||| Impact of Patient Distance from Center on Outcomes and Cost of Therapy for Patients Undergoing Chimeric Antigen Receptor T-Cell Therapy for B-Cell Lymphoma (Halls G-H - Blood Journals Studio (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_1208;
RESULTS : A total of 61 pts intended to receive axicabtagene ciloleucel (79%), tisagenlecleucel (7%), or brexucabtagene autoleucel (15%) with a median follow up of 17 months...Post referral therapy regimens were platinum-based (39%), polatuzumab-based (29%), other systemic chemotherapy (16%), oral targeted agents (16%), and radiation (1%)...NRM was high in this cohort and infection related deaths were more common for patients who lived more than 90 miles from the CAR-T center. Future multicenter studies should be conducted to better understand barriers to access and supportive care for patients undergoing CAR-T therapy.
- |||||||||| Kymriah (tisagenlecleucel-T) / Novartis, Yescarta (axicabtagene ciloleucel) / Gilead
Review of Study Designs in Appraisals of Gene Therapies by the French HTA Agency () - Nov 4, 2024 - Abstract #ISPOREU2024ISPOR_EU_3250;
The HAS tended to acknowledge a clinical added value for GTs based on lower quality of evidence than for other therapies, particularly for the first launched products. This advantage granted to GTs may not persist in the future.
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