CD19-targeted Chimeric Antigen Receptor T-cell Research Articles

Patients with aggressive B-cell lymphoma receiving CAR T-cell therapy have a low rate of severe infections despite lack of universal antibacterial and antifungal prophylaxis.

Our aim was to describe the frequency and severity of infectious complications after chimeric antigen receptor (CAR) T-cell therapy in patients with large B-cell lymphoma (LBCL). We retrospectively reviewed clinical records of LBCL patients treated with CD19-targeted CAR T-cell therapy from July/2018 to December/2021 at our institution, and identified all infectious episodes from CAR T-cell infusion until disease progression, death or last follow-up. Overall, 137 patients were included. Thirty six percent had received ≥3 previous lines of therapy and 26% an autologous hematopoietic cell transplantation (auto-HCT). Cytokine release syndrome occurred in 87 (64%) patients. Antibacterial prophylaxis was not used in any patient; only 38% received antifungal prophylaxis. Sixty three infectious events were observed in 41 (30%) patients. Fifty two (83%) of the infectious events had at least one pathogen identified (bacteria [n = 38], virus [n = 11], and fungi [n = 3]). Most of the infectious events occurred during hospitalization for CAR-T treatment. Infection-related mortality was observed in two patients. Independent risk factors for infection included male gender, previous auto-HCT, ≥3 lines of treatment and pre-lymphodepletion neutropenia. Infections after CAR T-cell therapy in patients with lymphoma are frequent but generally not severe. A conservative and tailored antimicrobial prophylaxis seems to be a safe approach.

Successful Treatment of Concomitant Myasthenia Gravis and Lambert-Eaton Myasthenic Syndrome with Autologous CD19-targeted CAR-T Cells (P4-14.006)

Successful Treatment of Concomitant Myasthenia Gravis and Lambert-Eaton Myasthenic Syndrome with Autologous CD19-targeted CAR-T Cells (P4-14.006)

IL-18-secreting multiantigen targeting CAR T cells eliminate antigen-low myeloma in an immunocompetent mouse model

AbstractMultiple myeloma is a plasma cell malignancy that is currently incurable with conventional therapies. Following the success of CD19-targeted chimeric antigen receptor (CAR) T cells in leukemia and lymphoma, CAR T cells targeting B-cell maturation antigen (BCMA) more recently demonstrated impressive activity in relapsed and refractory myeloma patients. However, BCMA-directed therapy can fail due to low expression of BCMA on myeloma cells, suggesting that novel approaches to better address antigen-low disease may improve patient outcomes. We hypothesized that engineered secretion of the proinflammatory cytokine interleukin-18 (IL-18) and multiantigen targeting could improve CAR T-cell activity against BCMA-low myeloma. In a syngeneic murine model of myeloma, CAR T cells targeting the myeloma-associated antigens BCMA and B-cell activating factor (BAFF-R) failed to eliminate myeloma when these antigens were weakly expressed, whereas IL-18–secreting CAR T cells targeting these antigens promoted myeloma clearance. IL-18-secreting CAR T cells developed an effector-like T-cell phenotype, promoted interferon-gamma production, reprogrammed the myeloma bone marrow microenvironment through type-I/II interferon signaling, and activated macrophages to mediate antimyeloma activity. Simultaneous targeting of weakly-expressed BCMA and BAFF-R with dual-CAR T cells enhanced T-cell:target-cell avidity, increased overall CAR signal strength, and stimulated antimyeloma activity. Dual-antigen targeting augmented CAR T-cell secretion of engineered IL-18 and facilitated elimination of larger myeloma burdens in vivo. Our results demonstrate that combination of engineered IL-18 secretion and multiantigen targeting can eliminate myeloma with weak antigen expression through distinct mechanisms.

Abstract CT244: HR001, a novel CD19-targeted CAR-T cell therapy for patients with relapsed/refractory non-Hodgkin's lymphoma: primary results of a phase II study (HRAIN01-NHL01-II)

Abstract Background: HR001 is a CD19-targeted CAR-T cell for patients with relapsed and refractory non-Hodgkin's (R/R NHL). Here, we report the primary results of the phase 2 study (HRAIN01-NHL01-II). Methods: HRAIN01-NHL01-II is an open-label, single-arm, and multicenter (17 centers) study in China. It enrolled R/R NHL patients treated with at least two lines of therapy (must-have anthracycline and CD20-targeted agents) or after autologous hematopoietic stem cell transplantation. All patients received a single infusion of HR001 at the 2.0 × 106 CAR+T cells/kg dose. The disease response was evaluated by the independent review committee with Lugano response criteria [2014]. Results: As of May 16th, 2023, 81 R/R NHL patients with ECOG 0-1 at baseline received the infusion HR001 from the Jinshan manufacturing facility [51.9% male; median age 53.4 years (range 23~74); 3.7% CD19 negative; 91.4% diffuse large B-cell lymphoma; 79.0% III-IV of Ann Arbor classification or Lugano] with a median follow-up of 160 days (range 7 to 454). The median time to best response was 30 days (range 28-358). The 3-month, 6 month and best objective response rate (ORR) was 53.1%(95% CI: 41.7-64.3), 45.7%(95% CI: 34.6-57.1) and 74.1% (95% CI: 63.1-83.2) respectively. The 3-month, 6 month and best complete response rate (CRR) was 32.1%(95% CI: 22.2-43.4), 29.6%(95% CI: 20.0-40.8) and 49.4%(95% CI: 38.1-60.7) respectively. Median duration of response (DOR) and progression-free survival (PFS) were 339 days (95% CI: 149-NE) and 176 days (95% CI: 91-NE) respectively. The overall survival (OS) was not reached. The most common treatment-related adverse events (AEs) happened in the hematologic system. The cytokine release syndrome (CRS) occurred in 95.1% of patients, with ≥3 grade CRS observed in 3.7% of patients. Immune effector cell-associated neurotoxicity syndrome (ICANS) happened in 8.6% of patients, without any ≥ 3 grade ICANS reported. The treatment-related mortality was 1.2%. The median time to CAR T-cell peak expansion was 240 hours (120~672) after infusion, median maximum expansion (Cmax) was 17413.9 copies/μg DNA (124.9~136382.2), and median AUC0-28d was 3201014.0 copies/μg DNA (205082.8~18400016.2). Positive tests for the anti-drug antibody (ADA) were noted in 14.8% of patients, while neutralizing antibody (Nab) tests were positive in 3.7% of patients. Among Nab-positive patients, the complete response was maintained until follow-up. Conclusions: Patients with R/R NHL could benefit from the HR001 treatment with satisfactory objective response, durable remission, and favorable safety profile. Citation Format: Yian Zhang, Yuhua Li, Kai Hu, Wuping Li, Hongwei Xue, Qi Deng, Zheng Ge, Liangquan Geng, Xianmin Song, Kang Yu, Hongmei Jing, Bing Chen, Xin Li, Zhimin Zhai, Jianping Shen, Jiang Cao, Qingming Wang, Peng Liu. HR001, a novel CD19-targeted CAR-T cell therapy for patients with relapsed/refractory non-Hodgkin's lymphoma: primary results of a phase II study (HRAIN01-NHL01-II) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT244.

Abstract 6327: Impact of G-CSF on safety and efficacy of CAR T-cell therapy in non-Hodgkin lymphoma

Abstract Introduction: Chimeric antigen receptor T-cell (CAR-T) therapy is an established treatment modality for the management of refractory and/or relapsed non-Hodgkin lymphoma (NHL). Despite restrictions on granulocyte colony-stimulating factor (G-CSF) use in registration clinical trials due to potential worsening of cytokine release syndrome (CRS), G-CSF is often prescribed for neutrophil recovery post-CAR-T in clinical practice. We conducted a retrospective study to assess the association between G-CSF use and the safety and efficacy of CAR-T. Methods: Following Institutional Review Board approval, we retrospectively analyzed NHL patients receiving commercial CD19-targeted CAR-T across Mayo Clinic sites (Arizona, Florida, and Minnesota) between October 2017 and May 2023. Demographics, labs, and post CAR-T events were collected. Electronic medical records were reviewed for G-CSF exposure within Day 1 - 100 post-CAR T. Differences by G-CSF status were examined using a Chi-square test and Kruskal Wallis tests. Hazard ratios (HR) and 95% confidence intervals (CI) for overall survival (OS) were calculated using Cox model. Results: Among 270 CAR-T patients; 106 received G-CSF within 30 days and 164 did not. Median age was 56.9 with G-CSF and 58.3 without G-CSF. Most were male (75.2% G-CSF, 62.6% no G-CSF). Diffuse large B cell lymphoma was the predominant NHL subtype (67.0% G-CSF, 65.2% no G-CSF). G-CSF within 30 days was not associated with reduced incidence of neutropenic fever (11.7% G-CSF vs 9.9% no G-CSF, p = 0.6593) or documented infection (22.1% vs 18.3%, p = 0.4439). G-CSF correlated with decreased profound neutropenia duration (ANC < 100 μL, 0 vs 2 days, p < 0.0001) and incidence within 30 days ( 31.7% vs 60.4%, p < 0.0001) as well as incidence of protracted profound neutropenia (> 7 days, 3.8% vs 22.8%, p < 0.0001). G-CSF was associated with a higher incidence of cytopenias between days 30 -100: severe neutropenia (ANC < 500/uL, 28.8% vs 15.2%, p = 0.0075), severe anemia (Hb < 8 g/dL, 21% vs 9.7%, p = 0.0114), and severe thrombocytopenia (Plt < 50 g/L, 35.2% vs 20.9%, p = 0.0099). Logistic regression analysis showed that none of the examined covariates, including prior autologous stem cell transplant, ECOG PS score, and receipt of bridging therapy, were associated with severe neutropenia likelihood. G-CSF was associated with a higher CRS incidence (89.6% vs 79.9%, p = 0.0343), but grade 3 CRS or higher (4.7% vs 3.7%, p = 0.6675) was no different. No difference in complete response rates (66% vs 61.1%, p = 0.4707) or 2-year OS (p = 0.523) was observed between the 2 groups. Conclusion: G-CSF within 30 days was associated with reduced duration and incidence of profound neutropenia without a significant impact on incidence of neutropenic fever or documented infections. There was a signal of association between G-CSF and increased incidence of low-grade CRS and delayed cytopenias (day 30-100) that warrants confirmation in larger studies. Citation Format: Lay She Ng, Claire I. Yee, Radhika Bansal, Mohamed A. Kharfan-Dabaja, Grzegorz S. Nowakowski, Allison C. Rosenthal, Javier Munoz, Januario Castro, Wern Lynn Ng, Hemant S. Murthy, Yi Lin, Matthew R. Buras, Madiha Iqbal, Yucai Wang, Talal Hilal. Impact of G-CSF on safety and efficacy of CAR T-cell therapy in non-Hodgkin lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6327.

Transient acute kidney injury after chimeric antigen receptor T-cell therapy in patients with hematological malignancies.

Acute kidney injury (AKI) occurs in 30% of patients infused with chimeric antigen receptor (CAR) T-cells. The purpose of this study was to identify risk factors and long-term outcomes after AKI in patients who received CAR T-cell therapy. Medical records of 115 adult patients with R/R hematological malignancies treated with CD19-targeted CAR T-cells at Vall d'Hebron University Hospital between July 2018 and May 2021. Baseline demographic data including age, gender, ethnicity, body mass index (BMI), and co-morbidities, as well as the type of hematological neoplasia and prior lines of therapy were collected. Laboratory parameters including serum creatinine and whole blood hemoglobin were retrospectively reviewed and values were gathered for days +1, +7, +14, +21, and +28 post-infusion. A total of 24/115 (21%) patients developed AKI related to CAR T-cell therapy; 6/24 with AKI over chronic kidney disease (CKD). Two patients had AKI in the context of lymphodepleting (LD) chemotherapy and the other 22 after CAR T-cell infusion, starting at day+1 in 3 patients, day+7 in 13 patients, day +14 in 1 patient, day+21 in 2 patients, and day+28 in 3 patients. Renal function was recovered in 19/24 (79%) patients within the first month after infusion. Male gender, CKD, cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS) were associated with AKI. Male gender, CKD, ICANS grade ≥3 and CRS grade ≥2 were identified as independent risk factors for AKI on multivariable analysis. In terms of the most frequent CAR T-cell related complications, CRS was observed in 95 (82%) patients and ICANS in 33 (29%) patients. Steroids were required in 34 (30%) patients and tocilizumab in 37 (32%) patients. Six (5%) patients were admitted to the intensive care unit (1 for septic shock, 4 for CRS grade ≥2 associated to ICANS grade ≥2, and 1 for CRS grade ≥3). A total of 5 (4.4%) patients died in the first 30 days after CAR T-cell infusion for reasons other than disease progression, including 4 cases of infectious complications and 1 of heart failure. Our results suggest that AKI is a frequent but mild adverse event, with fast recovery in most patients.

Streamlined measurement of chimeric antigen receptor T-cell concentration, size, viability and two-color phenotyping during manufacturing

Background aimsThe successful development of CD19-targeted chimeric antigen receptor (CAR) T-cell therapies has led to an exponential increase in the number of patients recieving treatment and the advancement of novel CAR T products. Therefore, there is a strong need to develop streamlined platforms that allow rapid, cost-effective, and accurate measurement of the key characteristics of CAR T cells during manufacturing (i.e., cell number, cell size, viability, and basic phenotype). MethodsIn this study, we compared the novel benchtop cell analyzer Moxi GO II (ORFLO Technologies), which enables simultaneous evaluation of all the aforementioned parameters, with current gold standards in the field: the Multisizer Coulter Counter (cell counter) and the BD LSRFortessa (flow cytometer). ResultsOur results demonstrated that the Moxi GO II can accurately measure cell number and cell size (i.e., cell volume) while simultaneously assessing simple two-color flow cytometry parameters, such as CAR T-cell viability and CD4 or CAR expression. ConclusionsThese measurements are comparable with those of gold standard instruments, demonstrating that the Moxi GO II is a promising platform for quickly monitoring CAR T-cell growth and phenotype in research-grade and clinical samples.

Early evaluation of CAR-T cell therapy response in R/R DLBCL patients using 18F-FDG PET/CT.

CD19-targeted chimeric antigen receptor T (CAR-T) cell therapy provides a durable response in patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). The role of fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) for early evaluation of response in patients with that immunotherapy was evaluated. Three separate 18F-FDG PET/CT examinations of 53 patients (29 males, 24 females; median 62 years old) with R/R DLBCL were conducted; before bridging therapy [time of decision (TD)], before CAR-T (tisagenlecleucel, n=37; lisocabtagenemaraleucel, n=16) infusion [time of CAR-T infusion (IT)], and one month (M1) after CAR-T infusion. Response was evaluated based on the Deauville 5-point scale and Lugano criteria. Among 21 patients (39.6%) with complete metabolic response (CMR) at IT-PET, 20 were able to continue CMR, while one showed progression at M1-PET. Among 32 patients (60.4%) with non-CMR at IT-PET, 12, 8, 4, and 8 showed CMR, partial metabolic response (PMR), (non-metabolic response (NMR), and progressive metabolic disease (PMD), respectively, at M1-PET as compared with IT-PET. Evaluations of M1-PET as compared with baseline TD-PET indicated 32, 7, 5, and 9 patients with CMR, PMR, NMR, and PMD, respectively. After a median 10.1 months, 26 patients showed progression and 13 had died from DLBCL. The 32 who achieved CMR showed significantly longer progression-free (P<0.0001) and overall survival (P<0.0001) periods as compared to the 21 non-CMR patients. Fluorine-18-FDG PET/CT findings obtained one month after CAR-T cell therapy showed accuracy for early response evaluation and prediction of progression in patients with R/R DLBCL.

Low-Dose Targeted Radioimmunotherapy (Iomab-ACT) Achieves Lymphocyte and Monocyte Depletion Prior to CD19-Targeted CAR T-Cell Therapy for Relapsed of Refractory B-Cell ALL or DLBCL with Minimal CRS and Icans

Low-Dose Targeted Radioimmunotherapy (Iomab-ACT) Achieves Lymphocyte and Monocyte Depletion Prior to CD19-Targeted CAR T-Cell Therapy for Relapsed of Refractory B-Cell ALL or DLBCL with Minimal CRS and Icans

T-Cell Large Granular Lymphocyte Population Involving Chimeric Antigen Receptor-Modified T (CAR T) Cells in Patients with Cytopenia after CD19-Targeted CAR T-Cell Therapy: Case Series

T-Cell Large Granular Lymphocyte Population Involving Chimeric Antigen Receptor-Modified T (CAR T) Cells in Patients with Cytopenia after CD19-Targeted CAR T-Cell Therapy: Case Series

Comment on: Rescue therapy of antisynthetase syndrome with CD19-targeted CAR-T cells after failure of several B-cell depleting antibodies.

Comment on: Rescue therapy of antisynthetase syndrome with CD19-targeted CAR-T cells after failure of several B-cell depleting antibodies.

Low-Frequency PPM1D Gene Mutations Affect Treatment Response to CD19-Targeted CAR T-Cell Therapy in Large B-Cell Lymphoma.

Chimeric antigen receptor T (CAR T)-cell therapy has become a standard treatment option for patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL). Mutations in the PPM1D gene, a frequent driver alteration in clonal hematopoiesis (CH), lead to a gain of function of PPM1D/Wip1 phosphatase, impairing p53-dependent G1 checkpoint and promoting cell proliferation. The presence of PPM1D mutations has been correlated with reduced response to standard chemotherapy in lymphoma patients. In this study, we analyzed the impact of low-frequency PPM1D mutations on the safety and efficacy of CD19-targeted CAR T-cell therapy in a cohort of 85 r/r DLBCL patients. In this cohort, the prevalence of PPM1D gene mutations was 20% with a mean variant allele frequency (VAF) of 0.052 and a median VAF of 0.036. CAR T-induced cytokine release syndrome (CRS) and immune effector cell-associated neuro-toxicities (ICANS) occurred at similar frequencies in patients with and without PPM1D mutations. Clinical outcomes were globally worse in the PPM1D mutated (PPM1Dmut) vs. PPM1D wild type (PPM1Dwt) subset. While the prevalent treatment outcome within the PPM1Dwt subgroup was complete remission (56%), the majority of patients within the PPM1Dmut subgroup had only partial remission (60%). Median progression-free survival (PFS) was 3 vs. 12 months (p = 0.07) and median overall survival (OS) was 5 vs. 37 months (p = 0.004) for the PPM1Dmut and PPM1Dwt cohort, respectively. Our data suggest that the occurrence of PPM1D mutations in the context of CH may predict worse outcomes after CD19-targeted CAR T-cell therapy in patients with r/r DLBCL.

CD19-Targeting CAR T-Cell Therapy in Transformed Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma: A Descar-T and US Collaborative Study

Introduction: Patients with histological transformation (HT) of Waldenström macroglobulinemia (WM) who relapse or are refractory (R/R) have a poor prognosis with standard chemoimmunotherapy, notably patients who are unable to undergo high dose chemotherapy (HCT) and autologous stem cell transplantation (ASCT) or who relapse after HCT/ASCT. CD19-targeted chimeric antigen receptor (CAR) T-cell therapies can lead to durable responses in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and thus may represent a promising therapeutic option in R/R transformed WM (tWM); however, data from pivotal trials is lacking. This study aimed to evaluate the efficacy and safety of anti-CD19 CAR T-cells in real-word patients with R/R tWM. Methods: We retrospectively identified patients with biopsy-proven transformed WM/lymphoplasmacytic lymphoma treated with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) in the French DESCAR-T registry (NCT04328298) and 2 US centers. The primary endpoint was best complete response rate (CRR). Secondary outcomes were best overall response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety. Responses were assessed according to the Lugano 2014 criteria at 1 month, 3 months and 6 months. Subsequent assessments were per institutional pratice. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to the ASTCT 2019 consensus criteria. Hematological toxicity and infections were graded according to the NCI CTCAE (version 5.0). Results: Between June 2017 and May 2023, 22 patients (18 from DECAR-T centers and 4 from US centers) with R/R tWM were treated with anti-CD19 CAR T-cells (13 axi-cel and 9 tisa-cel). Median age at WM diagnosis was 58 years (range 35-72). MYD88 L265P and CXCR4 mutations were present in 85% (11/13) and 29% (2/7) of patients with available data, respectively. Patients received a median of 1 prior line of treatment (range, 0-4) for WM and 2 prior lines (range, 1-4) for HT. Eight patients had received prior ASCT (2 for WM and 6 for HT) and 1 patient allogeneic SCT. The median time from WM to HT diagnosis was 4.5 years (range, 0-32) and 26 months (range, 3-90) from HT diagnosis to CAR T infusion. Of note, CNS involvement was present in 3 patients at DLBCL relapse before CAR T-cell therapy. At time of infusion, the median age was 66 years (range, 41-82) and 8 patients (36%) were older than 70 years. Median Eastern Cooperative Oncology Group (ECOG) was 1 (range, 0-2). Bridging therapy was administered to 16 patients (73%). Following bridging therapy, 6 patients had progressive disease (PD), 4 stable disease (SD) and 6 were responders (2 complete responses (CR) and 4 partial responses (PR)). After CAR T-cell infusion, best CRR was 82% and best ORR was 95%. The ORR/CRR was 95%/77% at 1 month, 76%/71% at 3 months and 68%/68% at 6 months. Seventeen patients (78%) experienced CRS, including 2 grade 3 (all after axi-cel), and 9 ICANS occurred (41%), including 1 grade 3 and 1 grade 4 (all after axi-cel). Eight patients (36%) presented infections, including 3 grade 3 and 1 grade 4. Neutropenia was reported in 78% (grade 3-4 = 68%), thrombocytopenia in 86% (grade 3-4 = 45%) and anemia in 86% (grade 3-4 = 32%) of patients. After a median follow-up of 17 months (range, 1-47), the 1-year PFS and OS were 70% and 84% respectively (figure). Five deaths were reported, 4 due to progressive disease and 1 from SARS-CoV-2 infection. Conclusion: This study shows a high efficacy of anti-CD19 CAR T-cell therapy in R/R tWM with no unexpected toxicity. Longer follow-up is needed to confirm the long-term efficacy of CAR T-cells in tWM.

Phase 2 Study of CD19 CAR T Cells with a Fully Human Binder for Large B-Cell Lymphoma in Relapse or Progression after a Murine Binder-Bearing CD19 CAR T-Cell Therapy

BACKGROUND T cells engineered with a CD19-targeted chimeric antigen receptor (CD19 CAR T cells) have revolutionized the treatment of high-risk, relapsed, or refractory large B-cell lymphoma (LBCL), but durable responses are only achieved in 30-40% of patients (pts). Outcomes are dismal in case of disease recurrence after CD19 CAR T-therapy; in this situation we have previously reported low efficacy and limited duration of response after a second infusion of the same CD19 CAR T-cell product (Gauthier, Blood, 2022). We observed that repeat CD19 CAR T-cell infusions were impaired by CD8+ T-cell responses against murine amino acid sequences located in the single chain variable fragment (scFv) of the CAR, which led to rapid immune rejection of CAR T cells. We hypothesized that CAR T cells engineered with a fully human scFv could circumvent anti-murine scFv immune responses in pts previously exposed to murine scFv-bearing CAR T cells. We report our phase 2 clinical trial results investigating treatment with fully human scFv-bearing CD19 CAR T cells (JCAR021) in R/R LBCL pts with relapsed or progressive disease after murine scFv-bearing CD19 CAR T-cell therapy. METHODS Pts with R/R LBCL were enrolled at the Fred Hutchinson Cancer Center on a phase II study (NCT03103971). Key eligibility criteria included: i) relapsed disease after complete response (CR) to prior CD19-targeted non-JCAR021 CAR T-cell therapy or persistent disease after partial response to prior CD19-targeted non-JCAR021 CAR T-cell therapy; ii) CD19-positive disease since completing the prior CD19-targeted CAR T-cell therapy. Pts received lymphodepletion (LD) with cyclophosphamide 300 mg/m2/d and fludarabine 30 mg/m2/d for 3 days. Cytokine release syndrome (CRS) and neurotoxicity (NT) were graded according to the Lee 2014 criteria and CTCAE v4.03 criteria, respectively. Disease response was evaluated at day +28 after JCAR021 infusion per PET-CT Lugano criteria. The planned sample size and CAR T-cell dose were n=27 and 7x10 6 CAR T cells/kg, respectively. RESULTS Pt characteristics, and outcomes are shown in the Table. All eight screened pts were enrolled, received LD, and JCAR021 infusion. Median age at enrollment was 63 (range: 41-77). Prior to lymphodepletion, 4 pts (50%) had bulky disease (largest lesion ≥5cm). All pts had extranodal disease. We observed elevated LDH prior to lymphodepletion in 6 pts (75%). Median prior lines of therapy was 5 (range: 3-7). Prior CD19 CAR T-cell product type was lisocabtagene maraleucel, n=4 (50%); axicabtagene ciloleucel, n= 3 (37%); or tisagenlecleucel, n=1. Response to the prior CD19 CAR T-cell therapy was CR in 5 pts (62%) and PR in 3 pts (38%). Median time from the first CAR T-cell infusion to relapse or progression was 165 days (range 49-434). Median time from the first CAR T-cell infusion to JCAR021 infusion was 304 days (range: 202-603). JCAR021 was administered at the dose of 7x10 6 (n=6, 75%) or 2x10 6 CAR T-cells/kg (n=2, 25%; dose reduction due to grade 5 NT in subject #6). We observed all-grade CRS in 4 pts (50%; grade 1, n=2; grade 2, n=2 not requiring vasopressors) and NT in 1 patient (dose limiting toxicity, grade 5 NT from intracerebral hemorrhage with concurrent acute kidney injury and toxic encephalopathy). At day+28 responses were seen in 3 of 8 pts (37%; CR, n=2; PR, n=1), all of whom received 7x10 6 CAR T-cells/kg. Two pts in CR after JCAR021 had bulky disease and elevated LDH prior to LD. In both pts, the prior CD19 CAR T-cell therapy had induced CR lasting ≥ 6 months. In the two evaluable responders (death in CR, n=1), we observed disease relapse or progression within 3 months. Median overall survival was 105 days (95%CI, 92-NA). We measured expansion of JCAR021 CAR T-cells in all pts. Exploratory analyses showed lower in vitro CAR T-cell expansion during manufacturing (fold expansion of CD8+ CAR T-cells, p&amp;lt;0.001) and lower in vivo CAR T-cell expansion (peak CD8+ CAR-T, p=0.002; AUC day0-28, p=0.01; JCAR021 dose, 7x10 6/kg) compared to pts receiving JCAR021 as their first CD19 CAR-T product (CAR-naïve cohort). CONCLUSION In LBCL pts with disease relapse or progression after a first CD19 CAR T-cell therapy, we observed low response rates and lack of durable responses after treatment with the fully human scFv-bearing product JCAR021, prompting early study termination. Lower CAR T-cell expansion during manufacturing in CAR-exposed pts suggest pre-existing T-cell dysfunction as a potential mechanism of failure.

Acalabrutinib in Combination with Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy in Relapsed/Refractory B-Cell Lymphoma: A Phase I/II Study of Safety, Efficacy and Immune Correlative Analysis

Introduction Limitations of effective CD19-targeted chimeric antigen receptor T-cell therapy (CAR-T) in relapsed/refractory (R/R) B-cell lymphoma include inability to control disease prior to CAR-T, lack of sustained remissions following CAR-T and the potential for life-threatening adverse effects such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). BTK inhibitors, ibrutinib and acalabrutinib are immunomodulatory and may enhance CAR-T expansion, engraftment and tumor clearance while decreasing the frequency and severity of CRS in chronic lymphocytic leukemia (Qin, et al. J Immunother 2020). Based on this, we hypothesized that acalabrutinib, when combined with CD19-targeted CAR-T, could enhance its efficacy and safety and may also serve as an effective bridging strategy. We report the initial safety, efficacy and correlative analysis of acalabrutinib in combination with axicabtagene ciloleucel (axi-cel) in R/R B-cell lymphoma. Methods We conducted a phase I/II, open-label trial (NCT04257578) involving adult patients meeting FDA-approved criteria for axi-cel; this included patients with R/R CD19+ large B-cell (LBCL) and follicular lymphoma (FL) with measurable disease. Acalabrutinib was continuously administered at 100 mg twice daily over the 3 study phases: 1) Bridging: Starting between 3 weeks and 24 hours prior to leukapheresis until lymphodepletion (LD), 2) Cell therapy: From LD to 30 days after axi-cel infusion, 3) Maintenance: From 30 days to 1 year after axi-cel infusion or until unacceptable toxicity or disease progression (Figure 1). Axi-cel was administered per institutional practice. The primary endpoint was safety based on rates of grade ≥3 CRS or ICANS within 30 days of axi-cel infusion. We also assessed bridging success rate (defined as receipt of axi-cel without any additional required treatment), overall response rate (ORR) and complete response (CR) rate following axi-cel infusion, progression-free survival, overall survival and immune response biomarkers. Results As of July 28, 2023, 17 patients have enrolled, 14 have received axi-cel infusion and are evaluable for response to CAR-T and 3 are earlier in treatment. Fourteen patients had LBCL (12 DLBCL [4 with double/triple hit, 3 with double/triple expressor, 1 with only MYC translocation] and 2 PMBCL) and 3 had FL (Table 1). Median age was 58 (range 34-74) years, largest lesion diameter was a median of 3.75 (1.7-7.1) cm and the median number of prior regimens was 3 (range 1-5). Of LBCL patients, 6 (43%) had primary refractory disease and 5 (38%) had relapsed within 12 months of initial therapy; 4 (31%) patients had previous autologous stem cell transplant. Fourteen of 15 patients (93%) who underwent axi-cel infusion were successfully bridged from prior to leukapheresis to LD with single agent acalabrutinib and no additional therapy; 1 received added radiation. After cell infusion, 13 (93%) and 8 (57%) patients had any grade CRS and ICANS, respectively. Three (20%) patients had grade 3 ICANS which resolved with dexamethasone and anakinra or tocilizumab. No patients received prophylactic dexamethasone. No patients experienced grade ≥3 CRS or any grade hemorrhage or tachyarrhythmia. No patients discontinued acalabrutinib at any time due to toxicity, meeting an interim safety endpoint. The ORR and CR rate at day 30 post axi-cel infusion was 93% and 71%, respectively. Through post axi-cel maintenance, there were no drug holds. One of the 3 patients with partial remission (PR) at day 30 converted to CR at day 180 post infusion while 2 suffered disease progression at day 90 post axi-cel infusion. No treatment related deaths were observed by time of data cutoff. At a median follow-up of 13.8 (range 1.7-29.1) months, 10 (73%) patients are alive and 9 are progression-free. Post axi-cel cytokines peaked at a median of day 6 [median IL-6 196 pg/ml (range 20-11803), ferritin 425 ng/ml (156-2051), CRP 52.9 mg/L (7.7-239.7), Table 1]. Impact of acalabrutinib on myeloid derived suppressor cells and the immunosecretome profile are underway and will be reported at time of presentation. Conclusions Acalabrutinib successfully bridged most patients in this trial when given concurrently with axi-cel and safely maintained high CR rates. CRP and ferritin levels were typically only modestly elevated after cell infusion. Severe CRS was not observed and high-grade ICANS was uncommon.

Efficacy of Chimeric Antigen Receptor T-Cell Therapy Is Not Impaired By Previous Bispecific Antibody Treatment in Patients with Large B-Cell Lymphoma

Introduction: Potential T-cell exhaustion after bispecific antibody (BsAb) treatment remains an open question, raising the theoretical concern that prior BsAb exposure could affect subsequent chimeric antigen receptor (CAR) T-cell efficacy. Clinical data on CAR T-cell outcomes after prior BsAb treatment in the setting of large B-cell lymphoma (LBCL) are scarce and highly awaited to better define treatment sequencing in relapsed/refractory (R/R) patients. Methods: We conducted a retrospective, international study including R/R LBCL patients treated with CD19-targeted CAR T-cells at 15 centers between July 2018 and January 2023 who had been exposed to BsAbs prior to apheresis. Then, we identified a control cohort from patients included in the DESCAR-T Registry (n=764). We carried out a 1:1 propensity score matching (PSM) to achieve balance between cohorts; 13 baseline covariates were included in the PSM. We compared response rates, survival outcomes and toxicity after CAR T-cell therapy, according to previous BsAb exposure. Results: We identified 47 LBCL patients who received BsAb therapy prior to CAR T-cell apheresis. Median age was 65 years (range 31-82), with a male predominance (66%), and median prior lines of therapy before BsAb were 2 (IQR 2-3) (Table). The BsAbs targeted CD20/CD3 (91%) or CD22/CD3 (9%), either in monotherapy (n=41, 87%) or in combination with other agents (n=6, 13%) (lenalidomide [n=2], polatuzumab [n=1], chemotherapy [n=2], missing [n=1]). The median time on BsAb treatment was 98 days (IQR 56-160) with a best overall (complete) response rate (ORR [CRR]) of 47% (19%). Median progression-free survival (PFS) and duration of response (DOR) were 3.1 months (95% CI 2.7-4.4 months) and 8.8 months (95% CI 2.2-NR), respectively. Cytokine release syndrome (CRS) occurred in 59% of patients (grade 3 in 4%). No neurologic toxicity (NT) was reported. In 26 (55%) patients, bispecific antibody was the last line before CAR T-cell therapy. Median washout between the last BsAb dose and lymphocyte apheresis for CAR T-cell manufacturing was 43 days (range 34-103 days). In terms of the subsequent CAR T-cell therapy, patients received axi-cel (n=22, 47%), tisa-cel (n=20, 43%) or liso-cel (n=5, 11%). Most patients developed CRS after infusion (79%, 6% grade &amp;gt;2), with a low rate of NT (23%, 2% grade &amp;gt;2). Neutropenia and thrombocytopenia grade &amp;gt;2 were reported in 66% and 45% of patients, respectively. Regarding efficacy, ORR after infusion was 83% (CR 43%). Median PFS and overall survival (OS) were 6.6 months (95% CI 2.6-not reached [NR]) and NR (95% CI 9.0-NR), respectively. The rate of overall (complete) response was similar between patients who had previously responded (CR or PR) or not (SD or PD) to BsAb therapy (82% [41%] vs 84% [44%], respectively, p=0.64). However, all 9 patients achieving CR after BsAb achieved subsequent response to CAR T-cells. Given the wide variability in the washout between last BsAb dose and lymphocyte apheresis, we evaluated the impact of this interval on CAR T-cell efficacy. The 6-month PFS and OS of patients previously exposed to BsAb within 45 days of lymphocyte apheresis was similar to patients who had a longer washout (59% vs 47% [p=0.25] and 83% vs 67% [p=0.21], respectively). In the second part of the analysis, we matched our cohort with a control group of CAR T-cell recipients not previously exposed to BsAbs. The final analysis included 2 sets of 42 patients with comparable characteristics. Median follow-up from CAR T-cell infusion was 11.5 months for the BsAb cohort (CI 95% 6.4-19.0 months) and 18.8 months for the control cohort (CI 95% 10.9-23.0 months). Patients with previous BsAb exposure showed a similar PFS (p=0.10, Figure) and OS (p=0.08) after CAR T-cell infusion in comparison to the control group. In terms of toxicity, there were no differences in the incidence of CRS (p=0.41) or NT (p=1.0) after infusion. Conclusions: Previous exposure to bispecific antibody treatment targeting different antigens does not have a negative impact on survival outcomes after CAR T-cell therapy. Lack of response to a previous BsAb does not predict for lower response rates after CAR T-cell infusion.

Multiplex Genome Editing of Human T Cells with Innovative Transformer Base Editor (tBE) for Construction of Next Generation CAR-T Therapies

Autologous chimeric antigen receptor T (CAR-T) cell therapy has achieved great success for antitumor treatments especially against hematological malignancies, and several autologous CAR-T therapies have been approved around the world. However, high manufacturing cost and long manufacturing process hinder the broader application of autologous CAR-T cell therapy. As a result, off-the-shelf universal CAR-T cell therapy with donor derived healthy T cells is of great interest and under development by many companies globally. Gene editing technologies including TALENs, CRISPR/Cas nucleases and base editors are of great potential in T cell engineering for allogeneic T cell therapy. The innovative transformer base editor (tBE) is a base editing system that avoids to cause DNA double strand breaks (DSBs) and exhibits higher editing efficiency, no detected off-target mutations and lower cytotoxicity. Due to its capability to avoid off-target mutations and DSB-caused chromosomal translocations, tBE is potentially one of the best gene editing tools to induce multiplex editing in cells. Here we show that the tBE was used to induce highly efficient single or multiplex gene editing in primary human T cells. With optimized electroporation conditions for tBE, TRAC, CD52 and PDCD1 could be knocked out simultaneously with editing efficiency up to ~90% for each target gene. tBE triggered no detected off-target mutation or chromosomal abnormalities, which were reported in the cases of CRISPR/Cas- or TALEN-mediated multiplex editing. CD19-targeted CAR-T cells with triplex base editing exhibits enhanced antitumor efficacy in vitro and in mouse models compared with unedited CAR-T cells. Our results demonstrated the application of tBE for construction of next generation universal or enhanced CAR-T therapies.

CD19-Targeted CAR-T Cells in Refractory Systemic Autoimmune Diseases: A Monocentric Experience from the First Fifteen Patients

Background: CD19-targeting chimeric antigen receptor (CAR) T cells are highly efficient in B cell malignancies. However, CD19 CAR T cells also target autoreactive B cells that trigger autoimmune diseases (AID) including systemic lupus erythematosus (SLE), idiopahtic inflammatory myositis (IIM) and systemic sclerosis (SSc). Achieving long-term remission in AID with standard therapy remains challenging and usually necessitates long-term treatment. Aim: To test whether CD19 CAR T cells achieve a deeper reset of B cells, eradicate autoimmunity, and achieve lasting drug-free remission in autoantibody-dependent AID. Methods: Patients with treatment-refractory SLE, IIM and SSc were eligible if they had signs of active organ involvement, failure of multiple immunomodulatory therapies, and serious or immediately life-threatening disease. CAR T cell therapy was offered via an expanded access program. Autologous CD19 CAR T cells MB-CART19.1 were produced with the Miltenyi prodigy platform. After leukapheresis on day -13, manufacturing commenced in house and lymphodepletion was started with fludarabine 25 mg/m2/d intravenously (i.v.) on days -5 to -3 and cyclophosphamide 1000 mg/m2/d i.v. on day -3. On day 1, all patients received 1x106 CAR T cells / kg body weight. Results: 15 patients (8 SLE, 4 SSc, and 3 IIM) were apheresed and were treated with a single infusion of CD19 CAR T cells. Median disease duration before CAR T was 3 years [1-20], median follow-up after CAR T was 12 months [2-28]. All patients failed on a median of 5 [2-14] previous treatments. Except for a maximum of 10 mg prednisolone daily, all immunomodulatory drugs were stopped prior to leukapheresis. After infusion, CAR T cells rapidly expanded till day 8.6 ± 0.8. CD19+ B cells were rapidly eliminated from peripheral blood after a mean of 5.9 ± 2.2 days. In 12/15 patients, B cells reoccurred at day 111±50. The last three patients with 77, 51 and 16 days follow-up are still B cell aplastic. All 8 SLE patient reached a complete remission after 3 months and maintain a SLE Disease Activity Index (SLEDAI) of 0 since. 3/3 IIM patients experienced major improvement and normalization of CK after 3 months which is ongoing. Of 4 SSc patients, 3 patients with &amp;gt;3 months follow-up show a decreased disease activity by EULAR AI by -4.3 [-4.3; -3.6]. All 15 patients entirely stopped immunosuppressive drugs. Overall safety of CAR T Cell therapy in AID was very favourable with cytokine-release syndrome (CRS) of grade 0 in 4, grade 1 in 10, and grade 2 in 1 patient. 6/15 patients received tocilizumab. One grade 1 immune-effector cell associated neurotoxicity syndrome (ICANS) presented as vertigo two weeks after CAR T infusion. No prolonged (&amp;gt;28 days) bone marrow suppression occurred. The Five SLE patients with a follow-up of 14-24 months stayed in remission despite reconstitution of B cells. In line, complement factor C3 stayed normal, proteinuria remained absent or at very low levels, and autoantibody seroconversion persisted. IgG responses to standard vaccines remained stable up to month 24 and were boosted by re-vaccination. Total B cell numbers gradually increased to a median of 230 cells/µl [183; 886] at month 12 and were mostly of a naïve phenotype. The early drop of CD19+CD27+ memory B cells increased again at month 12 indicating maturation of the B cells emerging after CAR T treatment. Conclusion: CD19 CAR T cells induce persistent, drug-free remission in three distinct autoantibody dependent AID with very good tolerability. Though hypothetical cure appears possible, longer follow up is needed. This unprecedented drug-free remission is remarkable as B cells functionally reconstitute. An investigator-initiated trial is currently expanding our experience of efficacy and safety.

Clinical Utility of Circulating Tumor (ct)DNA Quantity and Kinetics in Patients Undergoing CAR T-Cell Therapy for Relapsed/Refractory Aggressive B-Cell Lymphoma

Background: CD19-targeted CAR T-cells are approved for relapsed and/or refractory (RR) aggressive B-cell lymphomas. While some patients experience durable remissions, others do not respond or relapse. Improved patient selection and early identification of patients who may need additional therapies are thus necessary. ctDNA is a promising biomarker for prognostication in DLBCL and has the potential to guide therapeutic decisions. We aimed to explore the possible clinical utility of ctDNA quantitation in patients with aggressive B-cell lymphomas undergoing CAR T-cell therapy. Methods: Twenty-eight patients undergoing CAR T-cell therapy as part of standard of care pathways for RR aggressive B-cell lymphoma were included. Pre- and post-CAR T-cell infusion ctDNA samples were retrospectively analyzed with a panel of over 400 genes relevant to B-NHL using a modified version of the AVENIO ctDNA analysis workflow (Roche; Research Use Only) based on the previously described CAPP-Seq workflow (Kurtz, J Clin Oncol 2018). Peripheral blood was used as a source of germline DNA to allow selection of tumor-specific variants in the ctDNA. ctDNA levels were expressed as mean mutant molecules per mL (MMPM) and ctDNA clearance was determined using a detection cutoff of p = 0.005. ctDNA results were correlated with clinical findings and outcomes including response rate, PFS and OS. Results: Eighteen male and 10 female patients were included in the analysis (median age 63). Sixteen (57%) patients had a diagnosis of DLBCL while the remainder had transformed FL or MZL (n=6), HGBL (n=4) and PMBL (n=2). Seventeen patients were treated with tisagenlecleucel and 11 with axicabtagene ciloleucel. Twenty-five (89%) patients had stage III or IV disease and 15 (54%) patients had ≥3 lines of prior therapy. The median number of tumor-specific variants in baseline ctDNA samples was 31 (range 1-252). ctDNA levels correlated with metabolic tumor volumes across all time points (Spearman r=0.69, p&amp;lt;0.0001). There was a greater reduction in ctDNA quantity observed in those who achieved CR/PR (n=21) at day 28 vs those who progressed (n=7) (median MMPM log-fold reduction 1.3 vs -0.9). Baseline ctDNA quantity was significantly higher in those with an elevated LDH pre-lymphodepletion compared to those with a normal LDH (median MMPM 228.5 vs 7.6, p = 0.0003). Survival also correlated with baseline ctDNA measurement with patients with a ctDNA quantity above the median of the cohort having a significantly shorter OS compared to those below the median (median OS 6.7 mo vs not reached, p=0.0012). Four patients had no detectable ctDNA at day 28 post CAR T-cell infusion including 1 patient with pseudoprogression on imaging (SUVMax 10) who had no evidence of lymphoma on biopsy and remained in CR. Of the 4 patients who were ctDNA negative at day 28, 3 remained in long-term remission. In summary, measurement of ctDNA quantity and kinetics shows promising clinical utility in the context of CAR T-cell treatment for aggressive B-cell lymphoma including prediction of outcome and resolving radiological pseudoprogression. Larger prospective cohorts and standardized methodological approaches are required to optimize predictive thresholds for clinical outcomes.

The Bengaluru Score - a Prognostic Predictive Score for Clinical Efficacy Outcomes Based on Discovery Cohort of Patients Treated with Varnimcabtagene Autoleucel (IMN-003A) in the Phase-2 (IMAGINE) Study

Background: Recurrence of disease is seen in some patients post CD19 targeted CAR-T cell therapy. There is a need to develop CAR-specific efficacy risk-classification systems as established parameters of disease relapse are not predictive. In the Phase-2 IMAGINE study, multiple variables that may predict clinical outcomes were studied and the relevant clinical, laboratory and translational information were integrated. This abstract reviews the development of the Bengaluru Score as a predictive prognostic score for clinical efficacy outcomes based on discovery cohort of patients treated with varnimcabtagene autoleucel (IMN-003A). Methods: Multiple characteristics for disease progression were reviewed (n=36) and risk stratified as: 1) Baseline parameters (age, lines of treatment, bridging therapy, cytogenetics, blasts, total metabolic tumour volume (TMTV), sum of perpendicular diameter (SPD), refractory, relapse within 6m, laboratory parameters - haemoglobin, neutrophil count, lymphocyte count, platelet count, CRP, LDH, ferritin, baseline interleukin-6 (IL-6), baseline total T cells, CD4, and CD8 subsets in peripheral blood); 2) Apheresis (total T cells, naïve / central memory in CD4 and CD8 subsets); 3) Final Product characteristics [total CAR+ cells, naïve / central memory in CD4 and CD8 subsets, CD8 (naïve &amp; central memory subsets / tumour burden (TMTV and SPD), product doubling time] and 4) Post Infusion (CAR peak &amp; persistence, B cell aplasia, hypogammaglobulinemia, infections and intravenous immunoglobulin (IVIg) replacement). These parameters were analyzed using chi-square and appropriate multivariant odds ratio (OR) to examine the association with disease progression. Independent risk factors were identified and weighted score allocated for OR ≥10 to obtain a multifactorial prediction model - The Bengaluru Score. The specificity and sensitivity of this model was then studied in the discovery cohort. Results: In the IMAGINE study, with ORR 80.9% at primary endpoint (n=17/21) and median PFS not reached (range 12 to NR), relapse was seen in 37.5% (n=9/24) pts with median PFS of 178 days (range 28 to 319). Multivariant analysis of these parameters showed some statistical significance for following variables: Baseline Platelet count &amp;lt;200 x 10 9/L (overall); Final Product doubling time ≥1 day (B-ALL); Baseline SPD ≥2000 mm 2, Hb &amp;lt;12 g/dL, Platelet count &amp;lt;200 x 10 9/L and post infusion IVIg replacement (B-NHL), Of these variables, statistically significant association was seen with Final Product doubling time ≥1 day (B-ALL) and Baseline SPD ≥2000 mm 2 with Hb &amp;lt;12 g/dL and Platelet count &amp;lt;200 x 10 9/L (B-NHL). The impact of IVIg replacement on efficacy needs further study. A multiple factor-based prognostic score system - The Bengaluru Score was developed classifying patients into B-ALL low-risk (1 point) and high-risk (3 points) and for B-NHL low risk (&amp;lt;5 points) and high-risk (≥5 points), Table 1. The Bengaluru Score when applied to discovery cohort in the IMAGINE study was able to risk stratify patients for disease progression with Sensitivity, Specificity, Positive Predictive Value and Accuracy of 100.00%, 66.67%, 60.00% and 77.78% respectively (for B-ALL) and 100.00%, 100.00%, 100.00% and 100.00% respectively (for B-NHL), Table 2. Conclusions: The Bengaluru Score is probably the first predictive prognostic score for clinical efficacy outcomes and is based on multivariant statistical analysis in the discovery cohort of patients in the IMAGINE study integrating clinical, laboratory and translational data with a very high sensitivity, specificity and accuracy. The score highlights the role of overall T cell expansion in the final product for B-ALL (but not the T N+CM subsets on its own) and for B-NHL, disease burden and haematological reserve. This suggests that earlier use of varnimcabtagene autoleucel may positively influence efficacy outcome but needs to be proven in the real-world setting. The Bengaluru Score can guide informed treatment decisions and evolve clinical strategies, such as reinfusion, CAR-T targeting a different antigen or allogeneic transplant (if applicable), to reduce the risk of relapse / disease progression in high-risk patients. The Bengaluru Score needs validation in a larger cohort of patients following treatment with varnimcabtagene autoleucel and other CD19 targeted CAR-T cell therapies.