Immune Cell-associated Neurotoxicity Syndrome Research Articles

Addition of IL-6 and phosphate to the m-EASIX score and detection of ICANS and CRS progression.

e14511 Background: Cytokine release syndrome (CRS) and immune cell associated neurotoxicity syndrome (ICANS) can be severe complications of CAR-T infusion. Both syndromes have been associated with endothelial dysfunction which prompted prior use of a modified version of the Endothelial Activation and Stress Index (m-EASIX) to predict the occurrence of severe grades of ICANS and CRS. Recent studies have linked low phosphorous (P) levels to both syndromes, and IL-6 is a known mediator of both. Our study aimed to enhance early prediction of CRS and ICANS by integrating both P and IL-6 into the m-EASIX score. Methods: This retrospective study included 44 patients (26 male and 18 female) ranging from 42 to 86 years old with non-Hodgkin's lymphoma presenting to the University of Arizona Cancer Center for CAR-T treatment. P, CRP, IL-6, and LDH were recorded up to 7 days before and 14 days after CAR-T infusion. All platelet levels were recorded the day of infusion. Variations of the m-EASIX score as outlined in table 1 were then calculated. The values of P were cubed to ensure relative differences in P had proportional consistency to differences in other values. The scores were then used to generate ROC curves for the occurrence of CRS, ICANS, and the progression of CRS to grade ≥2 with CI generated through the Wilson/Brown method. Results: Of the 44 patients, 21 developed CRS alone, 12 developed ICANS+CRS, and 11 developed neither. 18 patients had progression of CRS to grade ≥2. The median day of onset for CRS, ICANS, and progression of CRS to grade ≥2 was 2, 5, and 4 days respectively. Day 3 post infusion yielded the highest values of area under the curve (AUC) with each variation of the m-EASIX score statistically significant with a p<0.001 as represented in table 1. The addition of P and IL-6 to the m-EASIX score increased AUC, sensitivity, and specificity for the occurrence of CRS, ICANS, and progression of CRS to grade ≥2. Conclusions: The inclusion of P and IL-6 in the m-EASIX score improved the sensitivity and specificity of detecting CRS, CRS progression, and the development of ICANS on the 3rd day post infusion. Larger scale studies investigating the efficacy of inclusion of P and IL-6 in the m-EASIX score in guiding early interventions to mitigate complications associated with CAR-T therapy are necessary. [Table: see text]

T-cell recruiting immunotherapies in B-cell lymphoma - the future backbone for all therapy lines?

The introduction of immunologically targeted therapies has represented a significant advancement in the treatment of B-cell lymphomas, particularly aggressive B-cell lymphoma. CD19 CAR-T cells such as Axicabtagen-Ciloleucel (Axi-cel) and Lisocabtagen Maraleucel (Liso-cel) have been approved since 2022 and 2023, respectively, for second-line therapy of Diffuse Large B-Cell Lymphomas (DLBCL), when there is primary refractory disease or relapse within 12 months after the end of first-line therapy. These therapies result in a significant improvement in progression-free survival compared to the previous standard therapy (salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation). Especially in elderly patients or patients with underlying medical conditions, CAR-T cell therapies like Axi-cel and Liso-cel demonstrate acceptable tolerability and high efficacy.Furthermore, bispecific T-cell-engaging antibodies ("bispecifics") such as Glofitamab, Epcoritamab, and Mosunetuzumab also represent promising treatment options for patients with relapsed disease after failure of second- or later line therapy and show efficacy even in a subset of patients relapsing after CD19 CAR-T cells. However, randomized study results for these substances are not yet available. They are expected to be used in earlier lines of therapy in the future, especially in combination with standard chemotherapy regimens. Common side effects of bispecific antibody therapies are cytokine release syndrome (CRS) and immune-mediated cytopenias, whereas immune-cell associated neurotoxicity syndrome (ICANS) is relatively rare compared to CD19 CAR T cells. In summary, bispecifics represent a novel, highly effective immunotherapy for the treatment of lymphomas with a very favourable toxicity profile.

A Phase 2, Single-Arm, Multicohort, Open Label, Multicenter Trial of Off-the-Shelf Natural Killer Cells (SAR445419) in Patients with High-Risk Myeloid Malignancies Undergoing Allogeneic HSCT

Background and Significance: Relapse remains the leading cause of treatment failure for patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although the risk depends on parameters such as age and conditioning intensity, relapse is experienced in 30-50% of patients after conventional HSCT in high-risk AML/MDS. Initial safety and post-HSCT relapse risk reduction results were reported in a phase I study of haploidentical (haplo) donor-derived natural killer (NK) cells expanded ex vivo on feeder cells expressing IL-21 and 4-1BBL in conjunction with haplo-HSCT (Ciurea et al, Leukemia, 2022). This study supported exploring SAR445419 (SAR'419), an off-the-shelf (OTS) product, derived from universal donor NK cells and expanded ex vivo in a feeder cell-free system using plasma membrane particles bearing membrane-bound IL-21 and 4-1BBL. Here, we aim to test whether SAR'419 can mediate an effective anti-leukemia response and reduce post-transplant relapse rate when administered in the peri-transplant period. Study Design and Methods: In this multicenter, multicohort, phase 2, single-arm trial (NCT05726682), patients with high-risk AML/MDS planned for allo-HSCT from matched sibling, matched unrelated or haplo donors will be enrolled in 2 cohorts. Cohort A will comprise patients aged 18‒65 years undergoing myeloablative conditioning with hematopoietic cell transplantation comorbidity index ≤3 and cohort B will comprise patients aged 18‒75 years undergoing reduced intensity conditioning. Patients with prior allogeneic transplantation or AML beyond first complete remission will be excluded from the study. Patients will undergo HSCT conditioning starting on Day ‒7 and will receive a peripheral blood stem cell graft on Day 0. Prophylaxis for Graft-versus-host disease (GVHD) using cyclophosphamide, mycophenolate mofetil, and tacrolimus will start on Day +3. SAR'419 will be administered as adjunctive therapy to the HSCT on Day ‒2, Day +7, and Day +28. To confirm the anticipated safety profile of SAR'419, a safety run-in will be conducted in 6‒12 patients in each cohort prior to open enrollment. Patients will be enrolled until 51 and 44 patients in cohorts A and B, respectively, receive at least the first 2 doses of SAR'419 at the target dose confirmed during safety run-in. In total, approximately 107 patients will be enrolled. The primary endpoint, relapse free survival (RFS), will be assessed at 12 months post-HSCT. Additional primary endpoints include frequency of graft failure, life-threatening infusion-related reactions or cytokine release syndrome, tumor lysis syndrome, immune cell-associated neurotoxicity syndrome, acute GVHD, overall mortality at 100 days post-HSCT, non-relapse mortality, and cytomegalovirus reactivation/infection. Secondary endpoints are safety, tolerability, and the impact of SAR'419 on HSCT outcomes, stem cell engraftment, GVHD, infection, and quality of life. Exploratory assessments include evaluation of the impact of SAR'419 on immune reconstitution, cytomegalovirus seroconversion, minimal residual disease, resource utilization, SAR'419 immunogenicity and persistence and their impact on outcomes in whole blood (including serum and plasma) and bone marrow aspirates. RFS will be reported as the percentage of patients who are relapse free and alive at 12 months from the date of HSCT and who received at least the first 2 planned doses of SAR'419. Adverse events will be graded by the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 and will be summarized using descriptive statistics.

Duvelisib for Cytokine Release Syndrome Prophylaxis during CD19-Targeted CAR T Cell Therapy

Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of patients with advanced non-Hodgkin lymphoma (NHL). However, treatment toxicity, including cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome (ICANS), can be significant. Effective prophylactic strategies may reduce the frequency and/or severity of CAR T cell therapy while also expanding the pool of patients eligible for such therapy. Duvelisib is an oral inhibitor of the gamma and delta isoforms of phosphoinositide 3-kinases (PI3K), which is an active therapy for CLL/NHL with an established safety profile. In addition, prior work from our group and others has demonstrated that PI3K inhibition can prevent CRS in an in vitro model (Amatya et al. ASH 2022) and can enhance antitumor cytotoxicity of CAR-T cells. Consequently, we performed a trial of duvelisib for CRS prophylaxis in patients undergoing standard-of-care (SoC) CAR T-cell therapy for NHL (NCT05044039). This was a phase I trial with a 3 + 3 dose escalation and two-arm dose expansion phase. The trial enrolled patients with NHL eligible for SoC CAR T-cell therapy and adequate organ function. Herein, we report data from the dose escalation cohort and the first dose expansion cohort, treated with duvelisib BID from day -2 to +28. The primary outcome was safety and tolerability. Secondary outcomes included the incidence and severity of CRS and ICANS, overall response rate (ORR), and progression-free survival (PFS). 17 patients are included in this analysis, including 6 patients in dose escalation and 11 of 14 planned patients in dose expansion cohort A, with full enrollment of cohort A expected prior to presentation. Median age was 68 years (range: 28 - 79) and 53% were male. Diagnoses included DLBCL (n = 13), MCL (2), FL (1) and PBMCL (1). For CAR-T cell therapy, patients received axi-cel (10), liso-cel (4), brexu-cel (2) and tisa-cel (1). 3 patients were enrolled on dose level 1 (15 mg BID) and 3 patients were enrolled on dose level 2 (25 mg BID). No patients experienced a dose-limiting toxicity (DLT) during dose escalation and consequently, 25 mg BID was selected as the recommended dose for expansion. 75 adverse events (AEs) were considered possibly (73) or probably (2) related to duvelisib by study investigators, including 14 severe (grade ≥3) AEs. The most common AEs were blood count abnormalities (41), liver function test abnormalities (12), fatigue (8) and nausea (6). The majority of severe AEs were cytopenias (13) and one patient had grade 3 hypokalemia. 13 patients (77%) had AEs attributed to duvelisib, including 6 patients (35%) with severe AEs. 76% of patients (13/17) experienced CRS at a median of 5 days following cell infusion (range 2 - 9) (Figure 1A). In 71% of patients (12/17), the onset of CRS was after day 3. Most were grade 1 (65%) and no patients experienced severe (grade 3 - 4) CRS. The median duration of CRS was 1 day (range: 1 - 7). ICANS occurred in 41% of patients (7/17) at a median of 7 days (range 4 - 10) and 12% of patients experienced severe (grade 3-4) ICANS. The median duration of ICANS was 5.5 days (range: 4 - 11 days). Toclizumab was given to 65% of patients for treatment of CRS and 53% received steroids for CRS and/or ICANS. All 17 patients were evaluable for disease response. At day +30, the overall response rate (ORR) was 71% (12/17) with 47% achieving complete response (CR) rate. At day +100, the ORR was 64% (9/14) with 50% CR. Best response was CR in 71% of patients and stable disease in 18% of patients. No patients had progressive disease (PD) as best response. CAR T cell expansion by flow cytometry was robust at all dose levels, consistent with prior reports (Figure 1B). With a median follow up of 93 days (range: 28 - 406), 53% of patients were alive and in remission. PD occurred in 6/17 (35%) patients with a median time to progression of 89 days (range: 28 - 182). Three patients enrolled on the study have died. One died from disease progression on day +266. Two died in remission from neutropenic sepsis (day +50) and vaping-induced lung injury (day +144). Data from this ongoing phase I study suggests that duvelisib with SoC CAR T-cell therapy is safe and tolerable. Preliminary data from this study suggest that the addition of duvelisib to CAR T-cell therapy may prevent grade 3-4 CRS and also delay the onset of CRS. Although limited follow-up is available, the depth and duration of response is similar to published data for CAR T-cells in this setting.

Immune-Effector-Cell-Associated-Neurotoxicity-Syndrome (ICANS) Pathophysiology Is Mediated By Microglia TGF-β-Activated Kinase-1 Signaling

Chimeric antigen receptor (CAR)-T cell therapy has revolutionized the field of immune therapy in treating relapsed and refractory B cell malignancies. Despite remarkable progress, CD19 CAR-T cell therapy is associated with major side effects, most significantly are cytokine-release syndrome and neurotoxicity. Of note, 40-60% of patients receiving CD19 CAR-T cells suffer from severe neurotoxicity termed immune cell-associated-neurotoxicity-syndrome (ICANS), which remains a major obstacle limiting their therapeutic efficacy. Several pre-clinical reports using xenograft mouse models have been published to address ICANS, however, they do not fully recapitulate the clinical scenario. Identifying and targeting the molecular mediators of neurotoxicity could help ameliorate ICANS induced by CD19 CAR-T cells. In order to understand the molecular mechanisms leading to CD19 CAR-T cell-induced ICANS, we established syngeneic ICANS mouse models for B-cell malignancies including non-Hodgkin's Lymphoma (B-NHL) and Acute Lymphoblastic Leukemia (B-ALL). Micro-array and single-nuclei RNA sequencing analyses were performed to unveil key signaling pathways in microglia leading to ICANS pathophysiology. Cognitive impairment resulting from the transfer of CD19 CAR-T cells was assessed with behavior studies in murine models. Imaging mass cytometry was performed on autopsied ICANS and control patient cohorts to study the relevance of microglial activation in patients. We previously demonstrated that microglial upregulation of tumor necrosis factor-alpha (TNFα) results in graft versus host disease of the central nervous system (Mathew and Vinnakota et al. JCI 2020). Similarly, our ICANS mouse models exhibit morphological and functional signs of microglial activation with increased expression of TNFα and GM-CSF along with endothelial damage in lymphoma-bearing mice that received CD19 CAR-T cells when compared to non-transduced controls. Behavioral studies revealed that mice receiving CD19 CAR-T cells exhibit cognitive deficits and increased anxiety. The behavior deficits were however rescued by microglia depletion indicating an important role for microglia in mediating CD19 CAR-T cells induced ICANS. Mechanistically, we identified the activation of p-38 mitogen-activated protein kinase (MAPK) in microglia isolated from mice receiving CD19 CAR-T cells. Furthermore, pharmacological inhibition of TGF-β-activated kinase-1 (TAK1), an upstream target for p-38 MAPK significantly reduced microglial activation, lowered microglia production of TNF and GM-CSF, and improved cognitive function in these mice. In line with these results, microglia-specific knockdown of TAK1 using Cx3cr1 creER:Tak1 fl/fl mice revealed reduced microglial activation and improved cognitive function when compared to littermate controls. Moreover, TAK1 inhibition combined with CD19 CAR-T cell therapy synergistically improved anti-lymphoma/leukemia effects leading to better survival in B-cell malignancy-bearing mice. Translocator-protein-positron-emission-tomography (TSPO-PET) on ICANS patients revealed signs of microglial activation. In addition, Imaging-mass cytometry analysis on post-mortem ICANS patient cohort revealed upregulation of myeloid cell markers further confirming the in vivo findings. In summary, our results identify TAK1/p38 MAPK-pathway as a key mediator of CAR19 CAR-T cell-induced neurotoxicity. Targeting this axis diminished the neurotoxicity associated with this therapy. This study provides a rationale for testing TAK1-inhibition in a clinical trial for treating CD19 CAR-T cell-induced neurotoxicity.

A Phase 1 Study of NKX101, a Chimeric Antigen Receptor Natural Killer (CAR-NK) Cell Therapy, with Fludarabine and Cytarabine in Patients with Acute Myeloid Leukemia

Introduction Relapsed or refractory (r/r) acute myeloid leukemia (AML) has a dismal prognosis. Treatment options are limited and include fludarabine (Flu) and cytarabine (Ara-C), +/- anthracyclines (e.g., FLAG-Ida). Recent progress has been limited to targeted therapies, which benefit only a subset of the population; efforts to develop cellular therapies have not been met with success. NKX101 is an NK cell therapy derived from healthy donors and engineered to express an NKG2D ligand-directed chimeric antigen receptor (CAR) to enhance killing of malignant cells, as well as a membrane bound form of interleukin (IL)-15 to promote persistence and activity. Because Ara-C is known to upregulate NKG2D ligand expression, use of Flu/Ara-C as an alternative to standard Flu/cyclophosphamide (Flu/Cy) for lymphodepletion (LD) was tested for NKX101. Methods Six patients with r/r AML were enrolled in this cohort of NKX101-101, a Phase 1 safety study. All patients had received at least one prior line of therapy, as well as approved targeted therapies for those with underlying genetic mutations. Patients received NKX101 at a dose of 1.5 billion (B) viable CAR+ cells/dose on Days 0, 7, and 14 after LD comprising Flu (30 mg/m2) and Ara-C (2 g/m2) each once daily for five days and 2 days of rest. Efficacy assessments were performed on Day 27 and included bone marrow aspiration and biopsy. Additional treatment cycles of LD and NKX101 were given to some patients to deepen or consolidate responses. Pharmacokinetic (PK) and cytokine sampling were performed throughout the treatment cycle(s). Results At baseline, five out of six patients had poor-risk genetic features, including TP53 mutation; the median bone marrow blast count was 35% (range: 20 - 86%). Patients had received a median of two prior lines of therapy, with all patients having previous venetoclax exposure (Table 1). All patients received at least three doses of NKX101 at 1.5 B cells/dose. There were no cases of cytokine release syndrome (CRS), immune cell associated neurotoxicity syndrome (ICANS), or graft-versus-host disease of any grade in any patients (Table 2). Myelosuppression and infection were the most common higher-grade toxicities. Four out of six patients had CR/CRi, with three out of six achieving CR. Three of these patients had no detectable MRD by flow, and one had 0.18% RUNX1-RUNX1T1 translocation via polymerase chain reaction testing on bone marrow. One subject was taken to consolidative hematopoietic cell transplant (HCT) and remains in CR. Another subject received a consolidative cycle of therapy and remains in CR. A third subject had three cycles of treatment with successive decrease in disease burden and remains in CRi. The fourth subject had CR after one cycle of treatment. PK profiling showed that NKX101 was consistently detected and correlated with infusion days (Figure 1). Cytokine data showed minimal post-infusion elevations above baseline; no association was observed between clinical response and elevation of serum cytokines (including IL-15, IL-6, IFNγ, IL-10, and IL-8). Data on the expression of NKG2D ligands (MICA, MICB, ULBP1, and ULBP3) in subject bone marrow samples were obtained via multiplex immunohistochemistry. This was evaluated as a composite H-score. Responders were split between those with relatively low ligand expression and those with higher ligand expression, suggesting that further factors may contribute to NK cell resistance. Conclusions Alternative LD with Flu/Ara-C followed by NKX101 shows promising early responses including MRD negativity in r/r AML. The toxicity profile of this regimen is manageable and was consistent with underlying AML and exposure to LD, without any events of CRS or ICANS. Expansion of enrollment and longer follow-up are needed. Despite being an allogeneic, non-HLA-matched cell product, NKX101 persisted for up to three weeks in PK testing. Directly comparing the data from patients treated with Flu/Cy with NKX101 versus Flu/Ara-C with NKX101 suggests that Flu/Ara-C can replace the Flu/Cy regimen common to CAR T cell therapy as LD without compromising overall NKX101 exposure.

Subcutaneous Epcoritamab Plus Lenalidomide in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma from EPCORE NHL-5

Background: The prognosis for patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) is poor, even if treated with salvage chemotherapy and autologous stem cell transplantation. CAR T cell therapy provides long-term remission in only 40% of patients. Epcoritamab, a subcutaneous CD3xCD20 bispecific antibody developed using the DuoBody ® platform, received accelerated FDA approval for adults with R/R DLBCL not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma after ≥2 lines of systemic therapy. Single-agent epcoritamab has demonstrated deep and durable responses (overall response rate, 63%; complete responses, 40%) and a manageable safety profile in patients with R/R large B-cell lymphoma in the EPCORE NHL-1 trial (Karimi et al, ASCO 2023, abstract 7525). Combining epcoritamab with antineoplastic agents that have different mechanisms of action may offer enhanced clinical benefit to patients. Therefore, EPCORE NHL-5 (NCT05283720) evaluated the safety, tolerability, and preliminary efficacy of epcoritamab, as well as defining its recommended dose when coadministered with other antineoplastic agents in patients with non-Hodgkin lymphoma. Here, we present results from arm 1 that evaluated epcoritamab combined with lenalidomide in patients with R/R DLBCL. Methods: EPCORE NHL-5 is a phase 1b/2, nonrandomized, open-label, multicenter study. In arm 1, adults with CD20 + R/R DLBCL (ECOG 0-2) received subcutaneous epcoritamab (weekly during cycle 1-3, every 4 weeks during cycle 4-12) and oral lenalidomide (once daily on days 1-21) for 12 cycles of 28 days. Patients had received at least 1 prior combined systemic therapy that contained an anti-CD20 monoclonal antibody. The primary endpoint was the identification of dose-limiting toxicities (DLTs). Key secondary endpoints included investigator-assessed best overall response by Lugano 2014 criteria and time to response. Safety endpoints included severity and incidence of adverse events (AEs) including AEs of special interest to epcoritamab (cytokine release syndrome [CRS], immune cell-associated neurotoxicity syndrome [ICANS], and clinical tumor lysis syndrome). Results: As of May 22, 2023, 26 patients (median age, 71 years; DLBCL, n=24 [92%]; follicular lymphoma grade [G] 3b, n=2 [8%]) had received epcoritamab plus lenalidomide. Median duration of epcoritamab exposure was 3.8 months (range, 0-7.5) and median duration of lenalidomide exposure was 4.0 months (range, 0.1-8.2); 15 patients (58%) remain on epcoritamab and lenalidomide. Median number of prior lines of therapy was 1 (range, 1-4), with 15 (58%) receiving 1 prior line of anticancer therapy. Six patients (23%) had received prior CAR T and 2 patients had undergone hematopoietic stem cell transplantation. One DLT (neutropenia) was observed. The most common G3-4 treatment-emergent AEs (TEAEs) were neutropenia (n=15; 58%), anemia (n=4; 15%), thrombocytopenia (n=4; 15%), and febrile neutropenia (n=3; 12%). Primary granulocyte colony-stimulating factor prophylaxis was not mandatory. TEAEs led to epcoritamab discontinuation in 1 patient (3.8%; thrombocytopenia). No patients experienced a TEAE leading to death that was considered related to epcoritamab. CRS was predominantly low grade (73% [19/26] any grade; 65% G1-2; 8% G3) and occurred mostly after the first full dose (C1D15). Preliminary biomarker analysis showed pharmacodynamic profiles consistent with the mechanism of action of epcoritamab. These include predictable cytokine peaks immediately after the first full dose (IFN-gamma, IL-2, and IL-6) with a rapid and sustained depletion of peripheral B cells. One patient experienced ICANS (G3), which resolved after 2 days. Among response-evaluable patients (n=24), the overall response rate was 75% (95% CI, 53.3, 90.2). Complete metabolic responses were seen in 14 patients (58%) and partial responses in 4 patients (17%), of which 3 were ongoing at time of data cutoff ( Table). Median time to first response was 1.8 months (range, 1.0-2.8). Follow-up is ongoing. Conclusions: Epcoritamab combined with lenalidomide showed promising antitumor activity with a tolerable safety profile in patients with R/R DLBCL.

Phase 3 trial of subcutaneous epcoritamab + R-CHOP versus R-CHOP in patients (pts) with newly diagnosed diffuse large B-cell lymphoma (DLBCL): EPCORE DLBCL-2.

TPS7592 Background: In pts with newly diagnosed DLBCL, standard treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has a 5-year progression-free survival (PFS) rate of 67.0%, 58.4%, and 45.8% for International Prognostic Index (IPI) 2, 3, and 4–5, respectively (Ruppert et al, Blood 2020). Epcoritamab is a subcutaneously administered, bispecific antibody that binds CD3 on T cells and CD20 on B cells, inducing potent and selective T-cell–mediated killing of malignant CD20+ B cells (Hutchings et al, Lancet 2021). Epcoritamab monotherapy demonstrated deep and durable responses (overall response rate [ORR], 63%; complete response rate, 39%) and was generally well tolerated in pts with relapsed/refractory (R/R) aggressive, large B-cell lymphoma (LBCL) (Thieblemont et al, J Clin Oncol 2022). Results from an ongoing phase 1/2 study in high-risk pts with newly diagnosed DLBCL (EPCORE NHL-2 arm 1; NCT04663347) show that epcoritamab + R-CHOP has promising efficacy and a manageable safety profile in high-risk pts with IPI 3–5. Among efficacy-evaluable pts (n = 31), ORR was 100% and complete metabolic response (CMR) was 77%; cytokine release syndrome (CRS) events (n = 17/33; 52%) were mostly low-grade, had predictable timing, and did not lead to treatment discontinuation (Falchi et al, ASCO 2022, abstract 7523). These encouraging data support further evaluation of epcoritamab + R-CHOP for the treatment of newly diagnosed DLBCL. Methods: This phase 3, global, multicenter, open-label study (NCT05578976) evaluates the efficacy and safety of epcoritamab + R-CHOP in adults newly diagnosed with one of the following CD20+ DLBCL (de novo or transformed from follicular lymphoma [FL]): 1) DLBCL, not otherwise specified (NOS); 2) high-grade B-cell lymphoma with MYC and BCL-2 and/or BCL-6 rearrangement; 3) T-cell/histiocyte–rich LBCL; 4) Epstein-Barr virus–positive DLBCL, NOS; or 5) FL grade 3b. Other key eligibility criteria include IPI ≥2 (pts with IPI 2 not to exceed ~30% of total pts), ECOG PS 0–2, and ≥1 measurable disease site. Approximately 900 pts will be randomized 2:1 to either epcoritamab + R-CHOP (6 cycles, followed by 2 cycles of epcoritamab) or R-CHOP (6 cycles, followed by 2 cycles of rituximab). The primary efficacy endpoint is PFS in pts with IPI 3–5 (based on IRC assessment per Lugano criteria). The secondary efficacy endpoints are PFS in pts with IPI 2–5, event-free survival, CMR, overall survival, and minimal residual disease negativity. Safety endpoints include incidence and severity of treatment-emergent adverse events (AEs), serious AEs, and AEs of special interest (CRS, immune cell–associated neurotoxicity syndrome, and clinical tumor lysis syndrome. Enrollment began in January 2023 globally. Clinical trial information: NCT04663347 , NCT05578976 .

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: In pts with newly diagnosed DLBCL, standard treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has a 5-year progression-free survival (PFS) rate of 67.0%, 58.4%, and 45.8% for International Prognostic Index (IPI) 2, 3, and 4–5, respectively (Ruppert et al., Blood 2020). Epcoritamab is a subcutaneously administered, bispecific antibody that binds CD3 on T cells and CD20 on B cells, inducing potent and selective T-cell–mediated killing of malignant CD20+ B cells (Hutchings et al., Lancet 2021). Epcoritamab monotherapy demonstrated deep and durable responses (overall response rate [ORR], 63%; complete response rate, 39%; median duration of response, 12 months) and was generally well tolerated in pts with relapsed/refractory (R/R) aggressive, large B-cell lymphoma (LBCL) (Thieblemont et al., J Clin Oncol 2022). Results from an ongoing phase 1/2 study in high-risk pts with newly diagnosed DLBCL (EPCORE NHL-2 arm 1; NCT04663347) show that epcoritamab + R-CHOP has promising efficacy and a manageable safety profile in high-risk pts with IPI 3–5. Among efficacy-evaluable pts (n = 31), ORR was 100% and complete metabolic response (CMR) was 77%; cytokine release syndrome (CRS) events (n = 17/33; 52%) were mostly low-grade, had predictable timing, and did not lead to treatment discontinuation (Falchi et al., ASCO 2022, abstract 7523). These encouraging data support further evaluation of epcoritamab + R-CHOP for the treatment of newly diagnosed DLBCL. Methods: This phase 3, global, multicenter, open-label study (NCT05578976) evaluates the efficacy and safety of epcoritamab + R-CHOP in adults newly diagnosed with one of the following CD20+ DLBCL (de novo or transformed from follicular lymphoma [FL]): 1) DLBCL, not otherwise specified (NOS); 2) high-grade B-cell lymphoma with MYC and BCL-2 and/or BCL-6 rearrangement; 3) T-cell/histiocyte–rich LBCL; 4) Epstein-Barr virus–positive DLBCL, NOS; or 5) FL grade 3b. Other key eligibility criteria include IPI ≥2 (pts with IPI 2 not to exceed ∼30% of total pts), ECOG PS 0–2, and ≥1 measurable disease site. Approximately 900 pts will be randomized 2:1 to either epcoritamab + R-CHOP (6 cycles, followed by 2 cycles of epcoritamab) or R-CHOP (6 cycles, followed by 2 cycles of rituximab). The primary efficacy endpoint is PFS in pts with IPI 3–5 (based on IRC assessment per Lugano criteria). The secondary efficacy endpoints are PFS in pts with IPI 2–5, event-free survival, CMR, overall survival, and minimal residual disease negativity. Safety endpoints include incidence and severity of treatment-emergent adverse events (AEs), serious AEs, and AEs of special interest (CRS, immune cell–associated neurotoxicity syndrome, and clinical tumor lysis syndrome). Enrollment began in January 2023 globally. © 2023 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2023 ASCO Annual Meeting. All rights reserved. The research was funded by: This study was funded by AbbVie and Genmab. Keywords: aggressive B-cell non-Hodgkin lymphoma, combination therapies, immunotherapy Conflicts of interests pertinent to the abstract. L. H. Sehn Consultant or advisory role AbbVie, Amgen, AstraZeneca, BeiGene, BMS/Celgene, Genentech/Roche, Incyte, Janssen, Kite/Gilead, Merck, Seattle Genetics Research funding: Teva, Roche/Genentech M. Chamuleau Consultant or advisory role AbbVie, Novartis, Incyte Research funding: BMS, Gilead, GenMab G. Lenz Consultant or advisory role Roche, Gilead, Janssen, Bayer, BMS, Novartis, AbbVie, Incyte, Genmab, Karyopharm, Constellation, ADC Therapeutics, Sobi, Miltenyi, PentixaPharm, Genase, Immagene, Hexal, Lilly Research funding: Janssen, Bayer, MorphoSys, AstraZeneca Other remuneration: Invited Speaker: Roche, BMS, Novartis, AbbVie, Incyte, Sobi, Hexal M. R. Clausen Consultant or advisory role AbbVie, Genmab, Janssen and Kite/Gilead C. Haioun Consultant or advisory role AbbVie, Genentech/Roche, Incyte, Kite/Gilead, Miltenyi A. Davies Honoraria: Roche, Kite, Incyte, BMS, AstraZeneca, AbbVie, Genmab Research funding: Roche, AstraZeneca, MSD, Cellcentric Educational grants: Roche T. Oki Employment or leadership position: AbbVie E. Szafer-Glusman Employment or leadership position: AbbVie R. Conlon Employment or leadership position: AbbVie Stock ownership: AbbVie H. Chiou Employment or leadership position: AbbVie D. Ipe Employment or leadership position: AbbVie B. Elliot Employment or leadership position: Genmab Stock ownership: Genmab J. Wu Employment or leadership position: AbbVie G. Salles Consultant or advisory role AbbVie, Bayer, BeiGene, BMS/Celgene, Epizyme, Genentech/Roche, Genmab, Incyte, Janssen, Kite/Gilead, Loxo, Miltenyi, MorphoSys, Novartis, Rapt, Regeneron, Takeda

Real-World Results of CAR-T Cell Therapy for Large B Cell Lymphoma with CNS Involvement: A GLA/DRST Study

Background CD19-directed chimeric antigen receptor T-cell (CAR-T) products are now part of standard of care (SOC) treatment for advanced large B cell lymphoma (LBCL). Because of concerns of potential immune cell-associated neurotoxicity syndrome (ICANS), patients with secondary central nervous system (CNS) manifestation of lymphoma have been excluded from most pivotal CAR-T studies. Consequently, data on outcome of CAR-T cell therapy for lymphoma patients with secondary CNS involvement are limited. Here, we show results of CD19 CAR-T cell therapy for relapsed/refractory secondary CNS lymphoma in a German multicenter real-world cohort. Patients and Methods 196 LBCL patients from the EBMT/DRST registry who had received SOC CD19 CAR-T cell therapy in 9 German centers between 2018 and 2021with sufficient detailed information on type of CNS involvementat the time of CAR-T therapy were included. In total, 28 patients with and 168 patients without secondary CNS involvement were identified. For the purpose of a more representative comparison, a matched-pair analysis of the 2 groups was performed using age, sex, performance status, and International Prognostic Index as matching factors. Results Of the 28 patients with CNS involvement, in 8 patients CNS was involved at initial presentation of lymphoma. Regarding the type of CNS manifestations, 16 patients (57%) had lymphoma manifestations in the brain only, 6 patients (21%) had meningeosis only and remaining 6 patients (21%) had both. 14 patients (50%) received axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) respectively after a median of 3 lines of prior treatments (range, 2-6 lines). 24 patients (86%) received bridging therapy before CAR-T infusion. Bridging included intrathecal therapy in 4 patients (14%), polatuzumab-based regimen in 5 patients (18%), CNS radiation in 3 patients (11%), venetoclax/ibrutinib in 4 patients (14%), gemcitabine-oxaliplatin in 2 patients (7%), other chemotherapies in 6 patients (25%). Median age was 58 years (range, 33-79 years) and median time from diagnosis to CAR-T infusion was 15 months (range, 4-105 months). 16 patients (57%) were male, with a median ECOG performance status of 1 (range, 0-3) and median International Prognostic Index of 3 (range, 1-5). Thirteen patients (48%) had normal levels of LDH at time of CAR-T. Median time to last documented follow-up of all patients (alive or dead) was 10 months (range 0.3-33 months). In terms of safety, CRS of any grade was seen in 24 patients (86%), grade 3 in 6 patients (21%). There was no grade 4 event. ICANS occurred in 13 patients (46%), grade 3 in 3 patients (11%), and grade 4 in 1 patient (4%). Median time to ICANS was 5 days (range, 3-15 days) after CAR-T infusion. No difference in occurrence of and time to ICANS was seen between axi-cel and tisa-cel (P=0.81 and 0.76) or type of CNS manifestation (P=0.15 and 0.52). In terms of efficacy, complete response rate was 33%, partial response rate 33%, progressive disease 25%, and stable disease 9%. Median progression-free survival of the total CNS cohort was 3.8 months (95% CI, 0.01-9.4 months). Progression-free survival (PFS) was significantly affected by type of manifestation (P=0.006), showing median of 3.8 months (95% CI, 0.01-11.9 months) for brain only manifestation versus 1.1 months (95% CI, 0.01-2.6 months) for meningeosis only versus not reached for others (both meningeosis and brain). 3 events of non-relapse mortality occurred, all due to blood stream infections at day 10, 13, and 27 after CAR-T infusion. In a matched comparison of 28 matched patients with and without CNS involvement, no difference was seen for incidence of CRS (P=0.43) and ICANS (P=0.71) between the groups. PFS was comparable (P=0.26), showing a median of 3.6 months (95% CI 0.4-6.9 months) for no CNS involvement versus 3.8 months for CNS involvement. PFS at 6 months was 45% (26-64%) versus 34% (16-52%) and at 12 months 41% (22-60%) versus 22% (6-38%) for patients with CNS vs. no CNS manifestation (Fig 1). Conclusion SOC CD19 CAR-T cell therapy for LBCL patients with secondary CNS involvement is safe, feasible, and results in efficacy comparable to outcome in those without CNS involvement These findings not only underline that CNS involvement should not preclude patients from clinical trials, but also the high potential of cell therapies for CNS lymphomas. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Comorbidities Associated with Early Mortality after CD19 CAR-T Cell Therapy

Objective: CD19 chimeric antigen receptor (CAR) T-cell therapy has changed the standard for treatment of relapsed and/or refractory (r/r) large b-cell lymphoma (LBCL). Currently, pre-treatment evaluation of patients and disease factors do not accurately predict outcomes. This study aims to identify risk factors associated with early mortality prior to day 100 after CAR-T infusion. Methods: We performed a single-centered retrospective adult patients (pts) with r/r LBCL who received CAR-T cell therapy between 2018-2021. CAR-T cell toxicities graded according to either CAR T-Cell Therapy-Associated Toxicity (CARTOX) grading system prior to May, 2019 or American Society of Transplantation and Cellular Therapy (ASTCT) consensus grading thereafter for cytokine release syndrome (CRS) and immune cell associated neurotoxicity syndrome (ICANS). Comorbidities defined as per Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI). (Sorror et al., 2009). Hepatic dysfunction defined as infection with hepatitis B or C or history of liver cirrhosis or elevated total bilirubin, AST, or ALT on at least two values on two different days from day -24 till day -10 prior to CAR-T. Cardiovascular (CV) comorbidity determined by presence of coronary heart disease, congestive heart failure or reduced ejection fraction detected by echocardiogram. Psychiatric disturbance defined as presence of depression and/or anxiety requiring treatment or consultation. Patient demographics, disease characteristics and clinical outcomes summarized through descriptive statistics. Wilcoxon rank sum test used to evaluate difference in a continuous variable between patient groups. Kaplan-Meier method used to estimate time-to-event endpoints including progression free survival (PFS), and overall survival (OS). Results: Two hundred and fifty patients included in analysis. Median age of 61years (range: 18-89) and 30.8% of patients were female (n=77). Histology was categorized as LBCL (65.9%) and included diffuse LBCL or high grade LBCL, transformed follicular lymphoma (26.9%), primary mediastinal b-cell lymphoma (6.4%) or follicular lymphoma (0.8%). Majority of pts received axicabtagene ciloleucel 95.6% (n=239) while 4.4% (n=11) received tisagenlecleucel and 52% (n=130) of pts received bridging therapy. CRS of any grade was 90.4% ; ICANS any grade was 57.2% while grade 3 CRS/ICANS occurred 6.4% and 38.4% respectively. Median follow-up 24.7 months (mo) (95% CI: 20.7 ~ 26.4 mo). One-hundred twenty-eight pts died during follow-up, 48 pts died within 100 days, and most common cause of death was progression of lymphoma (29.2%; n=73). Early 30-day mortality occurred in 4.8% pts and causes of death due to CAR-T related toxicity in 6 pts, disease progression in 3 pts, and infection in 1 pts. 100-day mortality rate was 24.6% (n=32) for pts >60 years old vs 13.3% (n=16) for <60 (p-value=0.02). 100-day mortality rate was 36.5% for ECOG 2-4 vs 14.9% for ECOG 0-1 (p-value=0.0005). In terms of non-relapsed mortality (NRM), risk stratification according to cumulative HCT-CI score was not associated with higher 100-day NRM (p=0.24). Pts with cardiac score of 1 had a higher NRM (26.9% vs. 8.1%; p-value=0.005). The 100-day NRM rates for hepatic score of 0, 1, and 3 were 8.9%, 14.3%, and 50% (p-value=0.04). Pts with psychiatric disturbance score of 1 had higher 100-day NRM (19.6% vs. 7.8%; p-value=0.03). Conclusion: This single center retrospective study observed an increase in 100-day mortality in correlation with pre-treatment performance status, and older age. Pts with cardiac comorbidity, hepatic dysfunction or psychiatric disturbance had a higher 100-day NRM. Similar to other studies, the combined HCT-CI score was not predictive of NRM, but individual variables were associated with higher non-CART related toxicity. These findings require validation with further studies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Phase 1b Trial of Subcutaneous Epcoritamab in Pediatric Patients with Relapsed or Refractory (R/R) Aggressive Mature B-Cell Neoplasms (EPCORE Peds-1)

Background: Burkitt lymphoma and diffuse large B-cell lymphoma (DLBCL) are the most common types of mature B-cell lymphoma (MBL) in children. A majority (90%-95%) of children with these malignancies are cured with initial chemoimmunotherapy (CIT), leaving a small portion of patients with relapsed or refractory (R/R) disease who have a poor prognosis (Cairo et al, J Clin Oncol 2012). R/R MBL is often treated with aggressive CIT regimens such as R-VICI or R-ICE, but a high, unmet need remains (Woessmann et al, Blood 2020). Long-term survival is observed in approximately 20% to 30% of pediatric cases of R/R MBL, with better long-term survival seen in those who attain complete response (CR) with reinduction CIT and reach consolidation with stem cell therapy. Patients with partial response (PR) after reinduction CIT may undergo stem cell transplant but typically have lower long-term survival rates than those experiencing CR (Burkhardt et al, Cancers 2021). Long-term survival or cure in patients with R/R MBL requires an effective therapy that results in CR before stem cell transplant. Epcoritamab is a bispecific antibody that binds CD3 on T cells and CD20 on B cells, inducing potent and selective T-cell-mediated killing of malignant CD20+ B cells. The phase 1/2 EPCORE NHL-1 study (NCT03625037) of epcoritamab monotherapy in adult patients with R/R B-cell non-Hodgkin lymphoma established the recommended phase 2 dose (RP2D) and demonstrated safety and promising efficacy, including deep and durable responses (overall response rate [ORR], 63%; CR rate, 39%; preliminary median duration of response [DOR], 12 months) in a population with highly refractory large B-cell lymphoma (n=157) (Thieblemont et al, EHA 2022). Because favorable safety and efficacy data were observed in adults, it is reasonable to investigate use of epcoritamab in children with R/R MBL who fail to achieve CR with reinduction CIT or are unable to receive further consolidation with stem cell therapy after CIT. Study Design and Methods: EPCORE Peds-1 is a single-arm, open-label, phase 1b study (NCT05206357) evaluating the safety, pharmacokinetics, pharmacodynamics preliminary efficacy, and immunogenicity of epcoritamab monotherapy in pediatric and young adult patients with R/R Burkitt lymphoma, Burkitt-like lymphoma/leukemia, DLBCL, or other aggressive CD20+ MBL. Primary endpoints are safety and tolerability, including incidence and severity of cytokine release syndrome, immune cell-associated neurotoxicity syndrome, and clinical tumor lysis syndrome, as well as pharmacokinetic parameters of maximum observed concentration and area under the concentration-time curve from time 0 to last measurable concentration within the dosing interval. Secondary endpoints include CR per International Pediatric Non-Hodgkin Lymphoma response criteria, event-free survival, overall survival, initiation of stem cell transplant/chimeric antigen receptor T-cell therapy, ORR, DOR, duration of CR, and immunogenicity. Exploratory endpoints include the monitoring of pharmacodynamic markers such as cytokines and immunophenotyping of B and T cells. At least 15 patients will be enrolled with a maximum age of 25 years (for those with Burkitt lymphoma), with at least 12 patients 1 year of age or older but younger than 18 years who are evaluable for primary endpoint assessment. Eligibility criteria require that patients have not reached remission with reinduction CIT or are ineligible for further consolidation with cell therapy and have acceptable performance status (Lansky, Karnofsky, or Eastern Cooperative Oncology Group, depending on age). Epcoritamab will be subcutaneously administered using step-up dosing (priming and intermediate doses on days 1 and 8 of cycle 1 [28 days/cycle], followed by 10 weekly full doses from day 15 of cycle 1 through cycle 3; Figure). Additional full doses will be administered every 2 weeks for cycles 4 to 9 and every 4 weeks for cycles 10 and beyond for a maximum of 2 years of treatment. Epcoritamab priming-, intermediate-, and full-dose regimens will be based on weight categories; patients weighing at least 40 kg will receive the adult RP2D. Disease status will be assessed by CT/MRI/PET prior to epcoritamab administration on day 1 and at a minimum at weeks 6, 12, 24, 36, and 48 and at 18 and 24 months. Patients will be followed for at least 3 years after enrollment. Enrollment is ongoing in North America, Asia, Europe, and Australia. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

P1440: BTK INHIBITORS IMPROVE CART19 CELL THERAPY BY MODULATING IMMUNE SYSTEM

Background: CD19-targeted chimeric antigen receptor-T (CART19) cell therapy has achieved extraordinary success in B-cell lymphoma and leukemia. However, recurrence and adverse effects, including cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome (ICANS), remain its obstacles. Recurrence, even resistance to CART19 cell therapy, might be attributed to CAR-T cell dysfunction and suppressor cells in the microenvironment. Cytokines required for CRS and ICANS are predominantly derived from monocytes and macrophages. Given that Bruton’s tyrosine kinase (BTK) is expressed on myeloid cells, we considered that BTK inhibitors (BTKi) could improve CAR-T cell therapy by modulating immune system. Aims: To systematically evaluate the effects of three BTKi, ibrutinib (IB), zanubrutinib (ZB) and orelabrutinib (OB), on T cells, CART19 cells and tumor microenvironment. Methods: T and CART19 cells were cultured with the three BTKi for 4 days, and the immune and differentiated phenotypes (PD1, TIM3, CTLA4, CD25, CD69 and CD28, CD45RA and CD62L) were analyzed by flow cytometry (FCM). The effects of BTKi on CART19 cytotoxicity against NALM-6 were assessed for 24-hour coculture. CART19, NALM-6 and macrophages differentiated from THP-1 upon PMA stimulation were cocultured and IL-6 in the supernatants was detected by cytometry bead assays. Lymphoma mouse models were established with BALB/c mice by subcutaneous injection of 5x106 A20 cells. IB, ZB and OB were administered to the BALB/c mice at 25, 10 and 10mg/kg respectively by oral gavage once daily for 28 days. Vehicle treatment was performed using 0.5% carboxymethylcellulose sodium. Mice in healthy controls were fed with no additional treatment. Splenocytes, bone marrow (BM) samples and tumor specimens were harvested, and single-cell suspensions were prepared to analyze immune phenotypes by FCM. Results: Compared with control T cells, IB-supplemented T cells significantly reduced the expression of PD-1 (62.28% vs 14.95%, P = 0.0024), TIM-3 (71.38% vs 7.88%, P <0.0001) and CTLA-4 (92.65% vs 15.5%, P <0.0001) following CD3/CD28 stimulation (Figure 1A). The downregulation of the suppressive markers was also observed in T cells treated with ZB, but not with OB (Figure 1A). In parallel, IB and ZB decreased activation markers expression and increased effector memory cell subsets, while decreased naïve T cells (Figure 1A and B). BTKi decreased IL-6 level in the supernatants of CART19, NALM-6 cells and macrophages (Figure 1C), and decreased CTLA-4 expression on CART19 (Figure 1D). The effects of BTKi on CART19 differentiated phenotypes were not observed (Figure E). Considering strong CD3/CD28 stimulation and tonic signaling could drive terminal differentiation and even apoptosis of CAR-T cells, we supposed BTKi could protect CART19 from excessive activation in long-term cultivation and stimulation (not shown). The three BTKi did not show synergistic effects on cytotoxicity of CART19 against NALM-6 cells (not shown). In lymphoma mice models, the three BTKi all increased the ratio of type 1 macrophages (M1) to type 2 macrophages (M2) and Th1 to Th2 in tumor, and reduced tumor-infiltrating macrophages (Figure 1F-H). BTKi induced significant decreases in exhaustion markers expression on T cells in BM tissues, but not in tumor specimens (Figure I). Image:Summary/Conclusion: Differentiation and exhaustion of CAR-T cells highly activated upon CD3/CD28 stimulation and tonic signaling can be prevented by BTKi. Moreover, BTKi can alter the tumor microenvironment and downregulate IL-6 level to improve the efficacy and safety of CART19 cell therapy.

Introducing innovative cellular therapies into the clinic: a 2-year retrospective experience of a chimeric antigen receptor T-cell programme at a single centre in Switzerland.

Chimeric antigen receptor T (CAR-T) cells are a powerful form of immune-cell therapy for patients with relapsed/refractory B-cell lymphoma and acute B lymphoblastic leukaemia. CAR-T cells have been commercially available in Switzerland since 2018. Because of the complexity and costs of this treatment it is critical to review patient outcomes in real-world settings, to examine whether the promising results from pivotal trials can be reproduced and to identify clinical parameters that determine their efficacy. Here we present results of a retrospective study analysing outcomes of patients treated with CAR-T cells in a single academic centre in Switzerland during the first two years after commercial approval (BASEC-No. 2020-02271). Cytokine release syndrome (CRS), immune-cell associated neurotoxicity syndrome (ICANS), responses to treatment, ancillary laboratory studies and administrative specifics of CAR-T treatment were examined and are discussed. From October 2018 to August 2020 CAR-T cell therapy was evaluated in 34 patients, mostly with relapsed/refractory aggressive B-cell lymphoma (87% had refractory disease). Thirty-one patients underwent leukapheresis. Three of 31 patients (9.6%) died of rapid disease progression before the CAR-T cell product was delivered, two patients were enrolled into a clinical trial, three patients were not given CAR-T cells for other reasons. Ultimately, 23 patients were infused with a commercial CAR-T cell product and included in this analysis. Fourteen (61%) patients received bridging therapy while waiting for a median of 41 days (range 31-62) for delivery of the CAR-T cell product. Toxicity and severe side effects were rare (CRS >3 in 13%, ICANS > grade 3 in 10% of patients), manageable and resolved completely thereafter. The best overall response rate was 65%, with complete responses in 38% of lymphoma patients. At 12 months postinfusion, 61% of patients were alive and 35% progression free. With a median follow-up of 14 months, 13/23 (56%) patients were alive at the time of writing. CAR-T cell therapy proved to be safe and manageable under adequate hospital conditions. Outcomes resemble results from pivotal trials. The majority of patients was heavily pretreated and refractory at the time of CAR-T cell infusion. Patient selection, time point of leukapheresis, bridging strategies and timing of CAR-T cell infusion may be critical to further improve outcomes.

Safety and efficacy of tisagenlecleucel in primary CNS lymphoma: a phase 1/2 clinical trial

AbstractCD19-directed chimerical antigen receptor T-cell (CAR-T) products have gained US Food and Drug Administration approval for systemic large B-cell lymphoma. Because of concerns about potential immune cell-associated neurotoxicity syndrome (ICANS), patients with primary central nervous system (CNS) lymphoma (PCNSL) were excluded from all pivotal CAR-T studies. We conducted a phase 1/2 clinical trial of tisagenlecleucel in a highly refractory patients with PCNSL and significant unmet medical need. Here, we present results of 12 relapsed patients with PCNSL who were treated with tisagenlecleucel and followed for a median time of 12.2 months (range, 3.64-23.5). Grade 1 cytokine release syndrome was observed in 7/12 patients (58.3%), low-grade ICANS in 5/12 (41.6%) patients, and only 1 patient experienced grade 3 ICANS. Seven of 12 patients (58.3%) demonstrated response, including a complete response in 6/12 patients (50%). There were no treatment-related deaths. Three patients had ongoing complete remission at data cutoff. Tisagenlecleucel expanded in the peripheral blood and trafficked to the CNS. Exploratory analysis identified T-cell, CAR T, and macrophage gene signatures in cerebrospinal fluid following infusion when compared with baseline. Overall, tisagenlecleucel was well tolerated and resulted in a sustained remission in 3/7 (42.9%) of initial responders. These data suggest that tisagenlecleucel is safe and effective in this highly refractory patient population. This trial was registered at www.clinicaltrials.gov as #NCT02445248.

Chimeric Antigen Receptor T-Cell Therapy in Paediatric B-Cell Precursor Acute Lymphoblastic Leukaemia: Curative Treatment Option or Bridge to Transplant?

Chimeric antigen receptor T-cell therapy (CAR-T) targeting CD19 has been associated with remarkable responses in paediatric patients and adolescents and young adults (AYA) with relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). Tisagenlecleucel, the first approved CD19 CAR-T, has become a viable treatment option for paediatric patients and AYAs with BCP-ALL relapsing repeatedly or after haematopoietic stem cell transplantation (HSCT). Based on the chimeric antigen receptor molecular design and the presence of a 4-1BB costimulatory domain, tisagenlecleucel can persist for a long time and thereby provide sustained leukaemia control. “Real-world” experience with tisagenlecleucel confirms the safety and efficacy profile observed in the pivotal registration trial. Recent guidelines for the recognition, management and prevention of the two most common adverse events related to CAR-T — cytokine release syndrome and immune-cell–associated neurotoxicity syndrome — have helped to further decrease treatment toxicity. Consequently, the questions of how and for whom CD19 CAR-T could substitute HSCT in BCP-ALL are inevitable. Currently, 40–50% of R/R BCP-ALL patients relapse post CD19 CAR-T with either CD19− or CD19+ disease, and consolidative HSCT has been proposed to avoid disease recurrence. Contrarily, CD19 CAR-T is currently being investigated in the upfront treatment of high-risk BCP-ALL with an aim to avoid allogeneic HSCT and associated treatment-related morbidity, mortality and late effects. To improve survival and decrease long-term side effects in children with BCP-ALL, it is important to define parameters predicting the success or failure of CAR-T, allowing the careful selection of candidates in need of HSCT consolidation. In this review, we describe the current clinical evidence on CAR-T in BCP-ALL and discuss factors associated with response to or failure of this therapy: product specifications, patient- and disease-related factors and the impact of additional therapies given before (e.g., blinatumomab and inotuzumab ozogamicin) or after infusion (e.g., CAR-T re-infusion and/or checkpoint inhibition). We discuss where to position CAR-T in the treatment of BCP-ALL and present considerations for the design of supportive trials for the different phases of disease. Finally, we elaborate on clinical settings in which CAR-T might indeed replace HSCT.

Tisagenlecleucel Demonstrates Safety, Efficacy and CNS Trafficking in Primary CNS Lymphoma

Tisagenlecleucel Demonstrates Safety, Efficacy and CNS Trafficking in Primary CNS Lymphoma

Practical aspects of the application of CAR T cells and management of their toxicities

CD19 CAR T cells induce - in part long-lasting - remissions in heavily pretreated patients with relapsed/refractory B-cell malignancies. However, they are associated with unique toxicities, and patient management therefore requires specific expertise.In this review, we outline the basics of their mode of action and present the currently available data on their efficacy in various B-cell and plasma cell malignancies. Currently approved therapies (Tisagenlecleucel, Axicabtagene ciloleucel, Brexucabtagene autoleucel) for patients are outlined as well as indications where approvals are expected in the near future. We discuss practical aspects of CAR T cell therapy from the patient's initial presentation, over leukapheresis, to CAR T cell transfusion. Additionally, we highlight the pathophysiology and principles of the management of the most common toxicities (cytokine release syndrome [CRS], immune cell associated neurotoxicity syndrome [ICANS] and cytopenias).

Ensuring center quality, proper patient selection and fair access to chimeric antigen receptor T-cell therapy: position statement of the Austrian CAR-T Cell Network

SummaryChimeric antigen receptor T cells (CAR-T cells) are a novel form of cellular immunotherapy for patients with hematologic and oncologic malignancies. Known side effects of these approved cellular immunotherapies are cytokine release syndrome, immune-cell associated neurotoxicity syndrome, cytopenias, infections and long-lasting B cell aplasia. Safe administration of CAR-T cell therapy requires thorough patient selection and patient care in qualified CAR-T cell centers.

Modifiers of Endothelial Permeability in the Setting of CAR-t Therapy Related Immune Cell Associated Neurotoxicity Syndrome

Background Chimeric Antigen Receptor T-cell therapy (CAR-t) for patients with relapsed or refractory B cell precursor acute lymphoblastic leukemia (ALL) is associated with high overall remission rates but also with significant complications. Cytokine release syndrome (CRS) and Immune Cell Associated Neurotoxicity Syndrome (ICANS) are life-threatening sequelae that may occur in CAR-t recipients. ICANS presents with varying symptoms ranging from confusion to seizure and cerebral edema. There is no consensus on specific biological events that incite ICANS. Blood brain barrier (BBB) permeability is altered in CD19 CAR-t therapy, but the cause of altered BBB permeability is not clear. IL6 targeted interventions that control symptoms of CRS are ineffective against ICANS, suggesting these entities have separate pathologic mechanisms. Criteria for ICANS severity grading and guidelines for supportive care management are published, but there is no universal predictor of ICANS. Identification of manipulable biologic factors to predict the onset of ICANS would represent significant progress for clinical management of ICANS. Methods We collected plasma samples from 12 adult patients with varying ICANS severity following CAR-t therapy, aged 24-74 years. Diagnoses were diffuse large B cell lymphoma (DLBCL), transformed follicular lymphoma (TFL), and primary mediastinal B cell lymphoma (PMBCL) in varying stages of progression or relapse. Pre-CAR-t, midpoint and 7 or 8 day post CAR-t samples were evaluated with multiplex cytokine arrays to quantify relative levels of 105 angiogenic cytokines. Results were compared between two groups: patients who did not develop ICANS (n=5), and patients who developed any grade of ICANS (n=7; 2 patients grade 0-2, 5 patients grade 3-4). Results There was a trend toward higher baseline relative levels of two angiogenic factors, ApoA1 and Angiogenin, in patients with ICANS relative to those without. Interestingly, ApoA1 increased over time in patients who did not develop ICANS; a 320 +/- 56 % increase in ApoA1 occurred from baseline to day 7/8. In contrast, ApoA1 decreased to 88 +/- 25% of baseline by day 7/8 in patients who developed ICANS (No ICANS vs ICANS; p=0.003). Similarly, Angiogenin increased by 289 +/- 77% over baseline by day 7/8 in patients who did not develop ICANS, while it decreased to 98 +/- 24 % of baseline by day 7/8 in patients who developed ICANS (No ICANS vs ICANS, p = 0.03). Conclusion Our data suggests that ApoA1 and Angiogenin levels at baseline, and changes in ApoA1 or Angiogenin over time, may indicate risk of ICANS. This correlation requires validation in a larger patient population as well as quantification of absolute ApoA1 and Angiogenin concentrations in blood. If ApoA1 and Angiogenin baseline levels are indeed correlated with the risk of ICANS, this may represent major progress in clinical management of ICANS.