Developed Cytokine Release Syndrome Research Articles

Effects of Consolidation Therapy With Autologous Hematopoietic Stem Cell Transplantation After BCMA-CAR T-Cell Therapy on the Survival of Patients With Relapsed or Refractory Multiple Myeloma

Despite the success of chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory multiple myeloma (RRMM), failure after CAR T-cell therapy remains an unmet medical need. An effective consolidation therapy after CAR T-cell therapy may improve the prognosis of RRMM. To investigate the effects of consolidation therapy with autologous hematopoietic stem cell transplantation (AHCT) after B-cell maturation antigen (BCMA)-targeted CAR T-cell therapy on the prognosis of RRMM patients. This retrospective study included 39 RRMM patients who received BCMA-targeted CAR T-cell therapy. Basic clinical, therapy, and outcome data were collected, and factors associated with survival were analyzed. Among the 39 RRMM patients included in the study, 15 had high-risk cytogenetics and 11 had extramedullary disease (EMD). All 39 patients reached peak CAR T-cell expansion within 28 days after infusion. Twenty-six patients developed cytokine release syndrome, including 12 grade 1 and 14 grade 2 cases. Survival analysis revealed that high-risk cytogenetics, high tumor load (International Staging System [ISS] stage III), and EMD were negatively associated with progression-free survival (PFS) and overall survival (OS). Thirteen patients received consolidation AHCT therapy 50-276 days after CAR T-cell therapy, with a median interval of 92 days. No serious complications occurred after consolidation AHCT. Survival analysis showed that consolidation AHCT effectively improved OS and PFS over maintenance chemotherapy. Moreover, Cox regression analysis identified low tumor load (ISS stage I/II) and consolidation AHCT as independent predictors of superior PFS and OS and high-risk cytogenetics as an independent risk factor for poor PFS. Consolidation AHCT after CAR T-cell therapy in RRMM patients can improve patient survival.

Real world experience of bispecific fusion protein in patients with metastatic uveal melanoma: Can we deliver?

e21504 Background: Effective treatments for patients with metastatic uveal melanoma has remained a longstanding unmet need. Poor response rates to checkpoint inhibitors has increased the need for patients to access new ways of targeting this disease. Tebentafusp is a first in class T Cell receptor bispecific fusion protein that has demonstrated an overall survival benefit. However although licensed it has yet to be approved in the UK for wider use. Methods: Prospective data collection on five patients receiving tebentafusp through the Managed Access Programme at a cancer centre that had not taken part in any trials of this therapy before. Patients were permitted with metastatic uveal melanoma; ECOG performance status 0-1 and were HLA-A*02:01 positive. Protocols were disseminated across the wider cancer teams for the management of side effects including cytokine release syndrome. Patients received extended monitoring for at least 16 hours, and vital signs (blood pressure, heart rate, temperature and pulse oximetry) taken every 2-4 hours. Drop in systolic BP < 20mmHg treated with IV fluids. Results: Five patients with advanced uveal melanoma participated in the Access Programme at one cancer site to assess efficacy, tolerability and workforce upskilling and capability with a first in class bispecific fusion protein therapy. All patients were HLA-A*02:01 positive. The patients commenced therapy between November 2021 and July 2023. All were male; median age 66. Four patients developed cytokine release syndrome commencing at cycle one. These patients required intravenous fluids for CRS grade 2, no patients required vasopressors. One patient required IV hydrocortisone. Four patients developed skin toxicity. These were managed with antihistamines and steroids. Three patients stopped due to confirmed disease progression, receiving 2-7 cycles; one made an informed decision to stop due to grade 3 skin toxicity. One patient continues on tebentafusp and has received 32 cycles to date. They recently had treatment paused for ablation and resection of oligometastatic disease that found residual uveal melanoma and have restarted. Conclusions: Real-world data suggests that using a gp100-targeting TCR/anti-CD3 bispecific fusion protein is tolerated and deliverable in new settings. Tebentafusp was delivered without any medical emergencies and CRS was successfully managed with proactive fluid management and steroids. The rate and grading of side effects reflects that described in the large randomised controlled trial. Patients with uveal melanoma can derive ongoing clinical benefit - including one patient who has received 32 cycles and proceeded to surgical resection of oligometastatic disease. Through workplace education and upskilling, the proactive management of the side effects including cytokine release syndrome can be managed in the oncology inpatients and seamlessly moved to outpatient settings.

Safety and efficacy of CD7-CAR-T cell in patients with relapsed/refractory T-lymphoblastic leukemia/lymphoma: Phase I dose-escalation/dose-expansion study.

6515 Background: Patients with relapsed/refractory T-lymphoblastic leukemia/lymphoma (r/r T-ALL/LBL) are clinically manifested by rapid disease progression, poor prognosis and lack of therapeutic options. There is an urgent need to develop other effective modalities. Apart from its expression in normal T and NK cells and no expression in other tissue cells, CD7 is highly expressed in T-ALL/LBL cells. Therefore, CD7 is considered a potential target for the development of CAR-T therapy for T-ALL/LBL. The challenge, however, is to avoid fratricide caused by the expression of CD7 in T cells. We developed a CAR-T cell injection based on CD7 nano antibodies, named PA3-17 injection, by blocking the expression of CD7 molecule on the surface of T cells through anti-CD7 protein expression blocker (PEBL) and evaluate the safety, efficacy and Recommended Phase II Dose (RP2D) of PA3-17 Injection in patients with r/r T-ALL/LBL in a phase I clinical study. Methods: The clinical study (NCT05170568) adopted a "3+3" dose escalation schema and proceed cohort expansion. T-ALL/LBL patients who met the inclusion/exclusion criteria were deployed by entering three dose groups (DL: 0.5×106, 2×106, 4×106 CAR-T/kg) to evaluate the initial safety, efficacy and dose-limited toxicities (DLTs). All patients were treated with lymphodepleting chemotherapy pre-treatment before CAR-T cell infusion. The primary endpoints were DLTs and maximum tolerable dose (MTD). Results: As of Nov 28th, 2023, a total of 12 patients were enrolled (3 patients in dose 1, 2, 3 group, 3 patients in RP2D group), all of whom received a single infusion of PA3-17 injection and completed a 28- day DLTs assessment. The median age of enrolled patients was 33.5 years (range 20-64), and 25.0% (3/12) of patients had previously received hematopoietic stem cell transplantation. No DLTs occurred. The RP2D was 2×106 CAR-T/kg. The safety analysis showed that 83.3% (10/12) of patients developed cytokine release syndrome (CRS), of which 25% (3/12) had grade 3, and no grade 4 CRS occurred, 16.7% (2/12) of patients experienced 1-2 grade of immune effector cell-associated neurotoxicity syndrome (ICANS), and no grade 3 or higher ICANS occurred. The efficacy data showed that the best ORR was 83.3% (10/12) and the CR rate was 75% (9/12). The median follow-up time was 213.5 days. Five patients (Pt 1/5/6/7/9) maintained CR for more than 6 months. One patient (Pt6) had a tumor mass with a diameter greater than 7cm at baseline prior CAR-T infusion but achieved CR 28 days after infusion, then she underwent transplantation at sixth month but died at eighth month because of heart problems, which is unrelated with PA3-17 infusion. Conclusions: PA3-17 injection has shown a good safety profile and encouraging efficacy in r/r T-ALL/LBL patients. RP2D has been determined and the key Phase II clinical study is about to begin. Clinical trial information: NCT05170568 .

Abstract CT071: Clinical activity of P-BCMA-ALLO1, a B-cell maturation antigen (BCMA) targeted allogeneic chimeric antigen receptor T-cell (CAR-T) therapy, in relapsed refractory multiple myeloma (RRMM) patients (pts) following progression on prior BCMA targeting therapy

Abstract Introduction: Despite therapeutic advances, multiple myeloma remains incurable. BCMA targeting immunotherapies, such as bispecific T-cell engagers (TCE) and autologous CAR-T provide high response rates, but relapses are common. Autologous CAR-T are logistically challenging due to the need for apheresis, prolonged manufacturing and occasional manufacturing failures. Importantly, pts who have progressed after a prior BCMA targeting immunotherapy are an emerging area of high unmet need. Emerging data indicate that autologous CAR-T have lower clinical activity in pts ho have progressed on TCE. Methods: P-BCMA-ALLO1 is an allogeneic CAR-T therapy manufactured from healthy donor T-cells available “off-the-shelf” and being evaluated in a phase 1 clinical trial (P-BCMA-ALLO1-001) in RRMM pts. This primary objective is to determine the maximum tolerated dose of P-BCMA-ALLO1, and the key secondary objective is to investigate the anti-myeloma activity. The pts must have progressed on a prior proteasome inhibitor, immunomodulatory drug and anti-CD38 monoclonal antibody. The study allows enrollment of pts who have received prior BCMA targeting therapy. The study is exploring escalating P-BCMA-ALLO1 doses and several different lymphodepletion chemotherapy (LD) regimens. Here we report the safety and early efficacy results for the 5 pts who were treated with P-BCMA-ALLO1 after having progressed on BCMA targeting CAR-T, TCE or both. These pts were treated in arms P1 (LD: cyclophosphamide (cy) 500 mg/m2 + fludarabine (flu) 30 mg/m2 X 3 days) or arm P2 (LD: cy 1000 mg/m2 + flu 30 mg/m2 X 3 days) at a P-BCMA-ALLO1 dose of > 2 X 106 to <6 X 106 cells/kg. Results: The median pt age was 62 years and median prior lines of therapy was 10. Three pts were treated in arm P2 and 2 in arm P1. Two pts had received prior teclistamab, 2 had received prior CAR-T and 1 had received prior teclistamab and CAR-T. P-BCMA-ALLO1 was well tolerated with no dose limiting toxicities or graft vs. host disease. Three of the five pts developed cytokine release syndrome (all grade (G) 2) and one developed G2 immune effector cell neurotoxicity syndrome. Three of the five pts (60%) achieved clinical responses with all three achieving the best response of very good partial response. The two non-responders had previously received and failed to achieve clinical response with teclistamab. One pt who had previously received both teclistamab and CAR-T achieved VGPR. Conclusion: In conclusion, P-BCMA-ALLO1 is an allogeneic CAR-T that is available “on-demand” with activity in RRMM pts who have progressed following prior BCMA targeted CAR-T and TCE. We believe this is the first such report of an allogeneic CAR-T showing clinical activity in such a pt population with high unmet need. Enrollment is continuing and updated data will be presented at the meeting. Citation Format: Bhagirathbhai Dholaria, Leyla Shune, Andrew Kin, Katherine McArthur, Jeff D. Eskew, Christopher E. Martin, Sabrina Haag, Joanne McCaigue, Hamid Namini, Sam DePrimo, Stacey Cranert, Julia Coronella, Devon Shedlock, Rajesh Belani. Clinical activity of P-BCMA-ALLO1, a B-cell maturation antigen (BCMA) targeted allogeneic chimeric antigen receptor T-cell (CAR-T) therapy, in relapsed refractory multiple myeloma (RRMM) patients (pts) following progression on prior BCMA targeting therapy [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 CT071.

Abstract CT069: Targeting EpCAM via CAR T-cells is an effective treatment for gastric cancer patients and subsequent toll-like receptor signaling activation in CD36+ monocyte underlies the resulting cytokine release syndrome

Abstract EpCAM is highly expressed in various cancer types of the gastrointestinal system and at metastatic sites. It serves as a promising prognostic marker and therapeutic target. We conducted a first-in-human, open-label, single-arm, multicenter, phase 1 clinical trial following the classical "3+3" dose escalation design. The endpoints of this clinical trial are to assess the safety, efficacy, and pharmacokinetic (PK)/pharmacodynamic (PD) profile of EpCAM CAR-T. The trial is still ongoing, and our interim analysis results revealed a favorable safety profile of EpCAM CAR-T. No treatment-related deaths were observed within the 4-week follow-up period after infusion. 2 (12.5%) patients in high dose group (3*106) experienced dose-limiting toxicity (DLT) and 8 (50%) patients experienced grade 1-3 CRS. EpCAM CAR-T showed promising efficacy in gastric cancer. In gastric cancer group, the overall response rate (ORR) and disease control rate (DCR) reached 20.0% and 90.0%, respectively. However, the efficacy of EpCAM CAR-T in treating colorectal cancer was suboptimal, with an objective response rate (ORR) of 0% and disease control rate (DCR) of 50%. In our study, we observed that patients in gastric cancer (GC) group who developed cytokine release syndrome (CRS) had a weak response to CAR-T cell therapy, which is consistent with previous observations in animal models. We employed single-cell RNA sequencing (scRNA-seq) to analyze peripheral blood mononuclear cells (PBMCs) from GC group patients receiving EpCAM CAR-T treatment to explore the potential antagonism between CRS and treatment efficacy. Our findings underscore the significant role of monocytes in the regulation of CRS and treatment response. Specifically, we identified an increased abundance of Toll-like receptor (TLR)-dependent CD36+ monocytes in non-responders experiencing CRS. In a mouse model, we demonstrated that blocking TLR signaling in monocytes attenuated CRS induced by EpCAM CAR-T cells. Conversely, CD16+ monocytes were enriched in responders, displaying upregulated antigen presentation pathways and enhanced tumor infiltration capacity. In vivo, experiments revealed that blocking the antigen presentation pathway or inhibiting tumor infiltration of CD16+ monocytes resulted in reduced anti-tumor response of EpCAM CAR-T cells. Our findings highlight the critical role of intrinsic monocyte subpopulations as determinants of CAR-T efficacy and CRS. These insights may provide valuable strategies for predicting and enhancing the safety and efficacy of CAR-T cell therapy for solid tumors. Citation Format: TIanhang Luo, Zhengmao Lu, Zhongen Wu, Yuxuan Dong, Yuanyuan Zhu, Mei Feng, Shenglin Mei, Weijia Fang, Di Zhu. Targeting EpCAM via CAR T-cells is an effective treatment for gastric cancer patients and subsequent toll-like receptor signaling activation in CD36+ monocyte underlies the resulting cytokine release syndrome [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 CT069.

Phase I Clinical Study of PA3-17 Injection in Patients with Relapsed/Refractory T-Lymphoblastic Leukemia/Lymphoma

B ackground Patients with relapsed/refractory T-lymphoblastic leukemia/lymphoma (r/r T-ALL/LBL) are clinically manifested by rapid disease progression, poor prognosis and lack of therapeutic options. Currently, only Nailabine was approved by the FDA in 2005 for the treatment of T-ALL/LBL patients who did not respond to at least two chemotherapy regimens or relapsed after treatment, with an ORR of 31% and a CR of 23%. Therefore, there is an urgent need to develop other effective modalities. Apart from its expression in normal T and NK cells and no expression in other tissue cells, CD7 is highly expressed in T-ALL/LBL cells. Therefore, CD7 is considered a potential target for the development of CAR-T therapy for T-ALL/LBL. The challenge, however, is to avoid fratricide caused by the expression of CD7 in T cells. We developed a CAR-T cell injection based on CD7 nano antibodies, named PA3-17 injection, by blocking the expression of CD7 molecule on the surface of T cells through anti-CD7 protein expression blocker (PEBL). After thorough pre-clinical studies demonstrating its safety and efficacy, PA3-17 injection was Investigational New Drug (IND) approved in China in August 2021, and here we report preliminary safety and efficacy data for PA3-17 injection in adult r/r T-ALL/LBL patients in a Phase I clinical study. M ethodology The Phase I clinical study (NCT05170568) adopted a classic “3+3” dose escalation schema. T-ALL/LBL patients who met the inclusion/exclusion criteria were deployed by entering three dose groups (DL: 0.5×10 6, 2×10 6, 4×10 6 CAR-T/kg) to evaluate the initial safety, efficacy and dose-limited toxicitys (DLTs). All patients were treated with lymphodepleting chemotherapy pretreatment before CAR-T cell infusion. The primary endpoints were DLTs and maximum tolerable dose (MTD). R esults As of June 30 th, 2023, a total of 9 patients were enrolled (3 subjects in each dose group), all of whom received a single infusion of PA3-17 injection and completed a 28-day DLTs assessment. The median age of enrolled patients was 33 years (range 20-64), and 33% (3/9) of patients had previously received hematopoietic stem cell transplantation. The safety analysis showed that 78% (7/9) of patients developed cytokine release syndrome (CRS), of which 33% (3/9) had grade 1-2, 44% (4/9) had grade 3, and no grade 4 CRS occurred, 22% (2/9) of patients experienced 1-2 grade of immune effector cell-associated neurotoxicity syndrome (ICANS), and no grade 3 or higher ICANS occurred. No DLTs occurred in any patients. The efficacy data (Figure 1) showed that the best ORR and CR were both 78% (7/9). The median follow-up time was 137 days, of which 1 patient (Pt1) sustained CR for 9 months until recurrence, 1 patient (Pt3) underwent transplantation after being evaluated as CR in 3 month. One patient (Pt6) had a tumor mass with a diameter greater than 7cm at baseline prior CAR-T infusion but achieved CR 28 days after infusion and is in sustained remission now (Figure 1). C onclusion PA3-17 injection has shown a good safety profile and encouraging efficacy in r/r T-ALL/LBL patients, and long-term data are continuing to be collected during follow-up.

Safety and Efficacy of Teclistamab in Patients with Relapsed or Refractory AL Amyloidosis: A Retrospective Case Series

Introduction: Teclistamab (Tec) is a T-cell redirecting bispecific antibody targeting CD3 on T-cells and B-cell maturation antigen on plasma cells. It has demonstrated a high rate of deep responses in patients with heavily pre-treated multiple myeloma in the MajesTec-1 study, gaining FDA approval in October 2022. However, patients with amyloidosis were excluded from the MajesTec-1, so the safety and efficacy of Tec in patients with AL amyloidosis is not currently known. Methods: We retrospectively analyzed adult patients with biopsy-proven AL amyloidosis that were treated with Tec 12/2022-7/2023 at the Hospital of the University of Pennsylvania. The revised Mayo Clinic criteria were used for staging. Adverse events (AE) were extracted from the electronic medical record. Patients were assessed for hematologic and organ response per consensus guidelines. Results: Four patients were included in this case series (Figure 1). The median age was 63 at time of Tec (range 59-65), 3/4 were female, and all had multi-organ involvement of amyloidosis, including 3/4 with cardiac (2 Stage III, 1 Stage IV), 4/4 with renal, 2/4 with gastrointestinal involvement, and 3/4 with subcutaneous involvement. All patients also met IMWG criteria for multiple myeloma. The median number of prior lines of therapy was 7, including cyclophosphamide, bortezomib, daratumumab, lenalidomide in all patients and pomalidomide in 3/4, elotuzumab in 2/4, carfilzomib in 2/4, bendamustine in 2/4, venetoclax in 1/4, and belantamab-mafodotin in 1/4 . Two patientshad previously underwent autologous stem cell transplant. The ORR was 100%, with all four patients eventually achieving hematologic complete response (hCR). The median time to hematologic very good partial response (hVGPR) was 12 days (range 11-12 days) and hCR was 62 days (range 32-117 days). One patient achieved a cardiac response at 144 days and another achieved a renal response at 191 days. All patients were still alive and in continued hCR at the time of this report, with a median duration of follow-up of 210 days (range 173-215 days) and a median completion of 4.5 cycles of Tec (range 2-7). Regarding safety, 2/4 patients developed cytokine release syndrome, 1 Grade I on day of first priming dose and the other Grade II on date of second priming dose, both of which lasted one day and improved after tociluzumab administration. No patients developed ICANS. Two patients had treatment-emergent neutropenia occurring several cycles into therapy, with one presenting as agranulocytosis that improved with G-CSF and treatment discontinuation. Additional non-hematologic AE of note included one patient developing Grade 1 acute kidney injury and one developing Grade 3 sclerouveitis, all during the first 5 days of exposure. No patients developed cardiac decompensation while on therapy. Conclusion: In this series of heavily pre-treated patients, Tec showed outstanding depth of response with all patients achieving hCR (FLC-diff <10 mg/L and negative serum/urine immunofixation), associated with organ responses in 2/4 patients (Figure 1). Tec was well-tolerated, with cytokine release syndrome being manageable in this population, though acute kidney injury and treatment-limiting neutropenia did occur. Teclistamab shows promise in treating patients with relapsed AL amyloidosis, but further prospective studies and longer duration of follow-up are needed to determine long-term outcomes and to optimize safety in this at-risk patient population.

Chimeric Antigen Receptor T-Cell (CAR-T) Therapy in Secondary Central Nervous System Large B-Cell Lymphoma (SCNSL): A Multicenter Retrospective Analysis

Introduction Secondary central nervous system (CNS) involvement develops in 2-10% of large B-cell lymphoma (LBCL) cases. Current treatment approaches for relapsed or refractory CNS disease generally do not provide durable responses. Limited data suggest efficacy and feasibility of CAR-T therapy in SCNSL. We report here the largest multicenter retrospective analysis of the safety and efficacy of CD19-directed CAR-T therapy in SCNSL patients. Methods This study included SCNSL patients who received commercial CD19-directed CAR-T therapy at 9 academic institutions in the United States between 2016 and 2022. SCNSL was defined as history of parenchymal and/or leptomeningeal/cerebrospinal fluid (CSF) involvement by lymphoma at any time prior to receiving CAR-T therapy. Systemic response was assessed using the Lugano criteria while CNS response was assessed as per International PCNSL Collaborative Group criteria. Kaplan-Meier curves were generated for progression-free survival (PFS) and overall survival (OS) for entire cohort, as well as subsets of patients with and without active CNS disease at the time of CAR-T infusion. Results Ninety patients were included in the analysis, with baseline characteristics shown in Table 1. CAR-T products utilized include axicabtagene ciloleucel (n= 38, 42%), tisagenlecleucel (n=37, 41%) and lisocabtagene maraleucel (n= 15, 14%). Fludarabine/cyclophosphamide was used as lymphodepletion in 84 patients (93%). 28 patients received CNS directed radiation therapy (RT) prior to CAR-T infusion (31%) within a median time of 28.5 days (range 5 - 906) from last day of RT. Amongst all patients at the time of CAR-T infusion 82 (91.1%) had active CNS and/or systemic involvement while 8 (8.9%) had no evidence of disease; 68 (75.5%) had active CNS involvement while 22 (24.5%) had a prior history of CNS involvement but no active at the time of CAR-T infusion. ( Table 1) Median follow up all patients was 0.5 year (range 0.01 - 4.7). 71 patients (79%) developed cytokine release syndrome (CRS; median time to onset 3 days) with 3.3% patients developing Grade 3-4. Immune effector cell-associated neurotoxicity syndrome (ICANS; median time to onset 5 days) was reported in 55 patients (61%), with 28.8% developing Grade 3-4. No patients died due to CRS or ICANS. At 1-month post CAR-T, 80 patients were evaluable for CNS response and 71 patients in the entire cohort were evaluable for systemic response. Similarly, at 3-months these numbers were 66 and 60, respectively. Objective response rates (ORR) were 75% and 80% at 1-month for CNS and systemic disease respectively, while corresponding ORRs at 3-months were 68% and 76.7%. At 1- and 3-months timepoint 36 (45%) and 33 (50%) patients, respectively achieved CNS complete remission (CR), while 44 (62%) and 42 (70%) patients respectively achieved systemic CR. 1- and 2-year PFS for entire cohort were 25% (95%Cl 15% - 34%) and 16% (95%Cl 8.5% - 28%) respectively, while 1- and 2-year OS were 46% (95%Cl 36% - 59%) and 31% (95%Cl 22% - 46%). Non-relapse mortality (NRM) were 4.6% (95%CI, 1.8% -12%) and 7.2% (95%CI 2.9% - 18%) at 1- and 2-year. Cumulative incidence of relapse at 1- and 2-year were 73% (95%Cl 63% - 83%) and 77% (95%Cl 68% - 88%), respectively. ORRs for CNS response in patients with active CNS disease at 1-month and 3-month interval were 71% (n=45) and 60% (n=31). Similarly, ORR for systemic response with active CNS disease at 1-month and 3-month interval were 85% (n=43) and 74.3% (n=32).The 2-year PFS for patients with and without active CNS disease at CAR-T infusion were 12% (95%Cl 5.4% - 27%) and 28% (95%Cl 12% - 65%) respectively, with a corresponding OS of 25% (95%Cl 15% - 41%) and 58% (95%Cl 37% - 91%). ( Figure 1) The 2-year NRM rates for patients with and without active CNS disease at CAR-T infusion were 4.6% (95%Cl 1.5% - 14%) and 14% (95%Cl 3.6% - 53%) respectively, while the cumulative incidence of relapse in similar order were 83% (95%Cl 73% - 95%) and 58% (95%Cl 39% - 88%). Conclusion In this largest known case series to date, CAR-T therapy appeared safe and feasible in patients with SCNSL, but is associated with high rates of treatment failure, particularly in patients with active CNS disease at CAR-T infusion. This warrants further study of optimal CNS-directed treatment strategies prior to CAR-T, development of novel cellular therapy platforms or consideration of post CAR-T maintenance therapy in these high-risk patients.

Teclistamab in Relapsed Refractory Multiple Myeloma Patients on Dialysis: A French Experience

Background Up to 50% of patients with multiple myeloma (MM) have renal impairment at diagnosis; about 5% require dialysis. Prognosis of these patients remains significantly worse and associated with early death. Teclistamab is a humanized immunoglobulin bispecific antibody directed against the BCMA and CD3 receptors and demonstrated clinical benefit as monotherapy for the treatment of patients with relapsed/refractory MM (RRMM) who have received at least 3 prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody. However, data in patients with dialysis-dependent renal failure are missing. Here, we report safety and efficacy data from RRMM patients treated with teclistamab in a dialysis setting. Methods This retrospective study included RRMM patients with end-stage renal failure requiring dialysis treated with teclistamab in French Acces Précoce program. Teclistamab was given every week at dose of 1.5 mg/kg subcutaneously after step-doses of 0.06 and 0.3 mg/kg. Premedication (including dexamethasone for step up doses and first full dose) were administered before teclistamab administration according the FDA and EMA recommendations. Teclistamab was administered after dialysis, but precise schedules vary slightly according to the rhythm of dialysis of each patient. Results To date, 13 patients with end-stage renal failure requiring dialysis have been treated with teclistamab in French hospitals. The median age was 67 years [59-83]. Median time since diagnosis was 6 years [2-9]. The median number of previous lines of therapy was 4 [3-9]. Most of the patients had a myeloma-related end-stage renal failure. Isotype of myeloma was free light chains in 75% of cases. Step-up dosing modalities were similar to the patients with normal renal function with the only difference being that teclistamab is administered within 1-2 days after dialysis. Half of the patients developed cytokine release syndrome grade 1 or 2, treated with tocilizumab, and addition of dexamethasone for one patient. No ICANS was reported. The infection rate seems not to be superior to non-dialysis patients with only grade < 3 events, except for one patient who presented a severe Covid infection and a pseudomonas aeruginosa bacteriemia, both resolved after short break of teclistamab and specific treatments. Taking precautions when interpreting such a small cohort, all evaluable patients responded and obtained a VGPR or better. With a median follow-up of 4 months, no progression or deaths were reported. Updated data will be presented during the meeting. Conclusion These first results suggest that teclistamab is a feasible, effective and safe option for patients with RRMM who need dialysis. These data are very important for such subgroup of patients typically excluded from clinical trials and for CAR T cell therapies that usually requires fludarabine-based lymphodepletion.

Enhancing MHC-Independent T Cell Receptors Using Rational Protein Engineering

The paradigm of synthetic receptors, chimeric antigen receptors (CARs), combine MHC-independence with T cell activation. While T cells engineered to express CARs are successful for some patients, the majority are not cured and clinical failures often result from CAR-driven T cell dysfunction (Lynn R, Nature 2019; Selli ME, Blood 2023). Simultaneously, many patients develop cytokine release syndrome, a hyperinflammatory state resulting from uncontrolled CAR-driven immune activation, indicating that CARs can drive both failure and toxicity. We hypothesized that these limitations result from CAR design which, in its simplicity, bypasses natural TCR regulation. To re-engage endogenous T cell regulatory circuits, we replaced the variable region of the TCR α and β chains with the CD19 binding domain used in several clinical CAR constructs. As shown recently by others (Liu Y, Sci Transl Med 2021; Mansilla-Soto Nature Medicine 2022), we found that this format of synthetic receptor expressed on the cell surface, clustered with endogenous CD3 molecules, and drove T cell cytotoxicity against CD19+ leukemia (Nalm6). Intriguingly, surface expression of these MHC-independent TCRs (miTCR) was markedly reduced in comparison to transgenic full-length TCRs and CARs. Examination of the chimeric interface created by joining the antibody and TCR parent chains revealed significant biochemical conflicts that, based on predictive modeling, disrupted naturally-occurring hydrostatic interactions and associated hydrogen bonds, collectively resulting in steric “strain” on the miTCR. We generated a series of miTCR mutants which resolved these conflicts in a step-wise fashion to more closely approximate the “relaxed” state of endogenous TCRs. We found that most mutations improved miTCR surface expression, and more importantly that some mutations significantly boosted T cell functionality as compared to the wild-type miTCR. Impressively, one mutant that closely approximated endogenous TCR structure (mut035) enabled functionality similar to CD19 CARs in short-term cytotoxicity assays. To further evaluate the functional implications of targeted interface mutation, we subjected miTCRs to chronic in vitro stimulation assays in which engineered T cells are exposed to high quantities of Nalm6 for prolonged periods until T cell lose function. We observed that mut035 outperformed all other miTCRs, but all miTCR T cells lost the ability to kill targets earlier than CAR T cells. To determine if a lack of costimulation was the cause of this reduced efficacy we engineered Nalm6 cells to express ligands for CD28 (CD80) and 41BB (41BBL). In the presence of these ligands, long-term functionality all miTCR T cells was profoundly improved. Notably, mut035 T cells persisted longer and killed Nalm6 better than CD19 CAR T cells under conditions of persistent and high-intensity stimulation. Finally, to determine if CD28 or 41BB engagement was most supportive of miTCR function we designed a “priming” experiment. miTCR T cells were initially cultured with Nalm6 expressing either no, one or both costimulatory ligands and then, after tumor clearance, were re-challenged with WT Nalm6, mirroring endogenous immune responses to infection. mut035 T cells initially exposed to CD80 were unable to clear WT cells on re-challenge, however priming with 41BBL enabled potent and prolonged co-stimulation-independent killing of large Nalm6 burdens, suggesting engagement of endogenous T cell functionality. These data demonstrate that classical approaches to combine protein domains can lead to biochemical conflicts that restrain chimeric protein function. Targeted mutation significantly enhanced miTCR function to exceed CAR under conditions of high-burden, high-antigen tumors.

CAR T cells and time-limited ibrutinib as treatment for relapsed/refractory mantle cell lymphoma: the phase 2 TARMAC study

AbstractCD19-directed chimeric antigen receptor T cells (CAR-T) achieve high response rates in patients with relapsed/refractory mantle cell lymphoma (MCL). However, their use is associated with significant toxicity, relapse concern, and unclear broad tractability. Preclinical and clinical data support a beneficial synergistic effect of ibrutinib on apheresis product fitness, CAR-T expansion, and toxicity. We evaluated the combination of time-limited ibrutinib and CTL019 CAR-T in 20 patients with MCL in the phase 2 TARMAC study. Ibrutinib commenced before leukapheresis and continued through CAR-T manufacture for a minimum of 6 months after CAR-T administration. The median prior lines of therapy was 2; 50% of patients were previously exposed to a Bruton tyrosine kinase inhibitor (BTKi). The primary end point was 4-month postinfusion complete response (CR) rate, and secondary end points included safety and subgroup analysis based on TP53 aberrancy. The primary end point was met; 80% of patients demonstrated CR, with 70% and 40% demonstrating measurable residual disease negativity by flow cytometry and molecular methods, respectively. At 13-month median follow-up, the estimated 12-month progression-free survival was 75% and overall survival 100%. Fifteen patients (75%) developed cytokine release syndrome; 12 (55%) with grade 1 to 2 and 3 (20%) with grade 3. Reversible grade 1 to 2 neurotoxicity was observed in 2 patients (10%). Efficacy was preserved irrespective of prior BTKi exposure or TP53 mutation. Deep responses correlated with robust CAR-T expansion and a less exhausted baseline T-cell phenotype. Overall, the safety and efficacy of the combination of BTKi and T-cell redirecting immunotherapy appears promising and merits further exploration. This trial was registered at www.ClinicalTrials.gov as #NCT04234061.

Racial and ethnic differences in clinical outcomes among patients with multiple myeloma treated with CAR T-cell therapy

AbstractIdecabtagene vicleucel (ide-cel) was the first chimeric antigen receptor T-cell therapy to gain US Food and Drug Administration approval for patients with relapsed/refractory multiple myeloma (RRMM). The clinical outcomes of standard of care (SOC) ide-cel in racially and ethnically diverse populations have been understudied. This study pooled data from 207 patients with RRMM (28% patients of racial and ethnic minority groups) treated with SOC ide-cel across 11 institutions to examine racial and ethnic differences in the incidence of toxicities and adverse events, response to ide-cel, and survival. This study included 22 (11%) Hispanic, 36 (17%) non-Hispanic Black, and 149 (72%) non-Hispanic White patients with RRMM. Compared with Hispanic and non-Hispanic White patients, non-Hispanic Black patients had higher median levels of C-reactive protein (1.0, 0.8, and 3.5 mg/dL, respectively; P = .02) and baseline ferritin (362.0 vs 307.0 vs 680.5, respectively; P = .08) and were more likely to develop cytokine release syndrome (77%, 85%, and 97%, respectively; P = .04). Although best overall response rate was lower among Hispanic patients (59%) than among non-Hispanic Black (86%) and White patients (86%; P = .01), there were no racial and ethnic differences in progression-free or overall survival. We provide, to our knowledge, the first and largest investigation of clinical outcomes of SOC ide-cel by race and ethnicity. Despite differences in safety and response to ide-cel, our findings encourage the use of ide-cel in all patients with RRMM. These findings should be confirmed in larger samples of diverse patients with RRMM, with longer follow-up time.

Negative Prognostic Impact of High-Dose or Long-Term Corticosteroid Use in Patients with Relapsed or Refractory B-Cell Lymphoma Who Received Tisagenlecleucel

The prognostic impact of corticosteroid therapy in patients receiving tisagenlecleucel (tisa-cel) treatment who are more likely to develop cytokine release syndrome (CRS) remains unclear. This study aimed to evaluate the clinical impact and lymphocyte kinetics of corticosteroid administration for CRS in 45 patients with relapsed and/or refractory B cell lymphoma treated with tisa-cel. This was a retrospective evaluation of all consecutive patients diagnosed with relapsed and/or refractory diffuse large B cell lymphoma, follicular lymphoma with histologic transformation to large B cell lymphoma, or follicular lymphoma who received commercial-based tisa-cel treatment. The best overall response rate, complete response rate, median progression-free survival (PFS), and median overall survival (OS) were 72.7%, 45.5%, 6.6 months, and 15.3 months, respectively. CRS (predominantly grade 1/2) occurred in 40 patients (88.9%), and immune effector cell-associated neurotoxicity syndrome (ICANS) of all grades occurred in 3 patients (6.7%). No grade ≥3 ICANS occurred. Patients with high-dose (≥524 mg, methylprednisolone equivalent; n = 12) or long-term (≥8 days; n = 9) corticosteroid use had inferior PFS and OS to patients with low-dose or no corticosteroid use (both P < .05). The prognostic impact remained even in 23 patients with stable disease (SD) or progressive disease (PD) before tisa-cel infusion (P = .015). but not in patients with better disease status (P = .71). The timing of corticosteroid initiation did not have a prognostic impact. Multivariate analysis identified high-dose corticosteroid use and long-term corticosteroid use as independent prognostic factors for PFS and OS, respectively, after adjusting for elevated lactate dehydrogenase level before lymphodepletion chemotherapy and disease status (SD or PD). Lymphocyte kinetics analysis demonstrated that after methylprednisolone administration, the proportions of regulatory T cells (Tregs), CD4+ central memory T (TCM) cells, and natural killer (NK) cells were decreased, whereas the proportion of CD4+ effector memory T (TEM) cells was increased. Patients with a higher proportion of Tregs at day 7 had a lower incidence of CRS, but this did not affect prognosis, indicating that early elevation of Tregs may serve as a biomarker for CRS development. Furthermore, patients with higher numbers of CD4+ TCM cells and NK cells at various time points had significantly better PFS and OS, whereas the number of CD4+ TEM cells did not impact prognostic outcomes. This study suggests that high-dose or long-term corticosteroid use attenuates the efficacy of tisa-cel, especially in patients with SD or PD. Additionally, patients with high levels of CD4+ TCM cells and NK cells after tisa-cel infusion had longer PFS and OS.

Early results from a phase 1, multicenter trial of PSCA-specific GoCAR T cells (BPX-601) in patients with metastatic castration-resistant prostate cancer (mCRPC).

140 Background: Prostate stem cell antigen (PSCA) is expressed in &gt;80% of metastatic prostate cancers. BPX-601 is an autologous PSCA-directed chimeric antigen receptor (CAR)-T cell immunotherapy engineered to express a rimiducid-inducible MyD88/CD40 costimulation switch to enhance T cell potency and persistence. Safety and activity of BPX-601 with rimiducid in mCRPC and pancreatic cancer is being assessed in an ongoing, phase 1/2 clinical trial (NCT02744287). Results from the first two prostate cancer cohorts are reported. Methods: Eligible mCRPC patients (pts) had progressed on ≥ 2 prior therapies including an androgen receptor antagonist and taxane. Using a 3+3 design, pts received lymphodepleting chemotherapy followed by a single-dose of 5 x 106 BPX-601 cells/kg and single or weekly doses of 0.4 mg/kg rimiducid infused over 2 hours beginning 7 days following cell infusion. Primary objective of phase 1 is to determine safety, tolerability and MTD or RP2D. Secondary objectives include characterization of clinical efficacy, PK of rimiducid and long-term safety. Biomarkers indicative of GoCAR-T cell expansion in blood, immune cell activity, and infiltration to tumor are being monitored. Results: As of Sept 2022, 8 pts received BPX-601 5x106 cells/kg; 3 and 5 pts received a single or weekly (range: 1-30) doses of rimiducid. Most common ≥ grade 3 adverse events were myelosuppression, attributed to lymphodepletion. All patients developed cytokine release syndrome (6 G1, 2 G3). Immune-effector cell associated neurotoxicity syndrome occurred and resolved in 2 pts (1 G1, 1 G4). One pt experienced a DLT of neutropenic sepsis (G5) with possible hemophagocytic lymphohistiocytosis (eg, IL-18, ferritin, M-CSF, fractalkine, MIP-1β and IL-1RA levels were elevated). Of 7 evaluable pts, PSA50 response was observed in 3 pts at Day 28. Preliminary RECIST-based results demonstrated partial response in 1, stable disease in 3, 1 progressive disease; at data cut off 2 had not reached imaging timepoint. One patient continues on study with SD after &gt;9 months, with persistent evidence of rimiducid responsiveness. Peripheral blood BPX-601 cells expanded to an average of 3466 vector copies / μg DNA +/- 3109 during the first week with continued re-expansion to an average of 30234 copies/ug DNA +/- 67031) following rimiducid treatment. Serum IFN-γ, GM-CSF and IL-6 rapidly increased over 24 hours following rimiducid treatment (mean IFN-γ increase 26.9-fold ± 14.2) and subsequently diminished over 2 days. Conclusions: BPX-601, a PSCA-directed GoCAR-T cell product, has preliminary evidence of biologic activity with toxicity characteristic of previously reported CAR-T studies. Markers of rimiducid-induced GoCAR-T cell activation and proliferation were observed. Exploration of escalating weekly rimiducid doses &gt; 0.4 mg/kg and BPX-601 cell doses is planned. Clinical trial information: NCT02744287 .

Late Infections in Patients Receiving Chimeric Antigen Receptor T Cell Therapy: Real World Retrospective Experience Form a Single Centre in United Kingdom

Introduction and aims: Chimeric Antigen Receptor T-cell therapy (CAR-T) cell therapy has emerged as an effective therapy for relapsed haematological malignancies. Due to the unique nature of its mechanism of action and on-target, off-tumour toxicity, leading to myelosuppression and prolonged B-lymphocyte aplasia, the risk of infectious complications is substantially increased during the first year (12-55%) based on the data from the registration trials.1,2 Here we present real world data from a single UK centre on late infections in CAR-T treated patients. Methods: Retrospective data was collected on 40 consecutive patients treated with CAR-T cell therapy for any indication at Bristol Haematology and Oncology Centre between February 2019 and September 2021. Results: A total of 40 patients received Axicabtagene Ciloleucel (n=26), Tisagenlecleucel (n=12), Brexucabtagene Autoleucel (n=1) and JNJ-68284528 (CARTITUDE-1) (n=1) with a median follow-up duration of 24 months (range 11-42) months. Median age was 59 (range 16-76), 67.5% were male (M=27, F=13) and 80% received bridging therapy. Median number of prior therapies received was 3 (range 2-5) with 40% of patients (n=16) having had a prior stem cell transplant. Of the total Non-Hodgkin lymphoma (NHL) patients (n=34), half (n=17) had progressive disease (PD) at the time of receiving CAR-T therapy while one-third of B-Acute lymphoblastic leukaemia (B-ALL) patients (n=4) had PD. 15% of patients (n=6) had 7 episodes of infections in the 30 days prior to CAR-T therapy and 10% (n=4) had moderate- severe pre-existing neutropenia. All patients received anti-viral and anti-fungal prophylaxis with Acyclovir and Fluconazole according to institutional protocol. Pneumocystis Jiroveci prophylaxis with Co-trimoxazole or Pentamidine was started from day 28 of CAR-T. All patient received standard lymphodepletion with Fludarabine and Cyclophosphamide. Significant neutropenia was observed in majority of patients (95%) with 7.5% having persisting neutropenia beyond 12 months. Of these patients, G-CSF therapy was used in 81% of patients (n=31). Hypogammaglobulinemia was present in 60% of patients following treatment (n=24) of which 37.5% (n=9) received at least one dose of Intravenous immunoglobulin (IVIg). 80% of patients developed Cytokine release syndrome and 32.5% had immune effector cell-associated neurotoxicity syndrome of any grade, with only 20% of patients (n=8) receiving steroid therapy. Total number of infections observed over the median follow-up period were 50, seen in 60% of patients (n=24). Types of infections over time are shown in Fig I. Highest number of infections (52%) were present in 2 - 12 month period (n=26) while 14% of all infections were observed after 12 months (n = 7). 42% of infections were mild (not requiring intervention), 46% moderate (requiring in-patient or out-patient treatment), 8% severe (requiring intensive care therapy) and 4% were fatal. In multivariate analysis, performance status was the only factor associated with higher infection risk (Hazard Ratio 2.83, P-value 0.027). All patients with B-ALL (n=6) achieved CR at day 30 post CAR-T while 61% of NHL patients achieved Complete response. With a median follow-up time of 24 months, 18 patients have died giving an overall survival of 55% for the entire cohort. The median overall survival of patients without any infections (A) was not reached while for patients with any infection (B) was 11 months (95% CI 3.8 - 18.2). The 2-year OS rates were 81.3% and 37.5% for Group A and B, respectively with p-value of 0.013 (Figure II). Conclusion: A small number of infections (mild-moderate) continued to occur after 12 months in our cohort of CAR-T patients suggesting that longer prophylaxis may be required in some patients on individualised basis. Despite the shortcomings of this study including retrospective nature and small sample size, there is suggestion of adverse outcomes in patients developing any infections following CAR-T, necessitating aggressive prophylactic approach including use of IVIg.

Severity of Cytokine Release Syndrome Influences Outcome After Axicabtagene Ciloleucel for Large B cell Lymphoma: Results from the US Lymphoma CAR-T Consortium.

The majority of patients with large B-cell lymphoma treated with axicabtagene ciloleucel (axi-cel), an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, develop cytokine release syndrome (CRS). Whether the lack of development of CRS with axi-cel is associated with inferior lymphoma outcomes is unknown. Additionally, relationship between CRS grade and lymphoma outcome is not well established. The US Lymphoma CAR T Consortium includes seventeen US academic centers that contribute data independently of manufacturers. We analyzed the modified intent-to-treat population of 275 patients receiving axi-cel in two different ways: 1) Two group analysis comparing no CRS with any grade CRS; 2) Three group analysis comparing grade 0 CRS with grade 1 to 2 CRS, and grade 3-5 CRS. In this large multi-center observational cohort of 275 patients receiving axi-cel, 9% (n = 24) did not develop CRS, 84% (n = 232) developed grade 1-2 CRS, and 7% (n = 19) developed grade 3 to 5 CRS. Patients without CRS, compared with those having any grade CRS, had similar overall response rates (ORR), lower complete response (CR) rates and inferior progression free survival (PFS) with no statistically significant difference in overall survival (OS). Patients experiencing grade 1 to 2 CRS had superior CR rate and PFS, as compared to those without CRS or with grade 3 to 5 CRS. Grade 3 to 5 CRS was associated with a worse OS. Overall, durable responses were seen in patients that did not develop CRS, however grade 1 to 2 CRS was associated with better outcomes while those with grade 3 to 5 experienced the worse outcomes.

CT-169 Cytokine Release Syndrome After Peripheral Blood Haploidentical Stem Cell Transplantation With Post-Transplant Cyclophosphamide: Time of Onset Matters

The use of post-transplant cyclophosphamide (PT-Cy) has favored haploidentical hematopoietic stem cell transplantation (haplo-HSCT) when an HLA-matched donor is not available or when an urgent transplant is needed. Although a high percentage of patients receiving PT-Cy haplo-HSCT develop cytokine release syndrome (CRS) after infusion, it only seems to affect prognosis in the reduced proportion of patients that develop severe CRS. Literature regarding the clinical impact of this complication is scarce. The aim of our study is to analyze new CRS characteristics and their prognostic implication on both transplant-related mortality (TRM) and overall survival (OS). From the cohort of 637 patients who underwent allo-HSCT at our center between January 2012 and December 2020, 150 patients who received PT-Cy haplo-TPH were selected for this retrospective analysis. Regarding CRS analysis, 16 patients were excluded due to the impossibility to distinguish between infectious and CRS fever. Median follow-up was 18 months (37 months for alive patients). Most patients (86%) developed CRS. The cohort was divided into two groups: patients who developed early-onset CRS (≤24h after infusion, 50%) and those with late-onset CRS or no CRS. Patients who developed early-onset CRS had a significant increase in first-year TRM (31% vs 15%, log-rank p=0.014) as well as lower first-year OS (60% vs 79%, log-rank p=0.008). Multivariate analysis of first-year TRM identified the following independent prognostic factors: SOS (HR 9.24, p<0.001), aGvHD grade ≥3 (HR 6.89, p<0.001), early-onset CRS (HR 3.09, p=0.007) and patient age at transplantation (HR 1.05 per year increment, p=0.002). Several risk factors were associated with developing early-onset CRS in a multivariate analysis: modified Baltimore haplo-HSCT platform (HR 7.54, p<0.001), active disease at transplantation (HR 2.94, p=0.015) and increased infused CD3+ cells (HR 1.05 per 107/kg increment, p=0.002). Graft-cryopreservation would be a protective factor (HR 0.14, p=0.005). We propose the definition of early-onset CRS as the one that is developed within 24h after haplo-HSCT infusion. Patients who develop early-onset CRS have a higher TRM and lower OS. However, this is a single-center retrospective study and further studies will be required in order to confirm these findings.

Safety and Efficacy of Chimeric Antigen Receptor T-Cell Therapy for Glioblastoma: A Systemic Review and Meta-Analysis.

BackgroundChimeric antigen receptor (CAR) T-cell therapy is a promising treatment option for patients with refractory hematological malignancies. However, its efficacy in glioblastoma remains unclear. Here, we performed a systematic review to summarize the safety and efficacy of CAR T-cell therapy in glioblastoma.MethodsThe PubMed, EMBASE, and Cochrane databases were searched to identify articles published before June 30, 2021 describing the use of CAR T-cell therapy in glioblastoma. Information on the toxicity of CAR T-cell therapy was summarized. The pooled objective response rate (ORR) and overall survival (OS) of patients who underwent CAR T-cell therapy were estimated using a random-effects model with an inverse-variance weighting model and quantile estimation method, respectively.ResultsOf 397 articles identified, eight studies including 63 patients with recurrent glioblastoma treated with various CAR T-cell regimens were included in the analysis. Six (9.5%) patients developed cytokine release syndrome (grade ≤2), and 16 (25.4%) experienced non-critical neurological events. The pooled ORR was 5.1% (95% confidence interval [CI], 0.0–10.4; I2 = 0.05%), and the pooled median OS was 8.1 months (95% CI, 6.7–9.5; I2 = 0.00%).ConclusionAlthough CAR T-cell therapy is a relatively safe therapeutic option in patients with glioblastoma, it shows marginal efficacy, suggesting that further research is necessary for its translation into clinical practice for the treatment of recurrent glioblastoma.

CD19/22 CAR T cells in children and young adults with B-ALL: phase 1 results and development of a novel bicistronic CAR

AbstractRemission durability following single-antigen targeted chimeric antigen receptor (CAR) T-cells is limited by antigen modulation, which may be overcome with combinatorial targeting. Building upon our experiences targeting CD19 and CD22 in B-cell acute lymphoblastic leukemia (B-ALL), we report on our phase 1 dose-escalation study of a novel murine stem cell virus (MSCV)-CD19/CD22-4-1BB bivalent CAR T-cell (CD19.22.BBζ) for children and young adults (CAYA) with B-cell malignancies. Primary objectives included toxicity and dose finding. Secondary objectives included response rates and relapse-free survival (RFS). Biologic correlatives included laboratory investigations, CAR T-cell expansion and cytokine profiling. Twenty patients, ages 5.4 to 34.6 years, with B-ALL received CD19.22.BBζ. The complete response (CR) rate was 60% (12 of 20) in the full cohort and 71.4% (10 of 14) in CAR-naïve patients. Ten (50%) developed cytokine release syndrome (CRS), with 3 (15%) having ≥ grade 3 CRS and only 1 experiencing neurotoxicity (grade 3). The 6- and 12-month RFS in those achieving CR was 80.8% (95% confidence interval [CI]: 42.4%-94.9%) and 57.7% (95% CI: 22.1%-81.9%), respectively. Limited CAR T-cell expansion and persistence of MSCV-CD19.22.BBζ compared with EF1α-CD22.BBζ prompted laboratory investigations comparing EF1α vs MSCV promoters, which did not reveal major differences. Limited CD22 targeting with CD19.22.BBζ, as evaluated by ex vivo cytokine secretion and leukemia eradication in humanized mice, led to development of a novel bicistronic CD19.28ζ/CD22.BBζ construct with enhanced cytokine production against CD22. With demonstrated safety and efficacy of CD19.22.BBζ in a heavily pretreated CAYA B-ALL cohort, further optimization of combinatorial antigen targeting serves to overcome identified limitations (www.clinicaltrials.gov #NCT03448393).

Invasive Yeast Infection after Haploidentical Donor Hematopoietic Cell Transplantation Associated with Cytokine Release Syndrome

The use of haploidentical donor hematopoietic cell transplantation (haploHCT) has expanded, but recent reports raise concern for increased rates of infectious complications. The incidence and risk factors for invasive fungal disease (IFD) after haploHCT have not been well elucidated. This study aimed to evaluate the incidence and risk factors for IFD after haploHCT. The identification of key risk factors will permit targeted prevention measures and may explain elevated risk for other infectious complications after haploHCT. This single-center retrospective study included all adults undergoing haploHCT between May 2011 and May 2021 (n=205). The 30-day and 1-year cumulative incidences of proven or probable IFD and 1-year nonrelapse mortality (NRM) were assessed. Secondary analyses evaluated risk factors for invasive yeast infection (IYI) using univariate and multivariable Cox regression models. Twenty-nine patients (14%) developed IFD following haploHCT. Nineteen (9.3%) developed IYI in the first year, 13 of which occurred early, with a 30-day cumulative incidence of 6.3% (95% confidence interval [CI], 2.9% to 9.6%) and increased NRM in patients with IYI (53.9% versus 10.9%). The majority of yeast isolates (17 of 20; 85%) were fluconazole- susceptible. The incidence of IYI in the first 30 days after haploHCT was 10% in the 110 patients (54%) who developed cytokine release syndrome (CRS) and 21% in the 29 patients (14%) who received tocilizumab. On multivariable analysis, acute myelogenous leukemia (hazard ratio [HR], 6.24; 95% CI, 1.66 to 23.37; P=.007) and CRS (HR, 4.65; 95% CI, 1.00 to 21.58; P=.049) were associated with an increased risk of early IYI after haploHCT. CRS after haploHCT is common and is associated with increased risk of early IYI. The identification of CRS as a risk factor for IYI raises questions about its potential association with other infections after haploHCT. Recognition of key risk factors for infection may permit the development of individualized strategies for prevention and intervention and minimize potential side effects.