Peak Expansion Research Articles

Allogeneic Donor-Derived Myeloid Antigen Directed CAR-T Cells - for Relapsed/Refractory Acute Myeloid Leukemia in Children after Allogeneic Hematopoietic Stem Cell Transplantation: Report of Three Cases

Introduction The outcome of HSCT among children with chemorefractory acute myeloid leukemia (AML) is poor. The incidence of relapse exceeds 50%. We hypothesized that myeloid antigen-directed CAR-T cell therapy may induce remission in children with refractory AML. Patients and methods Three pediatric patients with R/R AML were enrolled in a compassionate-use program. All cases had AML, relapsing after multiple lines of treatment, including previous HSCT (n=3). One patient had CD123-positive leukemia cell population in the bone marrow, 2 pts had CD33-positive population. At the time of allogeneic CAR-T application disease burden was overt leukemia (n=3), all patients had full donor chimerism in the CD3 cells. Baseline characteristics of the pts are summarized in table 1. Allo-CAR-T were derived from previous HSCT donors (haplo n=2, MRD n=1). The FlA chemotherapy regimen was used to reduce tumor burden, followed by the fludarabine and cyclophosphamide for lymphodepletion before CAR-T cell infusion in all patients. One patient received CD123 directed allo-CAR-T cells, 2 pts - CD33 CAR-T cells. Both CD33 and CD123 constructs were 2-nd generation 4-1BBz CARs, modified based on the published Ukrainskaya et al. Clinical grade manufacturing was performed on Prodigy bioreactor platform with retroviral transduction. Results Cytokine release syndrome (CRS) occurred in 3 patients and was grade ≤3, all pts received tocilizumab with good effect. Two patients had neurologic events (ICANS grade 1-2). In one patient rash and liver toxicity coincided with CRS, potentially representing aGVHD, with full response to corticosteroids. All pts had grade III/IV hematological toxicities. The median time to CAR-T cell peak expansion was 14 days. At 4 weeks after CAR-T infusion two patients achieved complete MRD negative remission with incomplete count recovery and good CAR-T cell expansion. One pt. had MRD positive remission with CD33 loss on residual blast cells. Two patients (#1 and #2) on d +37 and +45 receivedTotal body irradiation (TBI) at 4 Gy and TCRαβ+ depleted graft from original donors. Abatacept on d 0, +7, +14 was used as GVHD prophylaxis. One pt. (#3) received second HSCT on d +30 from haploidentical donor with full intensity TBI-based regimen. All patients engrafted recovered hematopoietic function) and had MRD-negative remission with full donors chimerism on d+30. Two patients, #1 and #2, relapsed after 4 and 2 months after graft infusion, respectively. Patient #3 remains in MRD-negative remission on day +100. All patients alive with median follow up 164 days (102-196). Conclusion Our early experience suggests that allogeneic myeloid antigen-directed CAR-T cells are effective as cytoreduction and have manageable toxicity. Myeloid antigen-directed CAR-T therapy can be used as a bridge to allo HSCT in r/r AML. We have documented CAR-T expansion and persistence. Prospective testing of the approach is warranted. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Biphasic Neutrophil Recovery after CD19 CART in R/R LBCL Is Associated with Superior PFS/OS, Robust CAR T-Cell Expansion in Relation to Baseline Tumor Volume, and a Decrease of Systemic Inflammation over Time

Background: Hematological toxicity and concomitant infectious complications drive the toxicity burden of CD19 CART. We recently proposed a classification system for CART-related hematotoxicity, defining three unique phenotypes of hematopoietic recovery (Rejeski et al, Blood 2021). The underlying mechanisms of these phenotypes and their relation to survival remain poorly understood. Here, we sought to understand patterns of post-CART neutrophil recovery and their influence on clinical outcomes. Methods: In this multicenter retrospective study, we analyzed 344 pt. receiving standard-of-care axi-cel (n=208) or tisa-cel (n=136) for R/R LBCL. The phenotypes of neutrophil recovery were defined as follows: Quick: sustained neutrophil recovery without a second dip below an ANC<1000/µl.Intermittent: neutrophil recovery (ANC>1500/µl) followed by a second dip with an ANC<1000/µl after day 21.Aplastic: continuous severe neutropenia (ANC<500/µl) ≥14 days. Multivariate analysis of patient-, disease-, and therapy-related factors was performed as binary logistic regression for the aplastic vs. non-aplastic phenotypes. Variables with a p<0.2 on univariate analysis were included. Clinical outcomes were studied via Kaplan-Meier estimates. Quantification of CAR T-cells was performed by qPCR or by flow cytometry in 146 pt. according to institutional protocols. To harmonize CAR T-cell expansion across centers, patients were divided into quartiles by their respective peak expansion. Plasma proteomics were performed in 56 pts. across four time points (day 0, 4, 14, 28) using a 92-protein multiplex proximity extension assay (Olink Proteomics). Key candidate serum markers were validated in 70 pt. using the Ella automated immunoassay system (ProteinSimple). Results: Across all patients, the distribution of the 'aplastic' (A), 'intermittent' (I) and 'quick' (Q) phenotypes was 18%, 42%, and 40%, respectively. The 'aplastic' patients exhibited a longer median duration of severe neutropenia, (A vs. I vs. Q: 26 vs. 10 vs. 5 days, p<0.001), a higher rate of severe infections (A vs. I vs. Q: 41% vs. 23% vs. 18%) and a trend towards higher 1-year non-relapse mortality (A vs. I: 9% vs. 3.5%, p=0.08). On multivariate regression (n=344), the aplastic phenotype was independently associated with the presence of BM infiltration (adjusted OR=3.2, p=0.004), ANC (aOR=0.28, p=0.002), and ferritin (aOR=2.3, p=0.039). Neither high-grade CRS or ICANS nor CAR product were linked to the aplastic phenotype. In the 'intermittent' cohort, we noted a significant decrease of both serum ferritin (median 776 vs. 321 U/L) and CRP levels (median 1.6 vs. 0.2 mg/dL) between CAR infusion and day 90 follow-up. When studying CD3+ CAR T-cell dynamics over time, we found that patients with 'intermittent' recovery displayed both an earlier and more pronounced expansion peak, and longer CART persistence compared to their 'quick' counterparts. While the 'aplastic' cohort displayed comparable peak CART expansion, these patients also exhibited high baseline LDH, indicative of a higher baseline tumor burden, or 'hill to climb' (top right quadrant, Fig. 1A). Conversely, the 'quick' cohort was characterized by both low expansion and low LDH. Serum proteome analysis revealed significant disruptions of endothelial function and immune dysregulation in the 'aplastic' patients at month 1 (Fig. 1B). Importantly, we confirmed higher peak IFNγ and IL-15 levels, and an increased ratio of ANG2 to ANG1 in the 'aplastic' patients in the independent validation cohort. Notably, progression-free (PFS) and overall survival (OS) was poor in the 'aplastic' patients (1-yr PFS 26%, 1-yr OS 46%). On the other hand, 'intermittent' patients exhibited the best survival outcomes (HRPFS I vs. A: 0.45, 95% CI 0.31-0.65). Median PFS was 3 vs. 20 vs. 4 months (A vs. I vs. Q, p<0.001); median OS was 8 months vs. not-reached vs. 23 months (A vs. I vs. Q, p<0.001). Conclusion: The 'aplastic' phenotype is driven by baseline inflammation and hematopoietic function, characterized by progressive endothelial dysfunction, and associated with poor PFS/OS. In contrast, the 'intermittent' phenotype (i.e. biphasic cytopenia) was associated with high levels of CART expansion and persistence, a decrease in systemic inflammation over time, and excellent survival outcomes. Overall, these data suggest potential interactions between host hematopoiesis and CART function and efficacy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Effective Cell Dose and Functional Attributes of Azercabtagene Zapreleucel (azer-cel; PBCAR0191) Associate with Allogeneic CAR T-Cell Safety and Efficacy in Patients with Relapsed/Refractory B-Cell Lymphoma

Background: Characterization of product cellular attributes contributing to the in vivo expansion and toxicity of allogeneic, CD19-directed chimeric antigen receptor (CAR) T-cell therapy is necessary to optimize efficacy and safety. Using a single step process, the azer-cel CD19 CAR is knocked into the T-cell receptor alpha constant (TRAC) gene locus via a TRAC-specific ARCUS nuclease in activated T cells. Unlike autologous CAR T-cell therapy, all allogeneic CAR T products are cryopreserved. In this phase I study of the allogeneic, CD19-directed CAR T azer-cel, we analyzed post-thaw product attributes and cell composition of the infused product associated with pharmacokinetics (PK), pharmacodynamics (PD), and clinical outcomes (NCT03666000). Methods: Azer-cel was administered as a single infusion to 44 subjects across several dose levels and fludarabine/cyclophosphamide lymphodepletion regimens. CAR T cell peak expansion (Cmax), PK and area under the concentration-time curve (AUC) was assessed by flow cytometry and PD by multiplex cytokine assays. Azer-cel post-thaw cell composition was assessed by flow cytometry (minimally differentiated stem central memory [SCM], CC-chemokine receptor 7 (CCR7)+; differentiated effector memory, CCR7-). Effective cell number infused for any antigenically defined population was estimated using the product of the population percentage and the total post-thaw viable cell number. Overall tumor burden was measured as sum of the products of perpendicular diameters of target lesions and response was evaluated using Lugano 2016 criteria. Responders had either a complete or partial response at Day 28 or later. Relationships to safety events and efficacy were assessed using univariate correlative analyses (variables selected based on Pearson correlation coefficients ρ(rho)>0.35 unless specified, P-value <0.05). Results: Peak azer-cel levels and AUC varied by dose level with median Cmax ranging from 38 cells/mL at DL2 to 6.7x 104 cells/mL at DL4b, whereas median AUC0-28 ranged between 3 x 102 to 5.1x 105(cells/mL*days). Both azer-cel Cmax and AUC correlated strongly with SCM cell dose (P=0.009 & P=0.0026, respectively). Development of cytokine release syndrome (CRS) associated with effective SCM CD8+ cell dose (P<0.05) and total tumor burden (P=0.0087), in addition to Cmax of the cytokines interleukin (IL)-6, TNFα, MIP1α, IL-10 and C-X-C motif chemokine ligand 10 (CXCL10) or Interferon gamma-induced protein 10 (IP10) (P<0.01). Immune effector cell-associated neurotoxicity syndrome (ICANS) correlated with azer-cel Cmax (P=0.035), AUC (P=0.0057), total tumor burden (P=0.004), and effective SCM CAR T cell dose (P<0.05), as well as changes in a distinct set of cytokines that included IL-2, IL-8, IIL-15, IL-6, and IP10 (P<0.05). Grade >3 ICANS correlated strongly with effective SCM CD4+ cell dose (P=0.0015), differentiated CD4+CCR7- cell dose (ρ =0.34, P=0.029) and CD4:CD8 ratio (ρ = 0.32, P= 0.036), in addition to Cmax of IL-6, IL-2 and IP10 (P< 0.01). Overall response to azer-cel treatment negatively correlated with differentiated CD4+ CCR7- cell dose (P=0.04). Conclusions: Post-thaw product composition and effective cell dose are predictive for in vivo expansion potential, CAR-T-related adverse events and response to treatment with azer-cel. This is the first analysis of an allogeneic CD19 CAR T product composition to demonstrate that strategies intended to maximize stem central memory T-cell fraction (CCR7+) while limiting CD4+ CCR7- differentiated fraction may improve safety and efficacy of CAR T therapy.

Experimental study on expansion and cracking properties of static cracking agents in different assembly states

Rolled static cracking agent (RSCA) can solve the intractable problem of traditional bulk static cracking agent (BSCA) in engineering applications. This paper innovatively studies the rational water-cement ratio of BSCA and the immersion soaking time of RSCA under the condition of controlling temperature. Through the expansion and cracking performance experiments, the development characteristics of expansion pressure, the cracking effect of the single-hole specimen and the performance of hole spraying prevention under the action of BSCA and RSCA were compared and analyzed. The results show that: (1) The volume growth rate of static cracking agent decreases with the increase of water-cement ratio, and the fluidity increases with the increase of water-cement ratio. The rational water-cement ratio for BSCA application is 0.3, and the rational immersion time of RSCA is 2–2.5 min; (2) Under the bore diameters of 30, 35, 40 and 45 mm, the expansion pressure of BSCA with a water-cement ratio of 0.3 is 38.2, 52.3, 61.5 and 68 MPa, and the expansion pressure of RSCA immersed in water for 2.5 min is 43.5, 58.8, 69.5 and 75.1 MPa, respectively. Among them, the development speed of expansion pressure of BSCA is higher than that of RSCA, and the arrival time of the peak expansion pressure of RSCA is 1.7 times that of BSCA; (3) The crack initiation speed of single-hole specimen under the action of RSCA is 10.3 % lower than that under the action of BSCA, but the cracking speed of the former is 72.6 % higher than that of the latter; (4) The hole spraying occurs in BSCA under the bore diameter of 50, 55 and 60 mm, while the hole spraying occurs in RSCA under the bore diameter of 60 mm. In terms of bore diameter, the hole spraying prevention of the RSCA is better than that of BSCA. The research results enrich the static blasting technology and provide data support and theoretical reference for field application.

MM-183 CARTITUDE-2 Cohort A: Updated Clinical Data and Biological Correlative Analyses of Ciltacabtagene Autoleucel (cilta-cel) in Lenalidomide-Refractory Patients With Progressive Multiple Myeloma (MM) After 1–3 Prior Lines of Therapy (LOT)

CARTITUDE-2 (NCT04133636) Cohort A is assessing cilta-cel in lenalidomide-refractory patients with progressive MM after 1-3 prior LOT. To present updated results from CARTITUDE-2 Cohort A. Phase 2, multicohort study. Lenalidomide-refractory patients with progressive MM after 1-3 prior LOT (PI and IMiD included) and no previous exposure to BCMA-targeting agents. Single cilta-cel infusion (target dose 0.75×106 CAR+ viable T-cells/kg) after lymphodepletion Main Outcome Measures: Primary endpoint was minimal residual disease (MRD) negativity at 10-5. Management strategies were used to reduce risk of movement/neurocognitive adverse events (MNTs). Pharmacokinetics (PK) (Cmax/Tmax of CAR+T-cell transgene levels), cytokine release syndrome (CRS)-related cytokines over time, peak cytokine levels by response/CRS, association of cytokine levels with immune effector cell-associated neurotoxicity syndrome (ICANS), and CAR+T-cell CD4/CD8 ratio by response/CRS/ICANS are being evaluated. As of January 2022 (median follow-up [MFU] 17.1 months), 20 patients (65% male; median age 60 years; median 2 prior LOT; 95% refractory to last LOT) received cilta-cel. Overall response rate was 95% (90% ≥complete response; 95% ≥very good partial response). Median times to first and best response were 1.0 month and 2.6 months, respectively. All 16 MRD-evaluable patients achieved MRD negativity at 10-5. Median duration of response was not reached. At 12 months, event-free rate was 79% and progression-free survival rate was 75%. 95% of patients had CRS (gr3/4 10%); median time to onset was 7 days and median duration was 3 days. Neurotoxicity was reported in 30% of patients (5 gr1/2; 1 gr3/4) and ICANS in 15% (all 3 gr1/2); 1 patient had gr2 facial paralysis. No MNTs were observed. 1 death occurred due to COVID-19 (treatment-related), 2 due to progressive disease, and 1 due to sepsis (not treatment-related). Preliminary PK analyses showed peak CAR-T cell expansion at day 10.5; median persistence was 153.5 days. At MFU of 17.1 months, a single cilta-cel infusion resulted in deep and durable responses in lenalidomide-refractory MM patients with 1-3 prior LOT. We will present updated PK/cytokine/CAR-T subset analyses and clinical correlation to provide novel insights into biological correlates of efficacy/safety in this population.

MM-153 Phase 2 CARTITUDE-2 Study (Cohort B): Updated Clinical Data and Biological Correlative Analyses of Ciltacabtagene Autoleucel (cilta-cel), a BCMA-Directed CAR-T Cell Therapy, in Patients With Multiple Myeloma (MM) and Early Relapse After Initial Therapy

CARTITUDE-2 (NCT04133636) Cohort B is evaluating cilta-cel in patients with MM and early relapse after initial therapy. These patients have functionally high-risk disease and unmet medical needs, as early relapse post-ASCT is associated with a poor prognosis. To present updated results from CARTITUDE-2 Cohort B. Phase 2, multicohort study. Eligible patients had MM, 1 prior LOT (PI and IMiD required), disease progression per IMWG, and no previous treatment with CAR-T/anti-BCMA therapies. Single cilta-cel infusion (target dose 0.75×106 CAR+ viable T-cells/kg) post lymphodepletion. Safety and efficacy were evaluated. Primary endpoint was MRD negativity at 10-5. Management strategies were used to reduce the risk of movement/neurocognitive AEs (MNTs). Assessments included pharmacokinetics (PK) (Cmax, Tmax of CAR+ T-cell transgene levels in blood), CRS-related cytokine (eg, IL-6) levels over time, peak cytokine levels by response and CRS, association of cytokine levels with ICANS, and CAR+ T-cell CD4/CD8 ratio by response, CRS, and ICANS. As of January 2022 (median follow-up 13.4 months), 19 patients (median age 58.0 years; 74% male; 79% with prior ASCT) received cilta-cel. ORR was 100% (90% ≥CR and 95% ≥VGPR). Median time to first response was 0.95 months and median time to best response was 5.1 months. Median DOR was not reached. Of 15 MRD-evaluable patients, 14 (93%) achieved MRD 10-5 negativity. At 12 months, the event-free rate was 88.9% and PFS rate was 90%. CRS occurred in 16 (84.2%) patients (1 gr 4); median time to onset was 8 days. CRS resolved in all patients. 1 patient had ICANS (gr 1); 1 patient had MNT (gr 3; previously reported). 1 death occurred post-cilta-cel due to progressive disease (day 158). Preliminary PK data showed CAR-T cell peak expansion on day 13.1 and median persistence was 76.9 days. A single cilta-cel infusion resulted in deep and durable responses and manageable safety in functionally high-risk patients with MM and early clinical relapse/treatment failure to initial therapy. We will present updated and detailed PK/cytokine/CAR-T subset analyses and clinical correlations to provide novel insights into biological correlates of efficacy/safety in this population.

Acoustic and Mechanical Properties of Polystyrene Composite Filled with Primary Sludge and Boiler Ash from Pulp Mill

The search for green composite for sound-absorbing material has increased a significant interest. In this study, polystyrene (PS) composite foam filled with primary sludge and boiler ash from pulp mill was produced. The product was characterized using analytical techniques such as FTIR, XRD, SEM, TGA, and DSC, while the mechanical properties and sound-absorbing coefficient were analyzed regarding ASTM D 2240 and ASTM E-1050-98, respectively. The results showed that the sludge has 1β crystalline polymorph cellulose from the pulp. The chemical reaction can be seen by the chemical bond formed during the mixing process. The peak expansion occurred at 1600.44 cm-1 indicating the presence of a C=C functional group of maleic anhydride with polymer and filler. SEM images showed that the filler was distributed and dispersed into the polymer matrix and no agglomeration was produced. The sound-absorbing composites had complied ISO 11654:1997 regarding the sound absorption coefficient rating level on materials for rooms with sound absorption classes D and C with the value of α 0.328-0.793.

S103: EFFICACY AND SAFETY OF ARI0002H, AN ACADEMIC BCMA-DIRECTED CAR-T CELL THERAPY WITH FRACTIONATED INITIAL THERAPY AND BOOSTER DOSE IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA

Background: ARI0002h is a lentiviral autologous CAR T-cell product with a 4-1BB co-stimulatory domain and a humanized single chain variable fragment targeting BCMA. In pre-clinical studies, this academic CAR-T has demonstrated potent in vitro and in vivo activity. Aims: We report the safety and efficacy results of the CARTBCMA-HCB-01 multicenter clinical trial for patients with relapsed/refractory multiple myeloma (RRMM) (NCT04309981) who received ARI0002h in 5 Spanish centers. Methods: Patients (pts) aged 18-75 years old with RRMM were eligible for this study if they had measurable disease, received ≥2 prior regimens, including a proteasome inhibitor, an immunomodulatory drug and an anti-CD38 antibody, and were refractory to the last line of treatment. Bridging therapy was allowed after apheresis. Cyclophosphamide (300 mg/m2) and fludarabine (30 mg/m2) were used as lymphodepletion regimen. The targeted dose was 3x106/kg CAR+ cells and was administered in a fractionated manner (10%/30%/60%), with at least 24h between infusions. A second dose of 3x106 CAR+ cells/kg was planned at least 4 months after the first dose in pts who achieved any grade of response any response and had not or serious complications after the first administration. Primary objectives were overall response rate (ORR; at least partial response -PR-) within 3 months of the first infusion and rate of cytokine release syndrome (CRS) and/or neurological toxicity in the first 30 days. Response was assessed as per IMWG criteria and bone marrow minimal residual disease (MRD) was analyzed by next-generation flow (NGF). Results: As of February 9th 2022, 35 pts (median age 61 years) with RRMM were included in the trial. Four pts could not receive ARI-0002h due to MM progression and one died of infection. Therefore, 30 pts received ARI0002h cells (modified intention-to-treat population), of which 47% received bridging therapy. Median CAR-T cell production time was 11 days (range 9-14) with a 100% manufacture success. Median follow-up after ARI0002h administration for surviving pts was 16 months. The ORR of 30 evaluable pts was 100%, with a stringent complete remission (sCR) plus very good partial response (VGPR) rate of 90%. Median time to first response was one month. Of 26 MRD-evaluable pts at day +100, 92% were MRD-negative in bone marrow by NGF. 53% of patients were alive and without progression at 16 months. Median overall survival (OS) was not reached and the 16-month OS rate was 80% (Figure 1). AEs reported in >70% of pts were CRS (87%; grade [gr] 3/4 0%; gr 1 73%), neutropenia (97%; gr 3/4 100%), anemia (85%; gr 3/4 43%), and thrombocytopenia (79%; gr 3/4 70%). Median duration of CRS was 4 days (range 1-12). No CAR-T cell-related neurotoxicity cases were reported. Tocilizumab and corticosteroids were administered in 76% (mainly for persistent grade 1 CRS) and 12% of pts, respectively. ARI0002h cells demonstrated peak expansion on day 14 (range 7 days-6 months). 24 out of 28 eligible pts (86%) received the second dose (range 1.2-3x106 CAR+ cells/kg). Median time after first infusion was 4 months and 38% received a second lymphodepletion regimen. No relevant toxicities after second infusions were reported. 7 pts (29%) improved their response after reinfusion. Image:Summary/Conclusion: ARI0002h is the first European academic CART for RRMM that has demonstrated deep and durable responses and a favorable safety profile, including the absence of neurotoxicity and the feasibility of a second booster dose.

S263: PHASE I OPEN-LABEL SINGLE ARM STUDY OF GPRC5D CAR-T CELLS (ORICAR-017) IN PATIENTS WITH RELAPTSED/REFRACTORY MULTIPLE MYELOMA (POLARIS)

Background: G-protein–coupled receptor class 5-member D (GPRC5D), a type-C 7-pass transmembrane receptor protein, is predominantly expressed on malignant plasma cell phenotype, including most malignant plasma cells from pts with multiple myeloma (MM). The autologous GPRC5D-directed CAR-T cell (OriCAR-017), owning to an additional proprietary Ori element, is the standard second generation CAR-T cell with improvement in expansion and durability of CAR-T cells post-transfusion. Here we report initial results from the phase I open-label single arm study of GPRC5D CAR-T Cells (OriCAR-017) in pts with Relapsed/Refractory (R/R) MM (NCT05016778). Aims: The primary objective in the dose escalation phase was to evaluate safety and tolerability of OriCAR-017. Secondary endpoints included efficacy and pharmacokinetics (expansion and persistence of OriCAR-017. Methods: Key enrolment criteria included adults with measurable MM, R/R or intolerant to established MM therapies, prior BCMA-targeted therapy allowed. Patient received lymphodepleting chemotherapy with Fludarabine 30mg/m2 daily and cyclophosphamide 300mg/m2 daily for 3 days followed by a single infusion of OriCAR-017. The trial followed a standard 3 + 3 design with the following dose cohorts: 1×106/kg, 3×106/kg and 6×106/kg CAR+ T cells. Results: Eleven pts with R/R MM were enrolled and underwent apheresis during June 9, 2021 and February 25, 2022. Nine of them have completed OriCAR-017 infusion to date. 2 pts were suspended infusion due to rapid disease progression. Of the 9 pts infused, median age of 65 years (range: 41-71) and a median of 6 (range 3-17) prior lines of therapy; 4 (44.4%) prior BCMA CART therapy. 3 (33.3%) pts with extramedullary plasmacytoma ≥ 1 and 7 (77.8%) pts with bone marrow plasma cells ≥60% at baseline. Five out of 6 pts had high-risk cytogenetic profiles, including 2 pts with del(17p). No dose-limiting toxicities occurred. The most common treatment-related AEs were hematological toxicities. All pts experienced Cytokine Release Syndrome (CRS, with 8(88.9%) pts in G1, 1 (11.1%) patient in G2), no G3/4 CRS was observed. All CRS cases were rapidly relieved after conventional CRS intervention, including tocilizumab and steroids. No neurologic toxicities were reported to date. All 9pts median follow up time was 118 days (range33—220). A 100.0% ORR were observed with 3 (33.3%) pts achieved CR/sCR, 3 pts (33.3%) were VGPR, 3 pts were PR (33.3%). 4 pts relapsed from BCMA CAR-T therapy had responses with 1 sCR, 2 VGPR, 1 PR. All 9 pts were Minimal Residual Disease (MRD) negative in the bone marrow by flow cytometry (sensitivity: 10-5) at day 28 after infusion, and 6pts continued MRD negative at month 3 and 2 pts at month 6 after infusion. Robust OriCAR-017 expansion in peripheral blood by using qPCR in 3 dose cohorts, median peak was 349866.1copies/ml (range 60837.5 – 2240358.5), median time to peak expansion was 10 days (range 7-14). 8 out of 9 patients detected CAR + cell in bone marrow at D28 after infusion with median 498048.3copies/ml (range 495.4- 2358538.6). Image:Summary/Conclusion: In this phase I study, OriCAR-017 was safe and showed impressive efficacy among previously heavily treated R/RMM pts. Majority of AEs were transient, manageable, and reversible. 100% ORR and 100% MRD negative rate, along with favorable safety evidenced support OriCAR-017 could be a competitive therapy for pts with R/RMM. Furthermore, pts who had relapsed from BCMA CAR-T therapy may still benefit from OriCAR-017 treatment.

S185: CARTITUDE-2 COHORT B: UPDATED CLINICAL DATA AND BIOLOGICAL CORRELATIVE ANALYSES OF CILTACABTAGENE AUTOLEUCEL IN PATIENTS WITH MULTIPLE MYELOMA AND EARLY RELAPSE AFTER INITIAL THERAPY

Background: CARTITUDE-2 (NCT04133636) is a phase 2, multicohort study evaluating the efficacy and safety of the chimeric antigen receptor (CAR) T-cell therapy ciltacabtagene autoleucel (cilta-cel) in patients (pts) with multiple myeloma (MM). Cohort B enrolled pts who had early relapse after initial therapy. These pts have functionally high-risk disease, as early relapse following autologous stem cell transplantation (ASCT) is associated with poor prognosis, representing an unmet medical need. Aims: To present updated results from CARTITUDE-2 cohort B. Methods: All pts provided informed consent. Pts had MM, received 1 prior line of therapy (proteasome inhibitor and immunomodulatory drug required), had disease progression per International Myeloma Working Group criteria (either ≤12 months after ASCT or ≤12 months after initiation of anti-myeloma therapy for pts not treated with ASCT), and were naive to CAR-T or other anti-B-cell maturation antigen therapies. After lymphodepletion, a single cilta-cel infusion was administered at a target dose of 0.75×106 CAR+ viable T cells/kg. Efficacy and safety were evaluated. The primary endpoint was minimal residual disease (MRD) negativity at 10-5. Patient management strategies were used to minimize risk of movement and neurocognitive adverse events (MNTs). Pharmacokinetic (PK) analyses, including Cmax and Tmax of CAR+ T-cell transgene levels in blood are being performed. Additional assessments include levels of cytokine release syndrome (CRS)-related cytokines (eg, IL-6) over time, peak levels of cytokines by response and CRS, association of cytokine levels with immune effector cell-associated neurotoxicity syndrome (ICANS), and CAR+ T cell CD4/CD8 ratio by response, CRS, and ICANS. Results: 19 pts (median age: 58.0 years [range: 44-67]; 74% male) received cilta-cel as of January 2022; 79% received prior ASCT. Median follow-up was 13.4 months (range: 5.2-21.7). Overall response rate was 100.0%, with 90% of pts achieving ≥complete response, and 95% achieving ≥very good partial response. Median time to first response was 0.95 months (range: 0.9-9.7) and median time to best response was 5.1 months (range: 0.9-11.8). Among 15 MRD-evaluable pts, 14 (93%) achieved MRD 10-5 negativity. Median duration of response was not reached. The 12-month progression-free survival rate was 90%; 12-month event-free rate was 88.9%. CRS occurred in 16 (84.2%) pts (1 grade 4); median time to onset was 8 days (range: 5-11) and all events resolved. ICANS (grade 1) and MNT (grade 3, previously reported) occurred in 1 pt each. 1 pt died post cilta-cel (progressive disease, day 158). Preliminary PK data showed peak expansion of CAR-T cells on day 13.1 (range: 8.96-209.9); median persistence was 76.9 days (range: 40.99-221.8). Summary/Conclusion: This functionally high-risk pt population with early relapse after initial therapy experienced deep and durable responses with manageable safety following a single cilta-cel infusion. Cilta-cel led to responses in pts with ineffective or insufficient response to ASCT. Follow-up is ongoing and responses continue to deepen. We will present updated and detailed PK, cytokine, and CAR-T subset analyses as well as clinical correlation to provide insight into biological correlates of efficacy and safety in these pts.

Abstract 3603: Reverse fate mapping of CD19-targeted CAR T cells in patients with large B-cell lymphoma

Abstract Autologous T cells genetically engineered to express a chimeric antigen receptor targeting CD19 (CD19-CAR) have achieved high complete response rates in patients with hematologic malignancies, but &amp;gt;50% of patients progress following therapy. Here, we sought to understand key T-cell intrinsic factors impacting efficacy, namely CAR T-cell expansion, persistence, and homing to the tumor. Using an approach called reverse fate mapping, we followed individual T-cell clones at the single-cell level from pre-manufacture apheresis to the infusion product, tumor-involved lymph node, and blood at peak and late expansion in 12 adult patients with relapsed or refractory large B-cell lymphoma treated with axicabtagene ciloleucel, an FDA-approved CD19-CAR T-cell immunotherapy. The resulting CAR T-cell atlas comprises matched transcriptome (scRNA-seq) and surface protein expression (CITE-seq) for 322,028 cells from 44 samples, with 119,397 unique T-cell receptor (TCR) clonotypes identified. This atlas enabled us to ask questions like: “What were the phenotypes of the most successful CAR T-cell clones at the time of infusion or pre-manufacture apheresis?” We found that T-cell clonotypes with juvenile features at apheresis, including IL7R expression, were the most successful at expansion to higher frequencies in the infusion product, while clones with effector gene expression programs, such as those encoding perforin and granzymes, contracted between apheresis and product. Conversely, it was GZMK-expressing T cells in pre-manufacture apheresis that were dominant in the tumor early following CAR T-cell infusion. Further, T-cell clonotypes with active effector programs at infusion dominated at peak expansion. Finally, we defined active expression modules and pathways in the infusion product for CAR T-cell clones that homed to the tumor or became dominant at late expansion. These analyses pinpoint the molecular mechanisms that could be modulated to rationally steer CAR T-cell differentiation trajectories at the genetic or pharmacological level. This work was supported in part by the Parker Institute for Cancer Immunotherapy, California Institute for Regenerative Medicine, Kite Pharma, and Stanford Cancer Institute. Citation Format: Zinaida Good, Mark P. Hamilton, Jay Y. Spiegel, Sreevidya Kurra, Moksha Desai, Snehit Prabhu, Eric Yang, Michael G. Ozawa, Paul J. Hanson, Fang Wu, Matthew J. Frank, John H. Baird, Lori Muffly, Gursharan K. Claire, Juliana Craig, Katherine A. Kong, Dhananjay Wagh, John Coller, Sylvia K. Plevritis, Bita Sahaf, David B. Miklos, Crystal L. Mackall. Reverse fate mapping of CD19-targeted CAR T cells in patients with large B-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3603.

Abstract 5186: Higher levels of circulating exhausted T-cells at pre- and post-infusion negatively associated with clinical efficacy in tisagenlecleucel (Tisa-cel) treated relapsed/refractory large B-cell lymphoma (r/r LBCL) patients (pts) in JULIET trial

Abstract Background: JULIET, a pivotal phase II trial of Tisa-cel, an anti-CD19 CAR-T cell therapy in pts with r/r LBCL demonstrated durable activity with a manageable safety profile (Schuster et al., 2021). We sequentially characterized peripheral blood T cell functionality by immunophenotyping and correlated with efficacy endpoints. Methods: Immunophenotypic characterization of both non-CAR-T and CAR-T cells was performed by flow cytometry in 378 blood samples from 111 pts collected at enrollment and within the first month post Tisa-cel infusion. Proportions of T cell subsets were identified by maturation (CCR7/CD45RA/CD45RO) and exhaustion (PD1/LAG3/TIM3) markers and then correlated with durable clinical response (Complete Response (CR) ≥ 6 mo vs. Non-response (NR)/Relapse), PFS and OS. Results: At enrollment, low T cell levels (&amp;lt;14.5% of PBMCs or &amp;lt;170 cells/uL) observed in 30% (31/105) pts were associated with NR/relapse (27/31) and with significantly shorter PFS and OS, compared to those with higher levels (median (m)PFS: 2.1 vs. 9 mo, p=0.0006; mOS: 6 vs. 28.5 mo, p=0.003). NR/relapse pts had higher levels of exhausted T cell subsets in both CD4 (LAG3+, LAG3+PD1+) and CD8 (PD1+, LAG3+, LAG3+PD1+) cells at enrollment. High levels (&amp;gt;median) of these subsets also had significantly shorter PFS and OS, with LAG+PD1+CD8+ ranked on top (mPFS: 2 vs. 34 mo; mOS: 4.6 mo vs. not reached, both p&amp;lt;0.0001) and remained significant in multivariate Cox models including LDH and Myc status (PFS: HR=3.1 [1.9 - 5.3]; OS: HR=2.8 [1.6 - 4.8]; both p&amp;lt;0.001). Hierarchical clustering showed concordant increase of all non-CAR-T exhausted subsets in NR/relapse pts, separating them from ongoing CRs. The trend continued at day 28 (D28), with almost all exhausted CD4 and CD8 subsets in both non-CAR-T and CAR-T cells being consistently higher in NR/Relapse compared to ongoing CRs. In addition, high levels of exhausted subsets in non-CAR-T cells at D28 were associated with shorter PFS and OS, with the strongest trend in PD1+, LAG3+, LAG3+PD1+ of CD8 and CD4 cells. Survival analyses for CAR-T exhausted subsets were less informative due to small sample size. Of note, several LAG3+ and LAG3+PD1+ subsets of CAR-T and non-CAR-T cells were also higher in NR/relapse at CAR-T peak expansion. In contrast, no obvious differences were observed for T cell memory subsets from both CAR-T and non-CAR-T cells across multiple timepoints. Conclusions: Decreased circulating T cells at enrollment, and increased circulating exhausted T cells in non-CAR-T (at enrollment and D28) and CAR-T (at D28) compartments, were associated with poor response and survival, suggesting these flow measurements may serve as surrogate for overall T cell function, which is critical for optimal Tisa-cel efficacy and early prognostication in LBCL. Citation Format: Ulrich Jäger, Xia Han, Davide Germano, David Quinn, Dalia Gaddis, Aisha Masood, Tanya Mulvey, Jennifer Mataraza, Michael R. Bishop, Gilles Salles, Richard Maziarz, Stephen Schuster. Higher levels of circulating exhausted T-cells at pre- and post-infusion negatively associated with clinical efficacy in tisagenlecleucel (Tisa-cel) treated relapsed/refractory large B-cell lymphoma (r/r LBCL) patients (pts) in JULIET trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5186.

Abstract CT522: Feasibility and safety of a novel CD19 CAR T cell therapy in adults with R/R B-NHL

Abstract Genetically engineered chimeric antigen receptor (CAR) T cells have exhibited distinct effectiveness against chemotherapy refractory CD19 expressing B cell malignancies in both adults and children. This phase I clinical trial tests a novel anti-CD19 CAR T cell product in adults with relapsed/refractory (R/R) B-cell Non-Hodgkin’s Lymphoma (B-NHL). The CAR construct is comprised of the short chain variable regions of the anti-CD19 monoclonal antibody FMC63, the TNFRSF19-derived transmembrane domain, the 4-1BB costimulatory domain, and the CD3-zeta signaling domain. CD19 CAR T cells were manufactured utilizing the CliniMACS Prodigy® T Cell Transduction Process (CD3/CD28 TransAct™ reagent) allowing for highly automated production, with IL-7 and IL-15 used for T cell expansion for 8-12 days. To date, 7 patients have been treated with an average dose of 1.2 ± 0.2 x 108 CAR T cells. The histology includes marginal zone lymphoma (n=1), follicular lymphoma Grade IIIA (n=1), transformed lymphoma (n=3), follicular lymphoma low grade (n=2), and diffuse large B-cell lymphoma (n=1). One patient required a second apheresis due to poor cell expansion. Despite heterogeneity in disease subtype and leukapheresis product quality, CAR T production and expansion have been consistent with final transduction efficiencies between 14-45%, cell viability between 88-91%, and an overall average yield of 3.2 ± 0.3 x 109 cells before harvest, allowing for product banking. No safety-related out of specifications (OOS) events have occurred, however, 2 patients had OOS product infused due to low transduction efficiency (both at 14% rather than the ≥ 20% release criteria). Two patients experienced Grade 2 CRS, 1 patient experienced Grade 2 neurotoxicity; otherwise, no new safety signals were detected. Disease response was assessed on Days 90, 180, 270, and 360 post-infusion. The assessments were based on 2014 Lugano criteria. Even with 2 OOS products, Day 90 scans showed a complete metabolic remission (CMR) in 6 evaluable patients to date. Of the 6 patients with CMR, 1 patient progressed at Day 180 and the others remain in remission (median f/u = 12 months). Flow cytometry was utilized to measure CAR T cell peak expansion and persistence in 5 patients. Peak CAR T cell expansion (2.9-44.4% of CD3 cells) ranged from Day 5 to 15. Cell persistence was detected for the 5 patients through at least Day 180. ddPCR is currently in development to perform persistence testing in parallel. Additionally, cytokine concentrations including INFγ, IL-10, IL-12p70, IL-13, IL1β, IL-2, IL-4, IL-6, IL-8, and TNFα were evaluated over the first 30 days. Overall, 7 patients diagnosed with 5 different B-NHL subtypes have been treated with the CD19 CAR T cell product. Manufacturing was successful for all patients with no safety related OOS, and no new post-infusion safety signals detected. To date, 6 out of 7 patients are alive, 5 with CMR and with CD19 CAR T cell persistence through at least 180 days. Citation Format: Manali Kamdar, Cheri Adams, Steven Bair, Boro Dropulic, Jonathon Gutman, Bradley Haverkos, Kimberly Jordan, Rebecca Mallo, Russell Marians, Felicia Mast, Lindsey Murphy, Andrew Roth, Matthew Seefeldt, Andrew Worden, Mike Kadan, Ying Xiong, Dina Schneider, Rimas Orentas, Terry Fry, Michael Verneris. Feasibility and safety of a novel CD19 CAR T cell therapy in adults with R/R B-NHL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT522.

Biological correlative analyses and updated clinical data of ciltacabtagene autoleucel (cilta-cel), a BCMA-directed CAR-T cell therapy, in lenalidomide (len)-refractory patients (pts) with progressive multiple myeloma (MM) after 1–3 prior lines of therapy (LOT): CARTITUDE-2, cohort A.

8020 Background: Cohort A of the multicohort phase 2 CARTITUDE-2 (NCT04133636) study is evaluating cilta-cel safety and efficacy in pts with MM who received 1–3 prior LOT and were len-refractory – a difficult-to-treat population with poor prognosis. We present updated results. Methods: Pts had progressive MM after 1–3 prior LOT, including a PI and IMiD, were len-refractory, and had no prior exposure to BCMA-targeting agents. A single cilta-cel infusion (target dose 0.75×106 CAR+ viable T cells/kg) was given post lymphodepletion. Safety and efficacy were assessed, and the primary endpoint was MRD negativity at 10-5. Management strategies were implemented to minimize risk of movement/neurocognitive AEs (MNTs). Pharmacokinetic (PK) analyses (Cmax and Tmax of CAR+ T-cell transgene levels in blood) are being conducted, as well as analyses of levels of CRS-related cytokines (eg, IL-6) over time, peak levels of cytokines by response and CRS, association of cytokine levels with ICANS, and CAR+ T cell CD4/CD8 ratio by response, CRS, and ICANS. Results: As of January 2022 (median follow-up [MFU] 17.1 mo [range 3.3–23.1]), 20 pts (65% male; median age 60 y [range 38–75]) received cilta-cel. Pts received a median of 2 (range 1–3) prior LOT, and a median of 3.5 y (range 0.7–8.0) since MM diagnosis. 95% were refractory to last LOT, and 40% were triple-class refractory. ORR was 95%, 90% achieved CR or better, and 95% had ≥VGPR. Median times to first and best response were 1.0 mo (range 0.7–3.3) and 2.6 mo (range 0.9–13.6), respectively. 16 pts were MRD-evaluable, all of whom achieved MRD negativity at 10-5. Median DOR was not reached and 12-mo event-free rate was 79%. The 12-mo PFS rate was 75%. Median time to onset of CRS was 7 d (range 5–9) and occurred in 95% of pts (gr 3/4: 10%), with median duration of 3 d (range 2–12). Neurotoxicity occurred in 30% of pts (5 gr 1/2; 1 gr 3/4). 3 pts (15%) had ICANS (all gr 1/2); 1 pt had gr 2 facial paralysis. No MNTs were seen. 1 death occurred due to COVID-19 (assessed as tx-related by the investigator), 2 due to progressive disease, and 1 due to sepsis (not related to tx). Preliminary PK analyses indicate that peak expansion of CAR-T cells occurred at d 10.5 (range 8.7–42.9) and median persistence was 153.5 d (range 57.1–336.8). Conclusions: At a longer MFU of 17.1 mo, a single cilta-cel infusion led to deepening and durable responses in pts with MM who had 1–3 prior LOT and were len-refractory. Follow-up is ongoing. Updated and in-depth PK, cytokine, and CAR-T subset analyses and clinical correlation will be presented and provide novel insights into biological correlates of efficacy and safety in this pt population. This pt population is being further evaluated in the CARTITUDE-4 study (NCT04181827), which has concluded enrollment. Clinical trial information: NCT04133636.

Phase I open-label single arm study of GPRC5D CAR T-cells (OriCAR-017) in patients with relapsed/refractory multiple myeloma (POLARIS).

8004 Background: GPRC5D, a type-C 7-pass transmembrane receptor protein, is predominantly expressed on malignant plasma cells from MM patients. The autologous GPRC5D-directed CAR-T cell (OriCAR-017), owning to an additional proprietary Ori element, is the 2nd generation CAR-T cell with improvement in expansion and durability. Methods: The primary objective of this study was to evaluate safety and tolerability of OriCAR-017. Key enrolment criteria included measurable MM adults, R/R or intolerant to established therapies. Patient received lymphodepleting chemotherapy with fludarabine 30mg/m2/d and cyclophosphamide 300mg/m2/d for 3 days followed by a single infusion of OriCAR-017. The trial followed 3+3 design with 1×106/kg, 3×106/kg and 6×106/kg CAR+ T cells cohorts. Results: Eleven patients were enrolled and underwent apheresis during June 9, 2021 and January 31, 2022. 9pts have completed infusion and 8pts available for efficacy and safety evaluation, the 9th pt completed infusion at January 23, 2022. 2 pts were suspended infusion due to rapid disease progression. Of the 9 infused pts, median age 65 years (range41-71) and a median of 6 (range3-17) prior therapy lines; 3 (33.0%)/1 (11.0%) triple-class/penta-drug exposed; 2 (22.0%)/1 (11.0%) triple-class/penta-drug refractory; 4 (44.0%) prior BCMA CART therapy. Five out of 6pts had high-risk cytogenetic profiles including 2pts with del(17p). No dose-limiting toxicities occurred. The most common TEAEs were neutropenia (G3/4 100%), thrombocytopenia (G3/4 100%), leukopenia (G3/4 100%), lymphopenia (G3/4 100%) and anemia (G3/4 87.5%). All pts experienced CRS with 7pts in G1, 1pt in G2. All CRSs were rapidly relieved after conventional intervention(tocilizumab and steroids). The median onset time was 3 days (range0-8), median duration 6 days (range5-8). No neurologic toxicities were reported. No nail disorders were reported. 8pts avaliable for efficacy evaluation, median follow up time was 109.5 days (range32-195 days). A 100.0% ORR were observed with 3pts CR/sCR, 2pts VGPR, 3pts PR. Three out of 4pts with prior BCMA CAR-T therapy were available for efficacy evaluation-1sCR, 1VGPR, 1PR. After infusion, 8pts were MRD negative in the bone marrow by flow cytometry (10-5) at day 28, 5pts continued at month 3 and 1pt at month 6. Robust OriCAR-017 expansion in peripheral blood by using qPCR for 8pts, median peak was 507,463.6copies/ml (range152093.7 – 1121996.9), median time to peak expansion was 10 days (range7-14). Conclusions: In this phase I study, OriCAR-017 was showed safe and impressive efficacy in RRMM patients. Majority of AEs were transient and manageable. 100% ORR and 100% MRD negative rate, along with favorable safety support OriCAR-017 to be a competitive therapy for RRMM. Furthermore, patients who had relapsed from BCMA CAR-T therapy may still benefit from OriCAR-017. Clinical trial information: NCT05016778.

Biological correlative analyses and updated clinical data of ciltacabtagene autoleucel (cilta-cel), a BCMA-directed CAR-T cell therapy, in patients with multiple myeloma (MM) and early relapse after initial therapy: CARTITUDE-2, cohort B.

8029 Background: In cohort B of the multicohort phase 2 CARTITUDE-2 (NCT04133636) study, the efficacy and safety of cilta-cel are being evaluated in patients (pts) with MM who had early relapse after initial therapy. These pts have functionally high-risk disease, with early relapse post autologous stem cell transplantation (ASCT) being a poor prognostic factor and representing an unmet medical need. We present updated results. Methods: Eligible pts had MM, received 1 prior LOT (PI and IMiD required), had disease progression per IMWG (either ≤12 mo after ASCT or ≤12 mo after start of anti-myeloma therapy for pts who did not undergo ASCT), and were tx-naive to CAR-T/anti-BCMA therapies. A single cilta-cel infusion (target dose 0.75×106 CAR+ viable T cells/kg) was given post lymphodepletion. Safety and efficacy were assessed, and the primary endpoint was MRD negativity at 10-5. Management strategies were implemented to minimize risk of movement/neurocognitive AEs (MNTs). Pharmacokinetic (PK) analyses (Cmax and Tmax of CAR+ T-cell transgene levels in blood) are being conducted, as well as analyses of levels of CRS-related cytokines (eg, IL-6) over time, peak levels of cytokines by response and CRS, association of cytokine levels with ICANS, and CAR+ T cell CD4/CD8 ratio by response, CRS, and ICANS. Results: As of January 2022, 19 pts (median age 58.0 y [range 44–67]; 74% male; median follow-up 13.4 mo [range 5.2–21.7]) received cilta-cel. 79% of pts received prior ASCT. ORR was 100.0%, 90% achieved CR or better, and 95% achieved ≥VGPR. Median time to first response and best response were 0.95 mo (range 0.9–9.7) and 5.1 mo (range 0.9–11.8), respectively. Of pts who were MRD-evaluable (n = 15), 14 (93%) achieved MRD 10-5 negativity during this study. Median DOR was not reached and 12-mo event-free rate was 88.9%. The 12-mo PFS rate was 90%. Median time to onset of CRS was 8 d (range 5–11) and occurred in 16 (84.2%) pts (1 gr 4). CRS resolved in all pts. ICANS (gr 1) occurred in 1 pt; MNT (gr 3) occurred in 1 pt, previously reported. 1 pt died post cilta-cel due to PD at d 158. Preliminary PK analyses indicate that peak expansion of CAR-T cells occurred on d 13.1 (range 8.96–209.9) and median persistence was 76.9 d (range 40.99–221.8). Conclusions: A single cilta-cel infusion led to deep and durable responses in a functionally high-risk pt population who experienced early clinical relapse/tx failure to initial therapy, with a manageable safety profile. In this pt population with ineffective or insufficient response to ASCT, cilta-cel led to responses. Responses continue to deepen, and follow-up is ongoing. Updated and in-depth PK, cytokine, and CAR-T subset analyses and clinical correlation will be presented and provide novel insights into biological correlates of efficacy and safety in this pt population. Clinical trial information: NCT04133636.

Preferential expansion of CD8+ CD19-CAR T cells postinfusion and the role of disease burden on outcome in pediatric B-ALL

AbstractT cells expressing CD19-specific chimeric antigen receptors (CD19-CARs) have potent antileukemia activity in pediatric and adult patients with relapsed and/or refractory B-cell acute lymphoblastic leukemia (B-ALL). However, not all patients achieve a complete response (CR), and a significant percentage relapse after CD19-CAR T-cell therapy due to T-cell intrinsic and/or extrinsic mechanisms. Thus, there is a need to evaluate new CD19-CAR T-cell products in patients to improve efficacy. We developed a phase 1/2 clinical study to evaluate an institutional autologous CD19-CAR T-cell product in pediatric patients with relapsed/refractory B-ALL. Here we report the outcome of the phase 1 study participants (n = 12). Treatment was well tolerated, with a low incidence of both cytokine release syndrome (any grade, n = 6) and neurotoxicity (any grade, n = 3). Nine out of 12 patients (75%) achieved a minimal residual disease-negative CR in the bone marrow (BM). High disease burden (≥40% morphologic blasts) before CAR T-cell infusion correlated with increased side effects and lower response rate, but not with CD19-CAR T-cell expansion. After infusion, CD8+ CAR T cells had a proliferative advantage over CD4+ CAR T cells and at peak expansion, had an effector memory phenotype with evidence of antigen-driven differentiation. Patients that proceeded to allogeneic hematopoietic cell transplantation (AlloHCT) had sustained, durable responses. In summary, the initial evaluation of our institutional CD19-CAR T-cell product demonstrates safety and efficacy while highlighting the impact of pre-infusion disease burden on outcomes. This trial was registered at www.clinicaltrials.gov as #NCT03573700.

Design and energy characteristic analysis of a flexible isobaric strain-energy compressed-air storage device

Considering the problems of traditional compressed-air storage devices, such as low energy efficiency, low energy density, and portability challenges, a flexible, isobaric strain-energy compressed-air storage device based on a hyperelastic rubber material was proposed. The device was composed of a flexible internal expandable rubber airbag and a rigid external shield. The main influencing factors of the charging and discharging processes of the gas storage device (peak pressure, expansion pressure, and contraction pressure) were explored and analyzed, and the effects of these factors on the pressure were verified. The fluctuation rates of the expansion and contraction pressures of the gas storage device were 0.5% and 0.4%, respectively, indicating that the gas storage device had good isobaric and stable energy storage and release characteristics. A mathematical model describing the energy storage efficiency of the device was developed based on the first law of thermodynamics. Furthermore, the charging and discharging characteristics of the device were tested. Experimental results showed that the average energy storage efficiency of the device reached 76.9%, and the volume energy density was 309.48 kJ/m3, which is twice that of a traditional rigid gas storage tank.

Correlation between boson peak and thermal expansion manifested by physical aging and high pressure

Correlation between boson peak and thermal expansion manifested by physical aging and high pressure

Abrupt intrinsic and extrinsic responses of southwestern Iberian vegetation to millennial‐scale variability over the past 28 ka

ABSTRACTWe present new high‐resolution pollen records combined with palaeoceanographic proxies from the same samples in deep‐sea cores SHAK06‐5K and MD01‐2444 on the southwestern Iberian Margin, documenting regional vegetation responses to orbital and millennial‐scale climate changes over the last 28 ka. The chronology of these records is based on high‐resolution radiocarbon dates of monospecific samples of the planktonic foraminifera Globigerina bulloides, measured from SHAK06‐5K and MD01‐2444 and aligned using an automated stratigraphical alignment method. Changes in temperate and steppe vegetation during Marine Isotope Stage 2 are closely coupled with sea surface temperature (SST) and global ice‐volume changes. The peak expansion of thermophilous woodland between ~10.1 and 8.4 cal ka bp lags behind the boreal summer insolation maximum by ~2 ka, possibly arising from residual high‐latitude ice‐sheets into the Holocene. Rapid changes in pollen percentages are coeval with abrupt transitions in SSTs, precipitation and winter temperature at the onset and end of Heinrich Stadial 2, the ice‐rafted debris event and end of Heinrich Stadial 1, and the onset of the Younger Dryas, suggesting extrinsically forced southwestern Iberian ecosystem changes by abrupt North Atlantic climate events. In contrast, the abrupt decline in thermophilous elements at ~7.8 cal ka bp indicates an intrinsically mediated abrupt vegetation response to the gradually declining boreal insolation, potentially resulting from the crossing of a seasonality of precipitation threshold.