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Abstract Background: Treatment with chimeric antigen receptor-T (CAR-T) cells has shown promising effectiveness in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), although the process of preparing for this therapy usually takes a long time. We have recently created CD19 Fast-CAR-T (F-CAR-T) cells, which can be produced within a single day. The objective of this study was to evaluate and contrast the effectiveness and safety of CD19 F-CAR-T cells with those of CD19 conventional CAR-T cells in the management of R/R B-ALL. Methods: A multicenter, retrospective analysis of the clinical data of 44 patients with R/R B-ALL was conducted. Overall, 23 patients were administered with innovative CD19 F-CAR-T cells (F-CAR-T group), whereas 21 patients were given CD19 conventional CAR-T cells (C-CAR-T group). We compared the rates of complete remission (CR), minimal residual disease (MRD)-negative CR, leukemia-free survival (LFS), overall survival (OS), and the incidence of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) between the two groups. Results: Compared with the C-CAR-T group, the F-CAR-T group had significantly higher CR and MRD-negative rates (95.7% and 91.3%, respectively; 71.4% and 66.7%, respectively; P = 0.036 and P = 0.044). No significant differences were observed in the 1-year or 2-year LFS or OS rates between the two groups: the 1-year and 2-year LFS for the F-CAR-T group vs.C-CAR-T group were 47.8% and 43.5% vs. 38.1% and 23.8% (P = 0.384 and P = 0.216), while the 1-year and 2-year OS rates were 65.2% and 56.5% vs. 52.4% and 47.6% (P = 0.395 and P = 0.540). Additionally, among CR patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) following CAR-T-cell therapy, there were no significant differences in the 1-year or 2-year LFS or OS rates: 57.1% and 50.0% vs. 47.8% and 34.8% (P = 0.506 and P = 0.356), 64.3% and 57.1% vs. 65.2% and 56.5% (P = 0.985 and P = 0.883), respectively. The incidence of CRS was greater in the F-CAR-T group (91.3%) than in the C-CAR-T group (66.7%) (P = 0.044). The incidence of ICANS was also greater in the F-CAR-T group (30.4%) than in the C-CAR-T group (9.5%) (P = 0.085), but no treatment-related deaths occurred in the two groups. Conclusion: Compared with C-CAR-T-cell therapy, F-CAR-T-cell therapy has a superior remission rate but also leads to a tolerably increased incidence of CRS/ICANS. Further research is needed to explore the function of allo-HSCT as an intermediary therapy after CAR-T-cell therapy.

With an incidence of ~50%, the absence or reduced protein level of p53 is much more common than TP53 mutations in acute myeloid leukemia (AML). AML with FLT3-ITD (internal tandem duplication) mutations has an unfavorable prognosis and is highly associated with wt-p53 dysfunction. While TP53 mutation in the presence of FLT3-ITD does not induce AML in mice, it is not clear whether p53 haploinsufficiency or loss cooperates with FLT3-ITD in the induction of AML. Here, we generated FLT3-ITD knock-in; p53 knockout (heterozygous and homozygous) double-transgenic mice and found that both alterations strongly cooperated in the induction of cytogenetically normal AML without increasing the self-renewal potential. At the molecular level, we found the strong upregulation of Htra3 and the downregulation of Lin28a, leading to enhanced proliferation and the inhibition of apoptosis and differentiation. The co-occurrence of Htra3 overexpression and Lin28a knockdown, in the presence of FLT3-ITD, induced AML with similar morphology as leukemic cells from double-transgenic mice. These leukemic cells were highly sensitive to the proteasome inhibitor carfilzomib. Carfilzomib strongly enhanced the activity of targeting AXL (upstream of FLT3) against murine and human leukemic cells. Our results unravel a unique role of p53 haploinsufficiency or loss in the development of FLT3-ITD + AML.

Although multiple myeloma (MM) responds well to immunotherapeutic treatment, certain portions of MM are still unresponsive or relapse after immunotherapy. Other immune molecules are needed for the immunotherapy of MM. Here, we revealed that leukocyte immunoglobulin-like receptor B4 (LILRB4) was highly expressed in multiple myeloma cell lines and patient samples and that the expression of LILRB4 was adversely correlated with the overall survival of MM patients. Knockdown of LILRB4 efficiently delayed the growth of MM cells both in vitro and in vivo. Mechanistically, IKZF1 transactivated LILRB4 expression to trigger the downstream of STAT3-PFKFB1 pathways to support MM cell proliferation. Blockade of LILRB4 signaling by blocking antibodies can effectively inhibit MM progression. Our data show that targeting LILRB4 is potentially an additional therapeutic strategy for the immunotherapeutic treatment of MM.

Chimeric antigen receptor-engineered T (CAR-T) cells have shown promising efficacy in patients with relapsed/refractory B cell acute lymphoblastic leukemia (R/R B-ALL). However, challenges remain including long manufacturing processes that need to be overcome. We presented the CD19-targeting CAR-T cell product GC007F manufactured next-day (FasTCAR-T cells) and administered to patients with R/R B-ALL. A total of 21 patients over 14 years of age with CD19+  R/R B-ALL were screened, enrolled and infused with a single infusion of GC007F CAR-T at three different dose levels. The primary objective of the study was to assess safety, secondary objectives included pharmacokinetics of GC007F cells in patients with R/R B-ALL and preliminary efficacy. We were able to demonstrate in preclinical studies that GC007F cells exhibited better proliferation and tumor killing than conventional CAR-T (C-CAR-T) cells. In this investigator-initiated study all 18 efficacy-evaluable patients achieved a complete remission (CR) (18/18, 100.00%) by day 28, with 17 of the patients (94.4%) achieving CR with minimal residual disease (MRD) negative. Fifteen (83.3%) remained disease free at the 3-month assessment, 14 patients (77.8%) maintaining MRD negative at month 3. Among all 21 enrolled patients, the median peak of CAR-T cell was on day 10, with a median peak copy number of 104899.5/µg DNA and a median persistence period of 56 days (range: 7–327 days). The incidence of cytokine release syndrome (CRS) was 95.2% (n = 20), with severe CRS occurring in 52.4% (n = 11) of the patients. Six patients (28.6%) developed neurotoxicity of any grade. GC007F demonstrated superior expansion capacity and a less exhausted phenotype as compared to (C-CAR-T) cells. Moreover, this first-in-human clinical study showed that the novel, next-day manufacturing FasTCAR-T cells was feasible with a manageable toxicity profile in patients with R/R B-ALL.

To evaluate the long-term efficacy and safety of gilteritinib compared with salvage chemotherapy (SC) in patients with relapsed/refractory FMS -like tyrosine kinase 3 ( FLT3 )-mutated acute myeloid leukemia (AML). In the phase 3 COMMODORE (NCT03182244) trial, patients with relapsed/refractory FLT3 -mutated AML from China, Russia, Singapore, Thailand, and Malaysia were randomized to gilteritinib (120 mg/day) or SC. The long-term follow-up included assessments every 3 months for a maximum of 3 years from the end-of-treatment visit. The primary endpoint was overall survival (OS). Secondary endpoints included event-free survival (EFS), complete remission (CR) rate, hematopoietic stem cell transplantation (HSCT) rate, and transfusion maintenance and conversion rates. Overall, 276 patients (gilteritinib, n  = 137; SC, n  = 139) completed the long-term follow-up. Most (88.0%) patients were Asian. The median (95% confidence interval [CI]) OS was longer with gilteritinib versus SC (10.3 [8.8, 12.7] vs 5.4 [4.1, 8.1] months, respectively; hazard ratio [HR; 95% CI], 0.612 [0.451, 0.832]), with a median follow-up of 34.6 months. The median (95% CI) EFS was longer with gilteritinib versus SC (2.1 [< 0.1, 3.2] vs 0.6 [0.2, 1.2] months, respectively; HR [95% CI], 0.589 [0.438, 0.792]). The CR rate was 20.4% and 11.5% in the gilteritinib and SC arms, respectively. During the entire study period, 22.6% and 7.9% of patients in the gilteritinib and SC arms underwent HSCT, respectively; 18.2% of patients in the gilteritinib arm received on-study HSCT. No new safety concerns were identified. Long-term gilteritinib treatment improved clinical outcomes compared with SC and was well-tolerated in a predominantly Asian population with relapsed/refractory FLT3 -mutated AML.

The stability of Ikaros family zinc finger protein 1 (Ikaros), a critical hematopoietic transcription factor, can be regulated by cereblon (CRBN) ubiquitin ligase stimulated by immunomodulatory drugs in multiple myeloma. However, other stabilization mechanisms of Ikaros have yet to be elucidated. In this study, we show that the pharmacologic inhibition or knockdown of Hsp90 downregulates Ikaros in acute myeloid leukemia (AML) cells. Proteasome inhibitor MG132 but not autophagy inhibitor chloroquine could suppress the Hsp90 inhibitor STA-9090-induced reduction of Ikaros, which is accompanied with the increased ubiquitination of Ikaros. Moreover, Ikaros interacts with E3 ubiquitin-ligase C terminal Hsc70 binding protein (CHIP), which mediates the STA-9090-induced ubiquitination of Ikaros. In addition, the knockdown of Ikaros effectively inhibits the proliferation of leukemia cells, but this phenomenon could be rescued by Ikaros overexpression. Collectively, our findings indicate that the interplay between HSP90 and CHIP regulates the stability of Ikaros in AML cells, which provides a novel strategy for AML treatment through targeting the HSP90/Ikaros/CHIP axis.

BackgroundPenpulimab is a humanized IgG1 mAb that blocks PD-1 binding to PD-L1. Penpulimab was engineered to eliminate Fc?R binding and ADCC/ADCP completely, as compared to majority of marketed IgG4 PD-1 antibodies with ADCC/ADCP activity. ADCC/ADCP effects can induce T-cell apoptosis and clearance and then compromise anti-tumor activity. The removal of Fc?R binding eliminates Fc receptor mediated immune-cell recruitment and activation and could potentially reduce immune-related adverse reactions. Penpulimab demonstrated a slower PD-1 antigen binding off-rate than marketed PD-1 antibodies, which result in better cellular activity and higher receptor occupancy. Penpulimab also showed numerous contacts with N58 glycosylation on the BC loop of PD-1 which could be an advantage to facilitate interaction of PD-1 antibody and may contribute to slower binding off-rate. These structural differentiations offer more robust biological effect and enhance anti-tumor activity of penpulimab.MethodsAK105-201 (NCT03722147) is a multicenter, single-arm, open-label study of penpulimab in R/R cHL. All pts received penpulimab 200 mg q2w until progression or unacceptable toxicity. Eligible pts had R/R cHL after ASCT, or at least 2 lines of prior chemotherapy. The primary endpoint was ORR based on the Lugano 2014 criteria as assessed by an independent review committee (IRC). Key secondary endpoints included CR rate, DCR, PFS, duration of response (DoR), safety, and tolerability.ResultsAs of 10 January, 2020, the median follow-up was 6.3 months (range, 3.5 to 17.0). The anti-tumor activity of penpulimab in the 73 pts evaluable for efficacy (defined as pts who had an opportunity to be followed for at least 16 weeks) is shown in the table 1. At data cutoff, 91.8% of responders remained ongoing and still on treatment. Treatment-related adverse events (TRAEs) occurred in 93.6% of pts (G3 in 13.8% [13/94], no G4 or G5, treatment discontinuation in 2.1% [2/94]). Treatment-related SAEs occurred in 3.2%. Most frequent TRAEs (≥15%) were fever (24.5%), hypothyroidism (21.3%), upper respiratory tract infection (18.1%), and ALT elevations (17.0%). Grade ≥3 TRAEs reported in ≥2 pts were platelet count decreased (2.1%). Immune-related AEs were reported in 42.6% of pts (G3 in 2.1%: psoriasis [n=1], IgA nephropathy [n=1]).ConclusionsPenpulimab was shown to be highly active resulting in a high CR rate in pts with R/R cHL. With longer follow-up, CR rate for penpulimab in R/R cHL could be further increased. Penpulimab demonstrated notably lower rates of SAE, TRAE leading to discontinuation, and Grade Grade ≥3 immune-related AEs in pts with R/R cHL.Trial RegistrationNCT03722147Abstract 791 Table 1Anti-tumor activity of penpulimab in R/R cHL

How particular bone marrow niche factors contribute to the leukemogenic activities of leukemia-initiating cells (LICs) remains largely unknown. Here, we showed that ATP levels were markedly increased in the bone marrow niches of mice with acute myeloid leukemia (AML), and LICs preferentially localized to the endosteal niche with relatively high ATP levels, as indicated by a sensitive ATP indicator. ATP could efficiently induce the influx of ions into LICs in an MLL-AF9-induced murine AML model via the ligand-gated ion channel P2X7. P2x7 deletion led to notably impaired homing and self-renewal capacities of LICs and contributed to an approximately 5-fold decrease in the number of functional LICs but had no effect on normal hematopoiesis. ATP/P2X7 signaling enhanced the calcium flux-mediated phosphorylation of CREB, which further transactivated phosphoglycerate dehydrogenase (Phgdh) expression to maintain serine metabolism and LIC fates. P2X7 knockdown resulted in a markedly extended survival of recipients transplanted with either human AML cell lines or primary leukemia cells. Blockade of ATP/P2X7 signaling could efficiently inhibit leukemogenesis. Here, we provide a perspective for understanding how ATP/P2X7 signaling sustains LIC activities, which may benefit the development of specific strategies for targeting LICs or other types of cancer stem cells.

Purpose Hemophagocytic lymphohistiocytosis (HLH), especially lymphoma-associated HLH (LA-HLH), is a refractory immune disorder with high mortality. There is still no consensus regarding the ideal treatment for LA-HLH. Methods We performed a prospective multicenter study (NCT 04077905) to explore the efficacy of a modified DEP regimen as induction therapy for LA-HLH. Twenty-eight patients from 6 clinical centers in China were enrolled between September 2019 and July 2021. We evaluated the efficacy of the modified DEP induction therapy 4 weeks after the initiation of treatment. Results The results showed that the overall response rate was 89.3% (25/28 patients), whereby 28.6% (8/28 patients) achieved a complete response and 60.7% (17/28 patients) were in partial response. Ferritin and soluble CD25 levels were decreased significantly 4 weeks after the modified DEP induction therapy ( P  = 0.001 and P  = 0.00016, respectively), while platelet count and total bilirubin improved significantly ( P  = 0.004 and P  = 0.001, respectively). The 1-year overall survival rate of all patients was 34.5%, with a median survival of 6.5 months (range 0.5–19 months). Patients with LA-HLH who underwent a stem cell transplantation had a significantly better prognosis than those not achieving complete response 4 weeks after modified DEP induction therapy ( P  = 0.034). Conclusion Our study suggests that the modified DEP regimen is a safe and effective induction therapy for LA-HLH. Timely stem cell transplantation can improve the prognosis of patients with LA-HLH. Trail registry number NCT 04077905. URL: https://clinicaltrials.gov/ct2/show/NCT04077905?id=NCT04077905&draw=2&rank=1 .

Small extracellular vesicles (SEVs) are functional messengers of certain cellular niches that permit noncontact cell communications. Whether niche-specific SEVs fulfill this role in cancer is unclear. Here, we used 7 cell type-specific mouse Cre lines to conditionally knock out Vps33b in Cdh5+ or Tie2+ endothelial cells (ECs), Lepr+ BM perivascular cells, Osx+ osteoprogenitor cells, Pf4+ megakaryocytes, and Tcf21+ spleen stromal cells. We then examined the effects of reduced SEV secretion on progression of MLL-AF9-induced acute myeloid leukemia (AML), as well as normal hematopoiesis. Blocking SEV secretion from ECs, but not perivascular cells, megakaryocytes, or spleen stromal cells, markedly delayed the leukemia progression. Notably, reducing SEV production from ECs had no effect on normal hematopoiesis. Protein analysis showed that EC-derived SEVs contained a high level of ANGPTL2, which accelerated leukemia progression via binding to the LILRB2 receptor. Moreover, ANGPTL2-SEVs released from ECs were governed by VPS33B. Importantly, ANGPTL2-SEVs were also required for primary human AML cell maintenance. These findings demonstrate a role of niche-specific SEVs in cancer development and suggest targeting of ANGPTL2-SEVs from ECs as a potential strategy to interfere with certain types of AML.