CD38 overexpression

Our study shows that the accumulation of peripheral CD8+CD57+T cells, CD8+CD38high T cells, and CD8+HLA-DR+CD38high T cells is reflective of an ongoing antitumor T cell response and a progressive immune dysfunction in MM. During chemotherapy, the recovery of immune function can be monitored by detecting the proportion of activated molecules of T lymphocytes.

This mouse V8-12 similar to human V2-5, and V2-5 showed several cancers with macrophages/neutrophils generated hepcidin+ ironlow or some showed hepcidin- iron+ with tumor, and mouse V8-12 with different Vk19-17 generate MZ B cells strongly increased macrophage++ in old aged and generated intestine/colon tumor. Conclusion, neonate generated TC-ATA B1 cells in old aged tumor generation are CD11b+ in the leukemia CLL together with lymphoma cancer with hepcidin-related Hamp2++ in B-1 cell generation to control iron.

P=N/A, N=330, Recruiting, The Second Affiliated Hospital of Chongqing Medical University

In sum, BN-CD38 induces an effective T cell synapse and IFNγ release, while concomitantly blocking the clonogenicity and inducing CD38 expression on LSCs. These studies suggest a new mechanism to unmask and target LSCs, providing the rationale for using BN-CD38 to effectively treat AML.

Anti-CD38 monoclonal antibodies (mAbs), daratumumab (dara) and isatuximab (isa), are approved to treat multiple myeloma (MM) in the first line and relapsed/refractory settings. Following characterization of a deletion, FISH could be used to monitor the clonal level longitudinally. Our suggestion that the presence of a CD38 deletion in >25% of malignant PC clones predicts for reduced CD38 mAb efficacy requires prospective validation.

However, the anti-CD38 monoclonal antibodies daratumumab and isatuximab have been associated with mobilisation impairment, yet the mechanism remains unclear. Finally, direct in vitro effect of isatuximab in upregulating JCAD and CLEC3B was confirmed by quantitative PCR. These findings suggest that upregulated adhesion-related interactions, rather than killing of CD34 cells by effector mechanisms, could be leading causes of decreased mobilisation efficacy in MM patients treated with anti-CD38 therapy.

Introduction: The implementation of CD38-targeting antibodies daratumumab and isatuximab into combination regimens including a proteasome inhibitor (PI) significantly improved outcome and prolonged survival of patients with multiple myeloma (MM)...In order to improve myeloma therapy, recently a phase II trial for RRMM patients was initiated combining the CD47 blocking antibody magrolimab with daratumumab or PIs (NCT04892446)...In responsive MM cell lines, ADCP mediated by CD38 antibodies in combination with the CD47 blocking antibody was slightly, but not significantly enhanced by pre-treatment with carfilzomib. Our findings demonstrate that blocking the CD47-SIRPa axis with a CD47 blocking antibody can improve ADCP of myeloma cells by therapeutic antibodies targeting CD38 and that PI treatment may enhance phagocytosis. Our findings demonstrate that blocking the CD47-SIRPa axis with a CD47 blocking antibody can improve ADCP of myeloma cells by therapeutic antibodies targeting CD38 and that PI treatment may enhance phagocytosis. Interestingly, there might be also MM cells with particular phenotypes rendering them resistant to phagocytosis. Further investigating these factors may help to identify MM patients that benefit from CD47 blockade.

A high frequency of tertiary lymphoid structures composed of CD31highCD38high plasma cells was associated with reduced recurrence after surgery in HNSCC. This data supports the notion that the structural architecture of the tumor immune microenvironment plays an essential role in tumor progression and indicates that type 1 tertiary lymphoid structures and long-lived CD31highCD38high plasma cells are associated with good prognosis in HNSCC.

O + D demonstrated no new toxicity concerns and yielded a clinically meaningful PFS6 rate and durable OTRs across several cancers with HRR defects, including rare cancers.

The novel striking finding of this study was an independent link between SF3B1 mutational status and poor response to RG7388. Overall, SF3B1 mutations in CLL patient samples were associated with resistance to treatment with RG7388 ex vivo, and patients with the wild type for both SF3B1 and TP53 are more likely to benefit from treatment with MDM2 inhibitors.

Example of T-cell activation measured by HLADR+CD38 high for healthy control (HC), p-HLH (primary hemophagocytic lymphohistiocytosis), sepsis, and LRBA deficiency (as an example of immune dysregulation disorder). Conclusions Flow cytometry-based direct assessment of HLADR+ CD38high in T cells subsets can reliably quantify T-cell activation and strongly correlate with sIL2R level across a spectrum of different hyperinflammatory and immune dysregulation disorders.

By adding Dasatinib, we enable the production of CD38 CAR T cells, without diminishing anti-CD38 reactivity andwithout the need of gene editing. The yield of SLAMF7 CAR T cells can be significantly increased under Dasatinib treatment. These CAR T cells show a significantly better state of fitness, which could be reflected in the therapeutic success.

Two FDA-approved drugs, all trans-retinoic acid (ATRA) and pomalidomide (Pom), significantly increased surface CD38 levels in low-CD38 expressing PEL cell lines, resulting in increased Dara-induced ADCC...Others had improvement in performance status and resolution of malignant ascites with Dara alone. Together, these data support the use of Dara monotherapy or in combination with ATRA or Pom as a potential therapeutic option for PEL.

We also identified several putative mechanisms of immune escape used by KSHV, as KIV displayed an overall decrease of co-stimulatory molecules with a remarkable lack of CD40 expression and are IL-10 producing cells. The identification of this specific and easily accessible KSHV+ circulating population brings new elements in the understanding of KSHV-MCD but also raises new questions that need to be clarified.

Hence our study is unique and very first of its kind in this regard. We conclude that flowcytometric enumeration of circulating CD34+CD38- h-MICL+ cell subset holds a potential as a robust diagnostic test, tool for prognostication, an indicator of disease progression and a potential target for therapy.

Combination of lemzoparlimab and felzartamab showed enhanced in vitro ADCP and in vivo anti-tumor efficacy in these CD47 high and CD38 low high-risk MM cells which were resistant to felzartamab or daratumumab mono-treatment. Our study provides preclinical evidence to explore the combination of lemzoparlimab and felzartamab in the treatment of high-risk MM patients.

Hence, an enhanced CD38 targeted therapy that unleashes the innate immune cell mediated tumor killing potential and overcomes daratumumab resistance mechanisms may present a unique opportunity to treat MM...Due to low-affinity binding to CD47, ISB 1442 engages CD47 efficiently only upon CD38 binding (avidity-induced binding), thereby reducing the potential for on-target, off-tumor effects, and it does not cause any detectable RBC depletion in vitro compared to magrolimab (Figure 2)...The study is currently open for enrollment. Clinicaltrials.gov identifier: NCT05427812.

Flow cytometry-based direct assessment of HLADR+CD38high in T cells subsets can reliably quantify T-cell activation and strongly correlate with sIL2R level across a spectrum of different hyperinflammatory and immune dysregulations disorders. If validated, this could be used as a real-time assessment of T-cell activation at disease onset and monitoring response to therapy.

Preclinical activity of ISB 1442 for the treatment of relapsed/refractory multiple myeloma (rrMM), including increased killing potency relative to daratumumab and magrolimab benchmarks as well as more favorable off tumor/on target specificity, was reported previously (Sammicheli et al. In summary, these data support the clinical development of 1442 in AML and T-ALL. Based on its unique design and multiple mechanisms of action, ISB 1442 is anticipated to have antitumor activity in AML and T-ALL patients in a single antibody relative to anti-CD38 or anti-CD47 monoclonal antibodies as well as their combination.

Next, we selected 3 HMCLs with low (JJN3), intermediate (XG2), and high (XG7) CD38 expression, and treated these cell lines with sublethal concentration of EZH2 inhibitor (EPZ-6438) for 9 days. CD38 re-expression was linked to an improvement of Daratumumab and Isatuximab ADCC efficiency. Thus, EZH2 targeting may be of therapeutic interest to overcome resistance to anti-CD38 targeted immunotherapies in Multiple Myeloma.

The identification of a singular KSHV-infected circulating population paves the way for a new approach to the study of KSHV+ MCD pathophysiology.

CLL cells were found to make low amounts of IFN via TANK-binding kinase 1 pathways, but p-STAT1 and -STAT2 proteins along with IFN-stimulated genes that reflect IFN activation were variably downregulated in cultured CLL cells by the neutralizing IFNAR1 Ab anifrolumab...Autocrine IFN protected responsive CLL cells from stressful tissue culture environments and therapeutic drugs such as ibrutinib and venetoclax in vitro, in part by upregulating Mcl-1 expression. These findings suggest hypersensitivity to IFN may promote aggressive clinical behavior. Specific blockade of IFN signaling may improve outcomes for patients with CLL with higher-risk disease.

Methods : This multicenter, open-label, Phase 1b study evaluated the safety, pharmacokinetics (PK), and efficacy of SC vs IV Isa + Pd in patients (pts) with RRMM who had received ≥2 prior lines of therapy, including lenalidomide and a proteasome inhibitor. A total of 34 pts were randomized and treated: 12 pts Isa IV 10 mg/kg + Pd, 12 pts Isa SC1000 + Pd, 10 pts Isa SC1400 + Pd. As of March 31, 2021, 7 pts (58%) IV, 4 pts (33%) SC1000, and 7 pts (70%) SC1400 remained on study treatment. Median time from initial MM diagnosis to first study treatment was ~5 years, and the median (range) number of prior lines of therapy was: 3.5 (2-7) in IV, 3.0 (2-6) in SC1000, and 2.5 (1-4) in SC1400 pts.

In conclusion, we demonstrated that high CD38 expression is an independent adverse prognostic factor associated with poor clinical outcomes compared to low CD38 expression. CD38 expression in DLBCL cells might be useful for predicting outcomes and designing risk-adapted therapies for patients with de-novo DLBCL.

Conclusions Novel gene editing techniques can be successfully applied to generate NK cells with enhanced antitumor capabilities. We established an efficient gene editing platform that can be utilized to produce NK cells optimized for adoptive combination with daratumumab.

MRD at the end of induction was confirmed as an important prognostic factor in the RALL-2016 study. However, immunophenotyping residual blasts could improve the prognostic impact of MRD. High expression of CD58 and CD38 on MRD cells dramatically decreases the duration of RFS in B-ALL patients.

Our data revealed that ex vivo expansion of HSCs using the FBS culture system induces an inflammatory response and high CD38 expression, indicating that this system might activate an inflammatory pathway and induce expression of the cancer marker CD38 during ex vivo expansion of HSCs. This study provides a transcriptional profile and new insights into the genomic functions of HSCs under different expanded cultures.

The monoclonal anti-CD38 antibody daratumumab is approved for treatment of multiple myeloma and provided a therapeutically relevant depletion of plasma cells in patients with SLE 1... Our data indicate that not only pathogenic plasma cells are potential target cells of CD38-targeting antibodies. The highly dysregulated CD38 expression across innate and adaptive immune cells in SLE could be of pathophysiological importance with respect to the potential efficacy and side effects of such therapies. Since CD38 expression did not correlate with disease activity, it may be assumed that it is not a response protein solely induced and modulated by type I interferons.

Interestingly, high CD25ABC trended toward shortened TTFT (p = .07). Quantitative antigen expression reflects CLL-IPI risk groups and Dohner-classification.