Human CD38 Research Articles

Real-World Analysis of Treatment Patterns and the Effectiveness and Safety Profile of Daratumumab-Based Regimens in Chinese Patients with Newly Diagnosed or Relapsed/Refractory Multiple Myeloma

Introduction: Daratumumab (DARA) is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. Several clinical trials have established DARA-based treatment as a standard of care globally for patients with newly diagnosed or relapsed/refractory multiple myeloma (MM). However, clinical trials do not always reflect routine clinical practice, and real-world (RW) studies thus provide an important complement to conventional clinical trials. Herein, we report results from an observational study that described RW treatment patterns and outcomes in routine clinical practice among patients with MM who were treated with DARA in China. This is possibly the first study to enroll a large population of Chinese patients with MM who were treated with DARA in the RW setting. Methods: This ongoing, multicenter, noninterventional, observational registry study is enrolling Chinese patients who have been diagnosed with symptomatic newly diagnosed or relapsed/refractory MM and either (1) started DARA treatment after August 1, 2019, and were expected to continue ongoing DARA at the time of study initiation (November 3, 2021) or (2) started DARA treatment after study initiation. Patients were excluded from the study if they had received ≥4 prior lines of MM therapy before starting DARA-based treatment or had a diagnosis of other cancers prior to their MM diagnosis. The decision to treat with DARA must have been made prior to and independently of the patient's inclusion in the study, and treatment was administered in accordance with local clinical practice. For patients who started DARA after August 1, 2019, but before study initiation, data were collected both retrospectively through medical chart review and prospectively after enrollment. RW baseline disease characteristics, treatment patterns, response rates, measurable residual disease (MRD), and safety are presented. Outcome and safety analyses were based on the DARA treatment period. Results: As of the cutoff date (April 30, 2023) for this analysis, 210 patients who received ≥1 dose of DARA have been enrolled in the study from 13 participating sites in China. At baseline (last status prior to the first DARA dose), patients had a median age of 64 y (range, 29-89) and a median time since MM diagnosis of 1 y (range, 0-12); the majority of patients had an ECOG performance status of 0 or 1 (82.4%) and a Durie-Salmon MM stage of III (74.4%). Most (83.8%) patients had received ≥1 prior line of therapy before initiating DARA, including 82.4% who had received prior protease inhibitors (PIs) and 58.1% who had received prior immunomodulatory drugs (IMiDs). A summary of prior therapies is provided in Table 1. DARA-based therapy included DARA monotherapy (n = 22) or combination with dexamethasone only (n = 21), PIs ± dexamethasone (n = 57), IMiDs ± dexamethasone (n = 71), PIs and IMiDs ± dexamethasone (n = 29), and other combinations (n = 10). The median DARA exposure time was 5.39 mo (interquartile range [IQR], 2.56-9.69), and the median follow-up time was 10.48 mo (IQR, 7.23-15.31). Of the 179 patients evaluable for response, a best overall response of partial response (PR) or better was achieved by 130 (72.6%) patients and a best response of very good partial response (VGPR) or better was achieved by 93 (52.0%) patients, with responses observed across DARA treatment regimens ( Table 2). MRD results were available for 53/179 (29.6%) patients, with 31/53 (58.5%) patients achieving MRD negativity. Adverse drug reactions were reported for 40 (19.0%) patients overall; events reported in ≥5% of patients included leukopenia (6.2%), thrombocytopenia (5.7%), and neutropenia (5.2%). Serious treatment-emergent adverse events were reported for 29 (13.8%) patients, with pneumonia (n = 10, 4.8%) the only serious event reported in ≥5 patients. Twenty-five patients died as of the cut-off date, regardless of timing (with/without DARA treatment period). Conclusions: This noninterventional, observational study provides RW insights into physician treatment decisions for patients with MM in China and the characteristics of patients who are selected for DARA-based treatment. In addition, the RW effectiveness, duration of therapy, and safety results support the use of DARA-based treatment as a standard of care in Chinese patients with newly diagnosed or relapsed/refractory MM. This study is ongoing, with a total planned enrollment of ~220 patients.

Efficacy and Safety of Daratumumab (DARA) Monotherapy in Patients with Intermediate-Risk or High-Risk Smoldering Multiple Myeloma (SMM): Final Analysis of the Phase 2 Centaurus Study

Introduction: SMM is a precursor disorder to multiple myeloma (MM) (Rajkumar SV, et al. Blood. 2015;125[20]:3069-3075). Current guidelines for SMM recommend active monitoring, with treatment initiation only upon progression to MM. However, therapeutic intervention at the SMM stage may help delay the progression to MM (Lonial S, et al. J Clin Oncol. 2020;38[11]:1126-1137; Mateos MV, et al. ASH 2022. Abstract 118). DARA is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. Given the deep and durable responses and favorable safety profile of DARA monotherapy in patients (pts) with relapsed/refractory MM (Usmani SZ, et al. Blood. 2016;128[1]:37-44), we hypothesized that DARA could delay the progression of SMM to MM. In the primary analysis of the phase 2 CENTAURUS study (NCT02316106), after a 15.8-month median follow-up, DARA monotherapy showed activity and was well tolerated in pts with intermediate- or high-risk SMM (Landgren CO, et al. Leukemia. 2020;34[7]:1840-1852). Activity and tolerability of DARA monotherapy were also observed in CENTAURUS after an additional 10 months of median follow-up (Landgren CO, et al. ASH 2018. Abstract 1994). Here, we present the final analysis of the CENTAURUS study, with a median follow-up of 85.2 months (~7 years). Methods: Eligible pts had a diagnosis of intermediate-risk or high-risk SMM for <5 years. Pts were randomized (1:1:1) to receive 8-week cycles of DARA 16 mg/kg intravenously (IV) on 1 of 3 dosing schedules. In the Intense dosing arm, pts received DARA QW (Cycle 1), Q2W (Cycles 2-3), Q4W (Cycles 4-7), and Q8W (Cycles 8-20). In the Intermediate dosing arm, pts received DARA QW (Cycle 1) and Q8W (Cycles 2-20). In the Short dosing arm, pts received 1 cycle of DARA QW. For pts in the Intense and Intermediate arms, there was an option to extend treatment (Extension phase) with DARA IV or with subcutaneous DARA (DARA SC; DARA 1,800 mg co-formulated with recombinant human hyaluronidase PH20 [2,000 U/mL; Halozyme, Inc.]) Q8W after the end of Cycle 20 per investigator discretion if there was a positive benefit/risk ratio, no grade ≥3 treatment-related toxicity, and at least stable disease had been achieved. Rate of complete response or better (≥CR) was a primary endpoint. Secondary endpoints included overall response rate (ORR) and overall survival (OS). Results: A total of 123 pts (41 pts per arm) were randomized. Median (range) age was 61 (31-81) years. Median duration of study treatment overall during the study was 44.0 months in the Intense arm, 35.2 months in the Intermediate arm, and 1.6 months in the Short arm. A total of 36 pts (21 pts in the Intense arm and 15 pts in the Intermediate arm) continued to receive DARA Q8W in the Extension phase (Cycles 21+). During the Extension phase, median duration of study treatment was 45.2 months in the Intense arm and 46.1 months in the Intermediate arm ( Table 1). 16 pts in the Intense arm and 10 pts in the Intermediate arm switched from DARA IV to DARA SC during the Extension phase. Efficacy results are summarized in Table 2. At a median (range) follow-up of 85.2 (0-94.3) months, ORR and ≥CR rate were higher in the Intense and Intermediate arms than in the Short arm. In the Intense and Intermediate arms combined, the ≥CR rate was 8.5%. Median OS was not reached in any dosing arm; the 84-month OS rate was 81.3%, 89.5%, and 88.1% in the Intense, Intermediate, and Short arms, respectively. Safety results are summarized in Table 1. Grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 65.9%, 41.5%, and 15.0% of pts in the Intense, Intermediate, and Short arms, respectively; grade 3/4 TEAEs were reasonably related to DARA in 12.2%, 2.4%, and 5.0% of pts, respectively. TEAEs that led to discontinuation of DARA occurred in 7.3%, 2.4%, and 5.0% of pts in the Intense, Intermediate, and Short arms, respectively. Conclusions: Findings from this final analysis of CENTAURUS continue to demonstrate the clinical activity of DARA monotherapy in pts with intermediate- or high-risk SMM after a median follow-up of ~7 years. A high proportion (44%) of pts in the Intense and Intermediate arms completed 20 cycles and remained on DARA monotherapy per investigator discretion, with a median duration of additional treatment of 46.0 months (~4 years) in the Extension phase. No new safety concerns were observed with extended follow-up.

Generation and Screening of Various CD70 CAR NK Cells Identify the Most Effective Construct Against Hematologic Malignancies

The ability to re-direct the intrinsic power of the immune system against cancer has resulted in unprecedented outcomes in certain patients with otherwise incurable diseases. Natural killer (NK) cells, similar to T cells, are powerful immune effectors that possess intrinsic anti-tumor properties and are capable of generating a strong cytotoxic response upon engaging tumor cells. However, unlike T cells, NK cells do not identify specific antigens and do so in a way that is HLA-independent, posing minimal risk of GvHD. Thus, NK cells have are being explored as a possible allogeneic source for over-the-counter cellular immunotherapy. CD70, the ligand for the CD27 receptor, is an attractive “pan-cancer antigen”, since in addition to being expressed in hematologic malignancies such as acute myeloid leukemia (AML) and lymphoma, it is also expressed on many solid tumors, including bladder, lung, triple negative breast cancer, renal cell carcinoma, pancreatic cancer, and melanoma. Moreover, CD70 is only transiently found on activated T and B lymphocytes and on dendritic cells. To target CD70-expressing cancers, we designed and tested a number of different chimeric antigen receptors (CAR). Briefly, we used the natural interaction between CD70 and CD27 to make a CAR construct that incorporated the extracellular domain of human CD27, which is the natural receptor for CD70. We generated various second-generation CAR constructs that differed in their transmembrane domains (CD27 vs. CD28) and costimulatory domains. We included co-stimulatory domains that are NK-centric (DAP10 and DAP12), T-cell-centric (CD28), or bi-centric (4-1BB). The CD3ζ chain was used as a signaling endodomain, and all the CAR constructs also included IL-15 to enhance in vivo proliferation and persistence. Cord blood (CB)-derived NK cells were efficiently retrovirally transduced with the different CAR constructs and subjected to an in vitro functional screen against various cancer cells to evaluate the best constructs for in vivo validation (Figure 1). The top constructs from our in vitro screen were further evaluated in multiple in vivo models, including a Raji lymphoma model and a THP-1 AML model. The best CAR construct in terms of superior tumor control and prolongation of survival was selected for GMP manufacturing. Based on these preclinical findings, a Phase I/II clinical study is now being conducted at our center to assess the safety and effectiveness of CD70 CAR NK cells against CD70-expressing hematologic malignancies (NCT05092451). Figure 1: Flow chart showing the screening process to identify the most effective CAR construct.

217.6: Beneficial effects of transgenic expression of human CD200 on top of quadruple-knockout/double-knockin (CD46/thrombomodulin) pigs on kidney xenograft survival in nonhuman primates

217.6: Beneficial effects of transgenic expression of human CD200 on top of quadruple-knockout/double-knockin (CD46/thrombomodulin) pigs on kidney xenograft survival in nonhuman primates

Insect cell‐derived human CD200‐Fc increases zonula occludens‐1 tight junction protein in urothelial carcinoma cells

AbstractCD200 is a ligand that interacts with the CD200 receptor 1, with an anti‐inflammatory effect. CD200 inhibits the nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) pathway, attenuating the inflammatory response and maintaining barrier function. In this study, human CD200 was fused with the fragment crystallizable (Fc) region of human immunoglobulin G (IgG) to generate the recombinant CD200‐Fc protein, produced in insect cells using the baculovirus expression vector system. The CD200‐Fc gene was cloned under the control of the polyhedrin promoter in the pFastBac‐1 vector of the baculovirus expression vector system. Immunoblot analysis confirmed the expression of CD200‐Fc in insect cells. The CD200‐Fc protein was successfully purified using protein A affinity chromatography. 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay revealed that purified CD200‐Fc protein inhibited the proliferation of TCCSUP cells, a bladder epithelial cancer cell expressing CD200 receptor 1, at concentrations of 1, 10 and 100 ng/mL. Quantitative real‐time reverse transcription PCR (qRT‐PCR) and immunoblot analyses confirmed that the mRNA and protein levels of zonula occludens‐1, a tight junction protein for barrier protection in epithelial tissues, were increased in TCCSUP cells treated with insect cell‐derived CD200‐Fc. These results suggest that insect cell‐derived CD200‐Fc could alter zonula occludens‐1 expression in bladder epithelial cancer cells, enhancing the function of the cell barrier protein, which could inhibit cancer metastasis. Taken together, the baculovirus expression vector system can be applied to express antitumor therapeutic CD200‐Fc protein for the inhibition of bladder cancer.

Production and characterization of a chimeric antigen, based on nucleocapsid of SARS-CoV-2 fused to the extracellular domain of human CD154 in HEK-293 cells as a vaccine candidate against COVID-19.

Despite that more than one hundred vaccines against SARS-CoV-2 have been developed and that some of them were evaluated in clinical trials, the latest results revealed that these vaccines still face great challenges. Among the components of the virus, the N-protein constitutes an attractive target for a subunit vaccine because it is the most abundant, highly conserved and immunogenic protein. In the present work, a chimeric protein (N-CD protein) was constructed by the fusion of the N-protein to the extracellular domain of human CD154 as the molecular adjuvant. HEK-293 cells were transduced with lentiviral vector bearing the N-CD gene and polyclonal cell populations were obtained. The N-CD protein was purified from cell culture supernatant and further characterized by several techniques. Immunogenicity studies in mice and non-human primates showed the N-CD protein induced high IgG titers in both models after two doses. Moreover, overall health monitoring of non-human primates demonstrated that animals were healthy during 228 days after first immunization. Data obtained support further investigation in order to develop this chimeric protein as vaccine candidate against COVID-19 and other coronavirus diseases.

A Fully Human IgE Specific for CD38 as a Potential Therapy for Multiple Myeloma.

Multiple myeloma (MM) is an incurable malignancy of plasma cells and the second most common hematologic malignancy in the United States. Although antibodies in clinical cancer therapy are generally of the IgG class, antibodies of the IgE class have attractive properties as cancer therapeutics, such as their high affinity for Fc receptors (FcεRs), the low serum levels of endogenous IgE allowing for less competition for FcR occupancy, and the lack of inhibitory FcRs. Importantly, the FcεRs are expressed on immune cells that elicit antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), and/or antigen presentation such as mast cells, eosinophils, macrophages, and dendritic cells. We now report the development of a fully human IgE targeting human CD38 as a potential MM therapy. We targeted CD38 given its high and uniform expression on MM cells. The novel anti-CD38 IgE, expressed in mammalian cells, is properly assembled and secreted, exhibits the correct molecular weight, binds antigen and the high affinity FcεRI, and induces degranulation of FcεRI expressing cells in vitro and also in vivo in transgenic BALB/c mice expressing human FcεRIα. Moreover, the anti-CD38 IgE induces ADCC and ADCP mediated by monocytes/macrophages against human MM cells (MM.1S). Importantly, the anti-CD38 IgE also prolongs survival in a preclinical disseminated xenograft mouse model using SCID-Beige mice and human MM.1S cells when administered with human peripheral blood mononuclear cells (PBMCs) as a source of monocyte effector cells. Our results suggest that anti-CD38 IgE may be effective in humans bearing MM and other malignancies expressing CD38.

Knowing Your Target: Altered Mental Status From an Unsuspected Source

Daratumumab is a human monoclonal antibody targeting CD38 that is used in the treatment of multiple myeloma. In addition to being a target for cancer-related treatment, CD38 also plays a significant role in the immune response to infection. CD38 deficiency can increase susceptibility to several bacterial infections. This article discusses the case of a 52-year-old female with a history of IgG multiple myeloma status post autologous stem cell transplant with relapse who was receiving therapy with daratumumab, lenalidomide, and dexamethasone. She presented to the emergency department with a history of 3 to 4 days of generalized weakness, poor appetite, nausea, vomiting, watery stools, and fevers. Her symptoms did not improve with initial fluid resuscitation and broad-spectrum antimicrobials; instead, she experienced progressive neurological decline. This case illustrates how utilizing targets for cancer-directed treatments can also affect immune function, which may leave patients susceptible to unique infections that may not otherwise be commonly encountered. Therefore, advanced practitioners must understand the functional role of these targets and the sequelae that could occur when expression is altered by pharmacological therapies to allow for expeditious recognition and management.

Platelet factor 4 (PF4) induces cluster of differentiation 40 (CD40) expression in human aortic endothelial cells (HAECs) through the SIRT1/NF-κB/p65 signaling pathway.

PF4 is a pro-atherosclerotic molecule. Endothelial CD40, upon binding to its ligand CD40L, induces endothelial cell (EC) activation, which is a vital pathophysiological process in the initiation and progression of atherosclerosis. However, the relationship between PF4 and endothelial CD40 remains elusive. This study aims to investigate whether and how PF4 affects endothelial CD40 expression using primary HAECs. PF4 treatment down-regulated sirtuin 1 (SIRT1) expression but upregulated the expression of acetylated NF-κB p65 (Ac-p65) and CD40 in HAECs in a concentration- and time-dependent manner. Pretreatment with SIRT1 agonist (SRT1720 or RSV) or SIRT1-overexpressing lentivirus attenuated PF4-induced Ac-p65 and CD40 expression in HAECs, whereas preincubation with SIRT1 antagonist (NAM or EX527) or SIRT1 shRNA had the opposite effect. To investigate whether NF-κB/p65 signaling pathway modulates CD40 expression in PF4-treated HAECs, PDTC, a NF-κB inhibitor, and p65-shRNA were introduced. PDTC or p65-shRNA treatment down-regulated Ac-p65 expression in HAECs. PDTC or p65-shRNA preincubation suppressed CD40 expression in HAECs after PF4 treatment. To better determine whether SIRT1 regulates CD40 expression in PF4-treated HAECs via the NF-κB/p65 signaling pathway, p65-knockdown HAECs were preincubated with SIRT1 agonists before PF4 treatment. SIRT1 agonist preincubation further decreased CD40 expression in p65-knockdown HAECs treated with PF4. Moreover, PF4 treatment promoted p65 nuclear translocation in HAECs. The results of dual luciferase assay demonstrated that four NF-κB binding sites in the promoter of human CD40 gene were activated in PF4-treated HAECs. In conclusion, our findings suggest that PF4 treatment facilitates CD40 expression in HAECs through the SIRT1/NF-κB/p65 pathway.

Chemerin triggers migration of a CD8 T cell subset with natural killer cell functions

The recruitment of cells with effector functions into the tumor microenvironment holds potential for delaying cancer progression. We show that subsets of human CD28-effector CD8 Tcells, CCR7- CD45RO+ effector memory, and CCR7- CD45RO- effector memory RA phenotypes, express the chemerin receptor CMKLR1 and bind chemerin via the receptor. CMKLR1-expressing human CD8 effector memory Tcells present gene, protein, and cytotoxic features of NK cells. Active chemerin promotes chemotaxis of CMKLR1-expressing CD8 effector memory cells and triggers activation of the α4β1 integrin. In an experimental prostate tumor mouse model, chemerin expression is downregulated in the tumor microenvironment, which is associated with few tumor-infiltrating CD8+ Tcells, while forced overexpression of chemerin by mouse prostate cancer cells leads to an accumulation of intra-tumor CD8+ Tcells. Furthermore, α4 integrin blockade abrogated the chemerin-dependent recruitment of CD8+ T effector memory cells into implanted prostate tumors invivo. The results identify a role for chemerin:CMKLR1 in defining a specialized NK-like CD8 Tcell, and suggest the use of chemerin-dependent modalities to target effector CMKLR1-expressing Tcells to the tumor microenvironment for immunotherapeutic purposes.

1628-P: Role of CD38 in the Regulation of Muscle Stem Cell Functions in Aged Mice

Skeletal muscle repair and regeneration is a complex process and is known to be delayed with aging, diabetes and obesity. This is in part due to infiltration of inflammatory macrophages which can delay the recovery process. Both macrophages and satellite cells require nicotinamide adenine dinucleotide (NAD+) for their biological functions. Aging-induced decline in NAD+ have been shown to worsen insulin resistance and muscle dysfunction. CD38 is an ectoenzyme that degrades NAD+ and is increased in inflammatory macrophages in aging, obesity and other insulin-resistant states. However, how inhibition of CD38 affects satellite cell functions in aged or obese mice, remains unknown. Here, we utilized aged CD38 knockout mice to assess the role of this protein and NAD+ in the recovery process in injured muscle. CD38 KO mice were found to be resistant to diet-induced obesity and had improved insulin sensitivity. Our data show that genetic deletion of CD38 in aged mice increased NAD+ levels and thus enhanced muscle stem/satellite cells differentiation and promote myogenesis. Deletion of CD38 also resulted in an enhanced number of regenerating myofibers. Furthermore, we found that deletion of CD38 significantly reduces fibrosis of muscle and also improved limb grip strength. Pharmacological inhibition of CD38 in C2C12 myoblasts and ex-vivo primary myoblasts significantly increased NAD+ levels and also enhanced the differentiation of satellite cells into myoblasts and myofibers. We, therefore, examined the rescue effects of 78c (CD38i) on human recombinant CD38 (hCD38) inhibition of muscle stem cells. Administration of hCD38 inhibited expression of MyoD and MyoG in primary myoblasts, while this effect was rescued through 78c treatment. Taken together, these data demonstrate that restoration of NAD+ levels either through genetic deletion/pharmacological inhibition of CD38 can improve muscle stem cell functions and muscle regeneration and might promote muscle regeneration in obesity, type 2 diabetes, and aging. Disclosure A.Nawaz: None. K.Yaku: None. I.Jeelani: None. K.Tobe: Other Relationship; MSD K.K., Novo Nordisk Pharma Ltd., Takeda Pharmaceutical Company Limited, Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Suntory Global Corporation, Ltd.,, Taiho Pharmaceutical Co. Ltd., Japan Diabetes Foundation, Japan Association for Diabetes Education and Care. T.Nakagawa: None.

A phase 1b, open-label, two-part safety, tolerability, and efficacy study of a soluble beta-glucan (odetiglucan) in combination with a CD40 agonistic monoclonal antibody (CDX-1140) in patients with metastatic pancreatic adenocarcinoma whose disease did not progress during first-line (1L) chemotherapy.

TPS4201 Background: Metastatic pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal disease with a 5-year overall survival (OS) rate of 3%. Standard of care treatment is continuous cytotoxic chemotherapy which produces modest improvements in OS but is also associated with significant toxicity raising the need for novel treatment paradigms. Although immunotherapy has yet to produce clinical benefit for most patients with PDAC, preclinical modeling demonstrates its potential and show that combinations of myeloid agonists can trigger robust synergistic anti-tumor activity against PDAC tumors that are otherwise resistant to immunotherapy including immune checkpoint blockade (anti-CTLA4, anti-PD1). In this study, odetiglucan (OD), a novel beta glucan pathogen associated molecular pattern (PAMP), will be combined for the first time with CDX-1140, a fully human Ig2K agonistic monoclonal CD40 antibody in the maintenance setting after an induction phase of cytotoxic chemotherapy. OD and a CD40 agonist directly promote the activation and maturation of antigen presenting cells and shift the suppressive TME to enhance T-cell responses through non-redundant myeloid signaling pathways. We hypothesize that the combination of OD and CD40 agonist therapy has the potential to trigger anti-tumor immunity in PDAC and thus, extend and deepen responses to 1L cytotoxic chemotherapy. Methods: A two-part Phase 1b study of metastatic PDAC pts who have evidence of response or stable disease following 16-24 wks of chemotherapy is being conducted. Part A uses a 3+3 design; pts will receive OD 4 mg/kg QW + CDX-1140 1.5 mg/kg Q3W. Following a dose-limiting toxicity observation period, the dose will be held at 1.5 mg/kg or decreased to 0.72 mg/kg Q3W. Once preliminary safety is established, the cohort will be expanded to 15 pts. Part B pts will receive OD 4mg/kg + CDX-1140 at the dose identified in Part A Q3W. The study will enroll 30 pts. Main eligibility criteria: Metastatic PDAC having durable stable disease or response to 1L chemotherapy; serum ABA ≥20 µg/mL, and no prior anti-CD40 mAb or immunomodulatory treatment exposure. Primary endpoints are MTD, RP2D, and safety. Secondary endpoints include DOR, PFS, ORR, and OS and exploratory endpoints include evaluating immune pharmacodynamic responses in peripheral blood and tumor. Safety parameters will be listed and summarized using descriptive statistics. ORR will be tabulated by overall frequency; DOR, TTF, PFS and OS will be summarized and presented using Kaplan-Meier and waterfall plots. 5 US sites will participate. Clinical trial information: NCT04834778 .

Efficacy and safety of mitazalimab in combination with mFOLFIRINOX in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): An interim analysis of the optimize-1 phase 1b/2 study.

4139 Background: Mitazalimab is a human CD40 agonistic IgG1antibody. Targeting CD40 kickstarts the cancer immunity cycle by licensing dendritic cells leading to tumor specific T cell priming and activation. Furthermore, in PDAC CD40 agonists on myeloid cells promote degradation of the desmoplastic tumor stroma, improving influx of T cells and chemotherapeutic agents into the tumor. OPTIMIZE-1 (NCT04888312) is a Phase 1b/2, open label, multicenter study designed to evaluate safety, tolerability, and efficacy of mitazalimab in combination with mFOLFIRINOX (Oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 150 mg/m2, 5-FU 2.4 g/m2) in patients (pts) with previously untreated mPDAC. In the first part of the study (phase 1b), 900 µg/kg mitazalimab was selected as the recommended phase 2 dose (RP2D). Methods: In the first 21 day treatment cycle, mitazalimab was administered IV at RP2D on day 1 and 10 and mFOLFIRINOX infusion started on day 8. In subsequent cycles, treatment followed a 14 day cycle where mitazalimab was always administered 2 days after mFOLFIRINOX. The primary endpoint of this ongoing study is overall response rate (ORR) per RECIST v1.1. Secondary and exploratory endpoints include progression free and overall survival, safety, PK and PD biomarker assessments. Futility was prespecified as ORR≤30% in pts treated at RP2D, based on historical data with FOLFIRINOX (Conroy, 2011). Results: As of December 8, 2022, 43 pts with untreated mPDAC were treated with mFOLFIRINOX and 450 µg/kg (N = 5) or 900 µg/kg (N = 38) mitazalimab and evaluated for safety. The most common grade (Gr) ≥3 TEAEs were neutropenia (16%), fatigue (12%) and hypokalemia (12%). Mitazalimab related Gr >3 AEs were fatigue in 3 (7.9%) pts, hypokalemia in 2 (5.3%) pts, diarrhea in 1 (2.6%) pt, pneumonia in 1 (2.6%) pt, increased ALT in 1 (2.6%) pt, headache in 1 (2.6%) pt, acute kidney injury in 1 (2.6%) pt. 10 pts (23%) experienced infusion reactions (all Gr 1-2) and 5 (12%) pts discontinued treatment due to TEAEs (pneumonia, gastric obstruction, neuropathy, bacteremia). At cutoff, 23 pts were evaluable for futility. Median follow up was 170 days and median exposure was 163 days. 18 pts (78%) remain on treatment, 6 (26%) beyond the 6 month treatment period. ORR was 52.2% (12 partial responses), an additional 8 pts achieved stable disease, resulting in a 91.3% disease control rate. Combination with mFOLFIRINOX had no impact on mitazalimab PK. The PD biomarker profile was consistent with the mode of action of mitazalimab, including upregulation of MCP-1 and IFN-γ. Conclusions: Mitazalimab + mFOLFIRINOX is a feasible regimen with a manageable safety profile. Mitazalimab administered at 900 µg/kg in combination with mFOLFIRINOX shows encouraging antitumor activity in mPDAC, meriting continued development. The study passes futility and continues to full accrual. Clinical trial information: NCT04888312 .

Abstract CT129: Trial in progress: ATHENA-1 - a phase 1, open-label, first-in-human study to assess safety and tolerability of REGN5837 in combination with odronextamab in patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphomas

Abstract Background: Many patients with relapsed/refractory (R/R) aggressive B-cell non-Hodgkin lymphoma (B-NHL) are unable to tolerate, access, or benefit from intensive chemo-therapeutic approaches or cellular therapies and will invariably relapse; therefore, novel approaches are urgently required. Odronextamab (REGN1979) is a hinge-stabilized, human CD20 × CD3 IgG4-based bispecific antibody that elicits T-cell-mediated cytotoxicity of malignant B cells. In a Phase 1 study, odronextamab monotherapy showed a manageable safety profile with encouraging preliminary activity in heavily pre-treated patients with R/R B-NHL (Bannerji R, et al. Lancet Haematol. 2022;9(5):e327-39). REGN5837 is a hinge-stabilized, human CD28 × CD22 IgG4-based bispecific antibody that provides a co-stimulatory signal (signal 2). When combined with odronextamab (signal 1), REGN5837 improved anti-tumor efficacy and survival in in vivo diffuse large B-cell lymphoma tumor models via enhanced T-cell expansion. We hypothesize that combining REGN5837 with odronextamab may deepen and extend anti-tumor activity in patients with aggressive lymphoma. Methods: ATHENA-1 (NCT05685173) is a Phase 1, open-label, first-in-human study of REGN5837 in combination with odronextamab in patients with R/R aggressive B-NHL. During induction, odronextamab and REGN5837 will be administered weekly over 21-day cycles. To mitigate potential CRS events, odronextamab will be introduced with step-up dosing as a monotherapy, followed by introduction of REGN5837 on C2 D15 with step-up dosing. Maintenance will consist of 28-day cycles (odronextamab and REGN5837 administration on D1, 15). Patients who achieve a sustained complete response (≥9 months) will have study drug(s) administration changed to once every 4 weeks. Patients must be aged ≥18 years, have Eastern Cooperative Oncology Group performance status ≤1, with adequate organ function, and have CD20+ aggressive B-NHL that progressed after ≥2 lines of systemic therapy containing at least an anti-CD20 antibody and an alkylating agent, with or without prior chimeric antigen receptor T-cell therapy. Exclusion criteria include prior allogeneic stem cell transplant, organ transplant, or CD20xCD3 bispecific antibodies, or mantle cell lymphoma or central nervous system lymphoma. Primary endpoints are incidence of dose-limiting toxicities and the incidence and severity of treatment-emergent adverse events. Secondary endpoints include pharmacokinetics of odronextamab and REGN5837, anti-drug antibody incidence, objective response rate, complete response rate, duration of response, progression-free survival, and overall survival. Enrolment is planned to open in early 2023. Citation Format: John Baird, Pim G. Mutsaers, Jeremy S. Abramson, Manjusha Namuduri, Jingjin Li, Nickolas A. Sophos, Min Zhu, Jurriaan Brouwer-Visser, Hesham Mohamed, Aafia Chaudhry, Andrew J. Davies. Trial in progress: ATHENA-1 - a phase 1, open-label, first-in-human study to assess safety and tolerability of REGN5837 in combination with odronextamab in patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT129.

CD74: a prospective marker for reactive microglia?

CD74: a prospective marker for reactive microglia?

Pharmacodynamic-Mediated Drug Disposition (PDMDD) Model of Daratumumab Monotherapy in Patients with Multiple Myeloma.

We aimed to quantify the daratumumabconcentration- and CD38 dynamics-dependent pharmacokinetics using a pharmacodynamic mediated disposition model (PDMDD) in patients with multiple myeloma (MMY) following daratumumab IV or SC monotherapy. Daratumumab, a human IgG monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action, has been approved to treat patients with multiple myeloma (MM). In total, 7788 daratumumab plasma samples from 850 patients with diagnosis of MMY were used. The serum concentration-time data of daratumumab were analysed using nonlinear mixed-effects modeling with NONMEM®. The PDMDD with quasi steady-state approximation (QSS) was compared to the previously developed Michaelis-Menten (MM) approximation with respect to the parameter estimates, the goodness-of-fit plots and prediction-corrected visual predictive check, as well as model-based simulations. The effect of patients' covariates on daratumumab pharmacokinetics was also investigated. The QSS approximation characterized the concentration- and CD38 dynamics-dependency of daratumumab pharmacokinetics within the doses ranging from 0.1 to 24 mg/kg after IV administration and 1200 and 1800 mg after SC administration in patients with MMY, mechanistically describing the binding of daratumumab and CD38, the internalization of the daratumumab-CD38 complex and the CD38 turnover. Compared to the previously developed MM approximation, the MM approximation with the non-constant total target and dose-correction provided substantial improvement of the model fit, but it was still not as good as the QSS approximation. The effect of the previously identified covariates as well as the newly identified covariate (baseline M protein) on daratumumab pharmacokinetics was confirmed, but the magnitude of the effect was deemed not clinically relevant. Accounting for the CD38 turnoverand its binding capacity to daratumumab, the QSS approximation provided a mechanistic interpretation of daratumumab PK parameters and consequently well described the concentration- and CD38 dynamics-dependency of daratumumab pharmacokinetics. CLINICAL STUDIES INCLUDED IN THE ANALYSIS WERE REGISTERED WITH THE NCT NUMBER BELOW AT HTTP://WWW. GOV : MMY1002 (ClinicalTrials.gov: NCT02116569), MMY1003 (NCT02852837), MMY1004 (NCT02519452), MMY1008 (NCT03242889), GEN501 (NCT00574288), MMY2002 (NCT01985126), MMY3012 (NCT03277105).

Abstract 1880: A novel CD137 agonist exhibits potent antitumor efficacy with a good safety profile

Abstract Background: CD137 (TNFRSF9, 4-1BB) is a member of the tumor necrosis factor receptor superfamily that functions as a costimulatory molecule of immunocytes and is mainly expressed on the surface of immune cells including activated T and natural killer (NK) cells. Agonists against CD137 have shown promising therapeutic activity in mouse tumor models but have suffered setback in the clinic due to notably hepatotoxicity, or suboptimal agonistic potency. Here, we developed a fully human agonistic anti-CD137 monoclonal IgG4 antibody, ZG033, with an exclusive epitope, to achieve a better efficacy and safety profile for immunotherapy. Methods: The antigen binding specificity and affinity of ZG033 were determined by ELISA, surface plasmon resonance (SPR). X-ray crystallography was conducted to resolve the binding epitopes of the respective binding arms. The activities were determined using cell-based and reporter gene assays. In vivo antitumor activities were evaluated in human 4-1BB transgenic mice bearing with syngeneic tumors, and possible toxicity was evaluated in humanized mice and cynomolgus monkeys. Cytokine release assay was conducted by incubating ZG033 with PBMCs from healthy donors. The pharmacokinetic (PK) behavior of ZG033 were characterized in cynomolgus monkeys. A phase 1 study was initiated to evaluate the safety and preliminary clinical activities of ZG033, as well as the immunogenicity and pharmacokinetics. Results: ZG033 showed high specificity for human CD137 without cross-species reactivity across mouse, rat and exhibited potent CD137 agonist activity dependent on FcγR crosslinking. The binding affinity of ZG033 determined by surface plasmon resonance (SPR) was moderate (KD=10 nM). X-ray crystallography revealed that the Fab of ZG033 binds CD137 at an epitope overlap with the ligand binding interface. ZG033 increased CD137-driven NFκB reporter gene activation and the production of IFN-γ by human T cells in a FcγR-dependent manner. In human CD137 transgenic mice, ZG033 showed robust antitumor activity and induced durable antigen-specific immunological memory that prevented the tumor formation in the rechallenged mice. There were no signs of toxicity in human cytokine release assay which confirmed that ZG033 did not induce pro-inflammatory cytokines in the absence of TCR stimulation. Toxicology data in mice showed that ZG033 was well-tolerated with normal ALT and AST levels. ZG033 was further confirmed to well tolerated up to 180 mg/kg (MTD≥180mg/kg) dose without systemic toxicity in cynomolgus monkeys. Patients with advanced tumors, who are refractory after exhausting available therapies, were enrolled for ZG033 treatment. We will report the results from early dose escalation part of the study. Conclusion: These data demonstrate that ZG033 is an FcγR crosslinking-dependent CD137 agonist that displays a favorable safety profile and has potential in either mono- or combinational immunotherapies. Citation Format: Yang Huang, Liangwei Li, Wenting Liu, Dayan Zhang, Pengfei Zhou, Qing Fang, Weiming Zhou, Fengrong Wang, Guodong Shen, Liansheng Cheng. A novel CD137 agonist exhibits potent antitumor efficacy with a good safety profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1880.

Abstract 6332: A humanized anti-cd40 antibody with anti-tumor pharmacological activity and cynomolgus monkey safety

Abstract LNF1901 is a humanized CD40 agonistic antibody. LNF1901 can bind to CD40 protein of human(EC50=23.6ng/mL) and monkey(EC50=23.5ng/mL), but cannot bind to CD40 protein of rat and mouse. LNF1901 had strong activation effect on DC cells(EC50=0.04ug/mL) and had strong ADCC and CDC effects. AT a dose of 20mg/kg, the TGITW of LNF1901 was 59.9% in Female NPG mice were inoculated with Raji/CIK/DC subcutaneous transplanted tumor model. Following intravenous infusion of LNF1901 at doses of 6, 30, or 150 mg/kg to cynomolgus monkeys weekly for 4 weeks, the highest non-severely toxic dose (HNSTD) was considered to be 150 mg/kg.LNF1901 had demonstrated manageable safety and promising antitumor activity in vivo and in vitro tests. Citation Format: Zhenyu Li, Lili Zhao, Guimin Zhang, Bin Li, Zhong Liu, Guangyan Li, Zhongsong Zhu. A humanized anti-cd40 antibody with anti-tumor pharmacological activity and cynomolgus monkey safety [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6332.

Abstract 696: Sensitizing breast cancers to immune checkpoint inhibitors through CD27 agonism and vaccination against tumor-associated antigen

Abstract Project objective: Despite the recent revolution in immune checkpoint inhibitors (ICIs), only modest improvement in overall survival and likely caused by not enough potent cellular immunity among BC patients. Our lab has been focus on inducing cellular immunity against HER2+ BC through vaccination against the tumor-associated antigen HER2. Approximately 20 years ago, we performed an experimental pilot study by administrating HER2 peptide and recombinant protein pulsed dendritic cells (DC vaccine) to six patients with refractory HER2+ advanced or metastatic (stage II (≥ 6 +LN), III, or stage IV) BC. We followed the patients on 2019 found that all of the six patients were still alive, 18 years after vaccination. Their blood sample were analyzed with cytometry by time-of-flight (CyTOF) and found there is a significantly increased presence of CD27 expressing memory T cells in response to HER2 peptide stimulation. Recent report on the SARS-CoV2 mRNA vaccine also suggested that CD27 expressing memory T cells plays a critical role in long-lasting cellular immunity against SARS-CoV2 infection. Therefore, we hypothesized that CD27 plays a critical role in cellular immunity against BC, and the stimulation of CD27 expressing T cells with mAb targeting CD27 significantly increase the cellular immunity triggered by vaccination against tumor-associated antigen. Results: We recapitulate the rise of CD27+ antigen specific T cells among the vaccinated patients using a transgenic mouse model expressing human CD27. When combined the adenoviral-vector based HER2 (Ad-HER2) vaccination with a single dose of human aCD27 antibody (Varlilumab), we found there is a robust increase in the HER2 specific T cells compared to vaccination alone, especially CD27+CD44+ memory CD4 T cells, even after 120 days post vaccination. Using an ICI-insensitive syngeneic HER2+ BC models, we found 50% of mice in the combination group of aCD27 antibody plus Ad-HER2 showed total tumor regression by the end of study. When combined with anti-PD1 antibody, the combination of AdHER2 and Varlilumab leads to total tumor regression in 90% of tumor bearing mice with syngeneic HER2+ BC, indicating that the vaccination against tumor associated antigen HER2 plus anti-CD27 antibody sensitized ICI-insensitive HER2+ BC toward ICI. Conclusions: Our data demonstrates that the administration of anti-CD27 antibody significantly increase the long term presence of CD27+ antigen specific memory T cells after vaccination against tumor associated antigen HER2. As consequence, combination of anti-CD27 with HER2 sensitized the immune unresponsive breast cancer toward anti-PD1 antibody. Our study suggests that the vaccination against tumor-associated antigen with mAb targeting CD27 leads to the robust cellular immunity, which is required for successful ICIs against breast cancer. Citation Format: Bin-Jin Hwang, Erika Crosby, Timothy Trotter, Li-Chung Tsao, Tao Wang, Xiao Yang, Herbert Kim Lyerly, Zachary Hartman. Sensitizing breast cancers to immune checkpoint inhibitors through CD27 agonism and vaccination against tumor-associated antigen [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 696.

Dynamic changes of the proportion of HLA-DR and CD38 coexpression subsets on T lymphocytes during IFN-based chronic hepatitis B treatment.

To investigate the changes of human leukocyte antigen DR (HLA-DR) and CD38 coexpression subsets on T lymphocytes following interferon (IFN) therapy for those who have chronic hepatitis B (CHB). A prospective cohort of CHB patients participated in this study. CHB patients without IFN treatment (including naïve and nucleoside [nucleotide] analogs [NAs]-treated patients) were given pegylated interferon alfa (Peg-IFNα) treatment. Peripheral blood samples were taken at baseline, 4 weeks and 12-24 weeks of Peg-IFNα treatment. For the patients who entered the Peg-IFNα plateau phase due to the stagnation of the decrease in HBsAg, and Peg-IFNα was discontinued and Peg-IFNα therapy was resumed after an interval of 12-24 weeks. During the interval, they received first-line NAs treatment. Peripheral blood samples were collected at the baseline of the plateau phase, 12-24 weeks of intermittent treatment, and 12-24 weeks of Peg-IFNα retreatment. The peripheral blood samples were taken to determine virological, serological and biochemical indices of hepatitis B virus (HBV), and T lymphocyte related phenotypes were detected using flow cytometry. In the process of long-term treatment of Peg-IFNα, the percentage of HLA-DR+CD38dim subsets increased significantly at first, then decreased gradually, while the percentage of HLA-DR+CD38hi subsets markedly increased. During long-term Peg-IFNα treatment, there was a considerable negative correlation between HBsAg and the HLA-DR+CD38hi subset percentage. The persistent high proportion of HLA-DR+CD38hi subsets was related to the occurrence of Peg-IFNα plateau phase. After Peg-IFNα intermittent treatment, the percentage of HLA-DR+CD38hi subsets decreased significantly. After Peg-IFNα retreatment, the level of HBsAg began to decrease again. At the same time, the percentage of HLA-DR+CD38hi subsets significantly increased, but it was still lower than that at the baseline level. The spectrum of HLA-DR and CD38 coexpression subsets on T lymphocytes changed during the long-term treatment of IFN. The establishment of the IFN plateau phase was linked to the persistence of a considerable proportion of HLA-DR+CD38hi subsets on T lymphocytes. IFN intermittent treatment could significantly reduce the proportion of HLA-DR+CD38hi subsets, helping regain the antiviral efficacy of IFN during IFN retreatment.