scholarly journals 317 A phase 1/1b study of SBT6050, a HER2-directed monoclonal antibody conjugated to a toll-like receptor 8 agonist, in subjects with advanced HER2-expressing solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A343-A343
Author(s):  
Leisha Emens ◽  
Muralidhar Beeram ◽  
Erika Hamilton ◽  
Sarina Piha-Paul ◽  
Valerie Odegard ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Antitumor Activity ◽  
Nk Cells ◽  
Solid Tumors ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Myeloid Cells ◽  
Preclinical Studies ◽  
Her2 Expression ◽  
Toll Like Receptor

BackgroundNew strategies are needed to improve outcomes in human epidermal growth factor receptor 2 (HER2)-expressing cancers. SBT6050 is a novel therapeutic comprising a specific small molecule toll-like receptor (TLR) 8 agonist conjugated to a HER2-directed monoclonal antibody. TLR8 is highly expressed in myeloid cells that are prevalent in human tumors, including dendritic cells (DCs) and macrophages, and modulates their pro-inflammatory activity. SBT6050 is designed to activate human myeloid cells only in the presence of moderate-to-high HER2 expression (immunohistochemistry [IHC] 2+ or 3+) and binds to the same epitope as pertuzumab. In preclinical studies, SBT6050 potently induces a broad spectrum of antitumor immune mechanisms, including proinflammatory cytokine and chemokine production, inflammasome activation, and indirect activation of T and natural killer (NK) cells. TLR8 agonism has emerged as a promising approach to overcome resistance to immune checkpoint inhibitors in tumors lacking T-cell infiltrates, as these cancers are often replete with myeloid cells. Using an SBT6050 mouse surrogate in vivo, curative single-agent efficacy was observed in multiple murine tumor models, including a model deficient in T, B, and NK cells. In preclinical toxicology studies in nonhuman primates, SBT6050 was well tolerated, supporting a first-in-human starting dose that is predicted to be pharmacologically active, with a short escalation to projected clinically active doses. Preclinical studies also support combinations with checkpoint inhibitors and with trastuzumab to further enhance antitumor activity.MethodsSBT6050-101 is an ongoing phase 1/1b, first-in-human, open-label, multicenter study. Eligible subjects are adults with histologically confirmed, HER2-expressing (IHC 2+ or 3+), locally advanced (unresectable) and/or metastatic cancer. Subjects must have measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and have previously received all therapies known to confer clinical benefit. SBT6050 is given subcutaneously every 2 weeks and treatment may continue for up to 2 years or until disease progression, unacceptable toxicity, or other reason for discontinuation. The trial objectives are to evaluate the safety and tolerability of SBT6050 and to identify the maximum tolerated dose and recommended phase 2 dose (RP2D). The study has 2 parts: Part 1, consisting of a dose escalation using a standard 3+3 design, and Part 2, consisting of 5 parallel expansion cohorts based on tumor type and HER2 expression level and treated with SBT6050 at the RP2D. Pharmacokinetics, immunogenicity, and antitumor activity will be evaluated and pharmacodynamic markers of myeloid cell activation will be assessed in peripheral blood and on-treatment tumor biopsies.ResultsN/AConclusionsN/ATrial RegistrationNCT04460456Ethics ApprovalThe study was approved by MD Anderson Cancer Center Institutional Review Board, approval number 2020-0326 MOD001.

394 Interleukin-8–neutralizing monoclonal antibody BMS-986253 plus nivolumab (NIVO) in biomarker-enriched, primarily anti–PD-(L)1–experienced patients with advanced cancer: initial phase 1 results

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A419-A419
Author(s):  
Diwakar Davar ◽  
Matteo Simonelli ◽  
Martin Gutierrez ◽  
Emiliano Calvo ◽  
Jason Melear ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Antitumor Activity ◽  
Solid Tumors ◽  
Clinical Benefit ◽  
Phase 1 ◽  
Elevated Serum ◽  
Interleukin 8 ◽  
List Type ◽  
Multiple Tumor ◽  
Grade 3

BackgroundInterleukin 8 (IL-8) is a C-X-C chemokine that exerts protumorigenic effects in the tumor microenvironment, including recruiting immunosuppressive PMN-MDSCs and promoting angiogenesis.1–3 Elevated serum IL-8 (sIL-8) is a negative prognostic indicator in patients with solid tumors and may have predictive value in patients treated with immunotherapies.2 4 5 BMS-986253, a fully human-sequence IgG1κ anti–IL-8 monoclonal antibody, binds IL-8 and prevents signaling through CXCR1/CXCR2 and has been shown to be safe in patients with advanced cancers.3 We present initial results of BMS-986253 + NIVO from a phase 1/2a trial in patients with advanced cancers who had detectable sIL-8 levels, the majority of whom had progressed on/after prior anti–PD-(L)1 (NCT03400332).MethodsDuring safety evaluation/dose exploration, patients with advanced metastatic solid tumors (melanoma, NSCLC, SCCHN, RCC, or UCC) and detectable sIL-8 (>10 pg/mL at screening) received BMS-986253 600 (n=16), 1200 (n=15), or 2400 mg (n=18) Q4W, or 1200 (n=12) or 2400 mg (n=59) Q2W, + NIVO 480 mg intravenously Q4W. Safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity were evaluated (investigator-assessed, RECIST v1.1).ResultsAs of March 20, 2020, 120 patients (median age, 63 years [range, 35–87 years]) received BMS-986253 + NIVO; 97% of patients received prior anti–PD-(L)1 therapy, and 25% received prior anti–CTLA-4 therapy. BMS-986253 + NIVO was well tolerated with no dose-limiting toxicities observed. Most TRAEs were grade 1–2. The most common (≥5% of patients) TRAEs (any grade; grade 3–4) were fatigue (9%; 1%), nausea (7%; 0%), rash/rash maculopapular (6%; 0%), pruritus (5%; 0%), and decreased appetite (5%; 0%). Grade 3–4 serious TRAEs were reported in 2 patients (infusion-related reaction, BMS-986253 2400 mg Q2W + NIVO; AST/ALT increased, BMS-986253 1200 mg Q4W + NIVO). BMS-986253 exposure increased dose proportionally and was not altered with NIVO. BMS-986253 resulted in dose-dependent reductions in free sIL-8 levels, with tumor IL-8 suppression detected in most patients evaluated; additional pharmacodynamic endpoints will be presented. Partial responses were observed in multiple tumor types, including 5 of 28 patients with melanoma who had progressed on/after prior anti–PD-(L)1; 4 of the 5 patients were also previously treated with anti–CTLA-4.ConclusionsBMS-986253 + NIVO demonstrated a tolerable safety profile with dose-proportional pharmacokinetics and robust sIL-8 suppression. Preliminary antitumor activity was observed across a range of doses/regimens in this biomarker-enriched, anti–PD-(L)1–experienced, heterogeneous patient population with advanced cancers. These findings support further evaluation of BMS-986253 in select advanced tumors.AcknowledgementsThe authors acknowledge Dr Charles Drake while at Columbia University Medical Center, New York, NY, USA, for his contributions to the study.Trial RegistrationNCT03400332Ethics ApprovalThis study was approved by the WCG Independent Review Board, approval number 20172711.ReferencesDavid JM, Dominguez C, Hamilton DH, et al. The IL-8/IL-8R axis: a double agent in tumor immune resistance. Vaccines (Basel) 2016;4:22.Schalper KA, Carleton M, Zhou M, et al. Elevated serum interleukin-8 is associated with enhanced intratumor neutrophils and reduced clinical benefit of immune-checkpoint inhibitors. Nat Med. 2020;26:688–692.Bilusic M, Heery CR, Collin JM, et al. Phase I trial of HuMax-IL-8 (BMS-986253), an anti–IL-8 monoclonal antibody, in patients with metastatic or unresectable solid tumors. J Immunother Cancer 2019;7:240.Yuen KC, Liu L-F, Gupta V, et al. High systemic and tumor-associated IL-8 correlates with reduced clinical benefit of PD-L1 blockade. Nat Med 2020;26:683–698.Sanmamed MF, Perez-Gracia JL, Schalper KA, et al. Changes in serum interleukin-8 (IL-8) levels reflect and predict response to anti–PD-1 treatment in melanoma and non-small-cell lung cancer patients. Ann Oncol 2017;28:1988–1995.

A phase I study evaluating COM701 in patients with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS2657-TPS2657
Author(s):  
Drew W. Rasco ◽  
Daniel A. Vaena ◽  
Ryan J. Sullivan ◽  
Jason J. Luke ◽  
Adam ElNaggar ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Locally Advanced ◽  
Maximum Tolerated Dose ◽  
Tumor Growth Inhibition ◽  
Mouse Tumor ◽  
Advanced Solid Tumors ◽  
Open Label

TPS2657 Background: There is a high unmet medical need for the treatment (tx) of patients (pt) who are refractory to or relapse following tx with checkpoint inhibitors. Newer checkpoint therapies with novel mechanisms of action that can activate T cells and demonstrate antitumor activity in this pre-tx pt population are urgently needed. COM701 is a novel first-in-class humanized IgG4 monoclonal antibody that binds with high affinity to PVRIG (poliovirus receptor related immunoglobulin domain containing) blocking its interaction with its ligand, PVRL2. Both PVRIG and PVRL2 are part of the DNAM axis as are TIGIT and PD1. Inhibition of PVRIG leads to enhanced activation of T and NK cells, and PVRIG results in tumor growth inhibition in mouse tumor models. We hypothesize that COM701 will demonstrate antitumor activity in pts who are checkpoint inhibitor pre-tx. Methods: NCT03667716 is an ongoing open-label first-in-human phase 1 study in pts with advanced solid tumors. The initial part of this study (Arm A) will evaluate escalating doses of COM701 monotherapy IV Q3 weekly with single pt cohorts for the initial 4 and then 3+3 design. Key Inclusion Criteria: Age ≥18 yrs, histologically confirmed locally advanced/ metastatic solid malignancy and has exhausted available standard therapy, ECOG 0-1, prior anti-PD-1, anti-PD-L1, anti-CTLA-4, OX-40, CD137 permissible. Key Exclusion Criteria: Active autoimmune disease requiring systemic therapy in the last 2 years, symptomatic interstitial or inflammatory lung disease, untx or symptomatic central nervous system metastases. Primary objectives are safety and tolerability of COM701 as measured by the incidence of adverse events (AEs) and dose-limiting toxicities (21-day DLT window), pharmacokinetics of COM701, and to identify the maximum tolerated dose and/or the recommended dose for expansion. Secondary objectives are to characterize the immunogenicity and preliminary antitumor activity of COM701. Statistical Considerations: AEs graded as per CTCAE v4.03, responses as per RECIST v1.1. The analyses of all study objectives will be descriptive and hypothesis generating. No DLTs have been observed in the single pt cohorts. Assessment of pts enrolled into cohort 5 is ongoing at the time of this submission. Clinical trial information: NCT03667716.

scholarly journals 384 A Phase 1 study to evaluate the safety, PK, and antitumor activity of AK117, an anti-CD47 monoclonal antibody, in subjects with relapsed/refractory advanced or metastatic solid tumors or lymphomas

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A409-A409
Author(s):  
Amy Prawira ◽  
Jermaine Coward ◽  
Anna Mislang ◽  
Adnan Nagrial ◽  
Hui Gan ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Antitumor Activity ◽  
Solid Tumors ◽  
Tumor Cells ◽  
Dose Escalation ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Tumor Type ◽  
Human Rbcs

BackgroundAK117 is a novel humanized IgG4 monoclonal antibody (mAb) targeting CD47, a macrophage immune checkpoint and ‘don’t eat me’ signal that allows tumor cells to evade immune destruction by phagocytic cells. Most human cancers express CD47 to varying degrees, making CD47 a universal target. The efficacy of anti-CD47 therapy has been studied, as monotherapy and in combination with other antineoplastic agents, in various malignancies, including acute myeloid leukemia, diffuse large B-cell lymphoma, multiple myeloma, colorectal cancer, hepatocellular carcinoma and breast cancer. Anemia is common with anti-CD47 therapy because CD47 is ubiquitously expressed on senescent red blood cells (RBCs). However, in comparison to other anti-CD7 mAbs, AK117 exhibits significantly weaker binding to human RBCs than tumor cells. In both in vitro and in vivo nonclinical studies, AK117 demonstrated robust anti-tumor activity without causing significant agglutination of human RBCs in vitro or anemia in monkeys.MethodsThis is a first-in-human, Phase 1, multicenter, open label, single arm, dose escalation and dose expansion study of AK117 administered intravenously to adult subjects with relapsed/refractory advanced or metastatic solid tumors or lymphomas. The primary objective is to assess the safety and tolerability of AK117 monotherapy; and determine the maximum tolerated dose (MTD). Antitumor activity, PK, pharmacodynamic profile and immunogenicity of AK117 will be studied as secondary objectives.The dose escalation parts of the study uses a 3+3+3 design to determine the Recommended Phase 2 Dose (RP2D) dose between 0.3 mg/kg to 45 mg/kg QW. Dose escalation is performed exclusively in solid tumors; and any dose escalation cohort not exceeding the MTD may be expanded up to a maximum of approximately 18 subjects, with a minimum of 6 subjects with lymphomas, to provide additional clinical data to inform the optimal dose level and treatment schedule for tumor type-specific dose expansion and subsequent clinical studies. In the dose expansion phase, AK117 will be studied in cohorts of 30 subjects each with selected solid tumors and selected lymphomas.Subjects with active or prior autoimmune disease that may relapse, history of hemolytic anemia of any cause within 3 months of first dose, hemophagocytic lymphohistiocytosis, defects in RBC production; or defects in hemoglobin production or metabolism will not be eligible for this study.ResultsN/AConclusionsN/ATrial RegistrationNCT04349969Ethics ApprovalThe study was approved by Bellberry Human Research Ethics Committee (Application No. 2020-02-016).

AdvanTIG-105: Phase 1 dose-escalation study of anti-TIGIT monoclonal antibody ociperlimab (BGB-A1217) in combination with tislelizumab in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2583-2583
Author(s):  
Sophia Frentzas ◽  
Tarek Meniawy ◽  
Steven Chuan-Hao Kao ◽  
Ruihua Wang ◽  
Yunxia Zuo ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Antitumor Activity ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Stable Disease ◽  
Group Performance ◽  
Phase 1 ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Study Objective

2583 Background: Anti-programmed death 1 (PD-1) therapy has improved clinical outcomes for patients (pts) with advanced solid tumors but unmet needs remain. T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains (TIGIT) is a co-inhibitory, immune checkpoint receptor. Ociperlimab (OCI; BGB-A1217) is a novel, humanized, monoclonal antibody that binds to TIGIT with high affinity and specificity. OCI has demonstrated competent binding with C1q and all Fcγ receptors and induces antibody-dependent cellular cytotoxicity. Preclinical studies demonstrated dual targeting with OCI and tislelizumab (TIS), an anti-PD-1 antibody, produces synergistic immune cell activation and enhanced antitumor activity. Methods: AdvanTIG-105 is a phase 1, open label, multicenter, dose-escalation study (NCT04047862) that assessed the safety and preliminary antitumor activity of OCI plus TIS in pts with advanced, metastatic, unresectable solid tumors, for which standard therapy was ineffective or unavailable. Eligible pts had an Eastern Cooperative Oncology Group performance score ≤1 and no prior therapy targeting TIGIT. Pts received OCI intravenously (IV) on Day 1 of Cycle 1 and TIS 200 mg IV on Day 8. Pts were monitored for dose-limiting toxicities (DLTs) until Day 28. If tolerated, OCI and TIS were administered sequentially on Day 29 and every 3 weeks (Q3W) thereafter. Pts received escalating doses of OCI (50-900 mg) plus TIS 200 mg. The study objective was determination of recommended phase 2 dose (RP2D) of OCI plus TIS. Study endpoints included assessment of adverse events (AEs), pharmacokinetics and antitumor activity. Data cut-off was October 12 2020. Results: 24 pts with various advanced solid tumors received OCI plus TIS. At baseline, pts had undergone a median of 2 prior treatment regimens; 9/24 (37.5%) pts had received prior immunotherapy. Median follow-up time was 17 weeks. No DLTs were observed. 20 pts had ≥1 treatment emergent AE (TEAE) and most TEAEs were grade ≤2; fatigue (6 pts) and diarrhea (4 pts) were most commonly reported. No pts had grade ≥4 TEAEs or TEAEs leading to death. There were 2 grade 3 immune related AEs (colitis and low cortisol). One pt on OCI 450 mg achieved partial response and 9 pts had stable disease. The longest duration of stable disease was 36 weeks (1 pt on OCI 150 mg). After administration, serum concentration of OCI decreased in a biphasic manner. Exposure to OCI increased proportionally with dose, and TIGIT receptor occupancy was sustained at ≥50 mg doses. Conclusions: OCI in combination with TIS was well tolerated across all doses in pts with advanced solid tumors. The RP2D was OCI 900 mg plus TIS 200 mg Q3W. Clinical trial information: NCT04047862.

Bgb-A425, an investigational anti-TIM-3 monoclonal antibody, in combination with tislelizumab, an anti-PD-1 monoclonal antibody, in patients with advanced solid tumors: A phase I/II trial in progress.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3146-TPS3146
Author(s):  
Jayesh Desai ◽  
Tarek Meniawy ◽  
Brandon Beagle ◽  
ZheZhen Li ◽  
Song Mu ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Immune Response ◽  
T Cell ◽  
Antitumor Activity ◽  
Combination Therapy ◽  
Solid Tumors ◽  
Phase 1 ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Tumor Types

TPS3146 Background: While immune surveillance plays a critical role in preventing tumor proliferation and metastasis, tumors develop resistance mechanisms to suppress and/or escape the immune system. T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) and programmed cell death protein-1 (PD-1) function as immune checkpoint receptors on tumor-infiltrating lymphocytes. Overlap in expression and function suggests TIM-3 and PD-1 cooperate to maximize effector T-cell exhaustion, leading to a decreased antitumor immune response. Although blockade of TIM-3 alone is unlikely to result in an efficacious antitumor immune response, combined TIM-3/PD-1 blockade may enhance the antitumor properties of anti-PD-1 therapies alone. BGB-A425 is an investigational IgG1-variant monoclonal antibody against TIM-3. Tislelizumab, an anti-PD-1 antibody, was engineered to minimize binding to FcɣR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. This phase 1/2 study will assess the safety/tolerability, pharmacokinetic (PK) profile, and antitumor activity of BGB-A425 in combination with tislelizumab in patients with advanced solid tumors. Methods: This is an open-label phase 1/2 study (NCT03744468) of BGB-A425 in combination with tislelizumab in patients with histologically/cytologically confirmed advanced, metastatic, unresectable solid tumors. Phase 1 will determine the recommended phase 2 dose (RP2D) for combination treatment; phase 2 will assess the antitumor effects of the combination in select tumor types. In phase 1, up to 42 patients will be enrolled into sequential cohorts of increasing doses of intravenous (IV) BGB-A425 in combination with tislelizumab 200 mg IV, based on a 3+3 study design. During Cycle 1, patients will receive BGB-A425 alone on Day 1 followed by tislelizumab alone on Day 8. If no dose-limiting toxicities are observed, patients will receive both BGB-A425 and tislelizumab sequentially on Day 29 and every 21 days thereafter. Once the RP2D is determined, the combination therapy will be evaluated in up to 120 patients with select tumor types in phase 2. Safety/tolerability profile and RP2D determination (phase 1) and objective response rate per RECIST v1.1 (phase 2) are primary objectives; secondary objectives include antitumor activity, PK profile, and immunogenicity of combination therapy. Clinical trial information: NCT03744468 .

287 Safety and antitumor activity of indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitor KHK2455 in combination with anti-CCR4 monoclonal antibody mogamulizumab in patients with advanced solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A313-A314
Author(s):  
Solmaz Sahebjam ◽  
Jameel Muzaffar ◽  
Timothy Yap ◽  
David Hong ◽  
Olivier Rixe ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Overall Survival ◽  
Antitumor Activity ◽  
Combination Therapy ◽  
Adverse Events ◽  
Solid Tumors ◽  
Ex Vivo ◽  
Advanced Solid Tumors ◽  
Grade 3 ◽  
Dose Dependent

BackgroundIDO-1 inhibitors have shown antitumor activity in combination with immunotherapeutic agents in multiple cancers. KHK2455 is a novel and selective oral IDO-1 inhibitor. KHK2455 inhibits IDO-1 apo-enzyme, with long-lasting and potent activity. Mogamulizumab is an anti-C-C chemokine receptor 4 (CCR4) monoclonal antibody that has shown synergy with KHK2455 in preclinical models. Mogamulizumab is approved in the US and EU for treatment of mycosis fungoides and Sézary syndrome.MethodsIn this first-in-human study, patients with advanced solid tumors received escalating oral doses of KHK2455 alone (0.3, 1, 3, 10, 30 and 100 mg once daily) for 4 weeks (Cycle 0), followed by combination with 1 mg/kg weekly of IV mogamulizumab for 4 weeks (Cycle 1), and then on Days 1 and 15 (from Cycle 2 onward) in a standard 3+3 Phase I design. Safety, tolerability, pharmacokinetics and IDO activity (kynurenine [Kyn] and tryptophan [Trp] levels and ex vivo Kyn production) were evaluated.ResultsThirty-six patients were enrolled across all cohorts. One patient with lower esophageal cancer in the 100 mg cohort exhibited dose-limiting toxicity (Grade 3 gastrointestinal necrosis). The most frequent (≥10%) treatment-emergent adverse events (TEAEs) are presented in table 1. Overall numbers of TEAEs, ≥Grade 3 TEAEs, and serious TEAEs related to KHK2455 and mogamulizumab are presented in table 2. Serious KHK2455-related TEAEs included gastrointestinal necrosis (KHK2455 monotherapy), and nausea and drug eruption (combination therapy). In addition, five drug-related TEAEs in combination therapy led to discontinuation; there were no fatal outcomes related to either study drug. Plasma KHK2455 concentrations reached steady state by Day 8 (Cycle 0) and increased dose-dependently. Potent dose-dependent inhibition of IDO activity was demonstrated by plasma Kyn concentration and Kyn/Trp ratio (median inhibition 70.5% and 70.8%, respectively, at 100 mg dose on Day 15, compared to baseline) and ex vivo Kyn production (>95% inhibition at ≥10 mg KHK2455), confirming target modulation. Six of 26 evaluable patients from all dosing groups achieved durable disease stabilization (≥6 months, RECIST 1.1), and one patient with bevacizumab-resistant glioblastoma demonstrated confirmed partial response (43.5% tumor reduction over a 2-year observation period). Median overall survival was 13.4 months, with 30% of subjects surviving for 2 years or longer (figure 1).Abstract 287 Table 1Study 2455-001: Treatment-Emergent Adverse Events (≥10% by Preferred Term)Abstract 287 Table 2Abstract 287 Figure 1Study 2455-001: Overall SurvivalConclusionsKHK2455 in combination with mogamulizumab was well-tolerated and manageable at all doses tested, suppressed Kyn production in a dose-dependent and sustained manner, and demonstrated signals of antitumor activity. These data support the continued development of this combination.AcknowledgementsMedical writing assistance was provided by Susan E. Johnson, PhD, S.E. Johnson Consulting, LLC, New Hope, PA, USA.Trial RegistrationNCT02867007 (www.clinicaltrials.gov)Ethics ApprovalThis study was approved by Ethics Committees at all participating study institutions.

scholarly journals 150 GAIA-102: a new class off-the-shelf allogeneic NK-like cells that can eliminate solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A163-A163
Author(s):  
Yui Harada ◽  
Yoshikazu Yonemitsu
Keyword(s):  
Nk Cells ◽  
Solid Tumors ◽  
Tumor Cells ◽  
Adoptive Immunotherapy ◽  
Nk Cell ◽  
Peritoneal Dissemination ◽  
Checkpoint Inhibitors ◽  
Antitumor Effects ◽  
Car T

BackgroundCancer immunotherapy has been established as a new therapeutic category since the recent success of immune checkpoint inhibitors and a type of adoptive immunotherapy, namely chimeric antigen receptor-modified T cells (CAR-T). Although CAR-T demonstrated impressive clinical results, serious adverse effects (cytokine storm and on-target off-tumor toxicity) and undefined efficacy on solid tumors are important issues to be solved. We’ve developed a cutting-edge, simple, and feeder-free method to generate highly activated and expanded human NK cells from peripheral blood (US9404083, PCT/JP2019/012744, PCT/JP2020/012386), and have been conducting further investigation why our new type of NK cells, named as GAIA-102, are so effective to kill malignant cells.MethodsCryopreserved PBMCs purchased from vendors were mixed and processed by using LOVO and CliniMACS® Prodigy (automated/closed systems). CD3+ and CD34+ cells were depleted, and the cells were cultured with high concentration of hIL-2 and 5% UltraGRO® for 14 days in our original closed system. Then, we confirmed the expression of surface markers, CD107a mobilization and cell-mediated cytotoxicity against various tumor cells and normal cells with or without monoclonal antibody drugs in vitro and antitumor effects against peritoneal dissemination model using SKOV3 in vivo.ResultsImportantly, we’ve found that our GAIA-102 exhibited CD3-/CD56bright/CD57- immature phenotype that could kill various tumor cells efficiently from various origins, including Raji cells that was highly resistant to NK cell killing. More importantly, massive accumulation, retention, infiltration and sphere destruction by GAIA-102 were affected neither by myeloid-derived suppressor cells nor regulatory T-lymphocytes. GAIA-102 was also effective in vivo to murine model of peritoneal dissemination of human ovarian cancer; thus, these findings indicate that GAIA-102 has a potential to be an ‘upward compatible’ modality over CAR-T strategy, and would be a new and promising candidate for adoptive immunotherapy against solid tumors.ConclusionsWe now just started GMP/GCTP production of this new and powerful NK cells and first-in-human clinical trials in use of GAIA-102 will be initiated on 2021.Ethics ApprovalThe animal experiments were reviewed and approved by the Institutional Animal Care and Use Committee of Kyushu University (approval nos. A30-234-0 and A30-359-0).

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