scholarly journals Phase 1 trial of IL-15 trans presentation blockade using humanized Mik-Beta-1 mAb in patients with T-cell large granular lymphocytic leukemia

Blood ◽  
2013 ◽  
Vol 121 (3) ◽  
pp. 476-484 ◽  
Author(s):  
Thomas A. Waldmann ◽  
Kevin C. Conlon ◽  
Donn M. Stewart ◽  
TatYana A. Worthy ◽  
John E. Janik ◽  
...  
Keyword(s):  
T Cell ◽  
Phase 1 ◽  
Critical Role ◽  
Human Study ◽  
Lymphocytic Leukemia ◽  
Refractory Celiac Disease ◽  
Significant Toxicity ◽  
Clinical Responses ◽  
In Cis ◽  
Lgl Leukemia

Abstract In the present study, Hu-Mikβ1, a humanized mAb directed at the shared IL-2/IL-15Rβ subunit (CD122) was evaluated in patients with T-cell large granular lymphocytic (T-LGL) leukemia. Hu-Mikβ1 blocked the trans presentation of IL-15 to T cells expressing IL-2/IL-15Rβ and the common γ-chain (CD132), but did not block IL-15 action in cells that expressed the heterotrimeric IL-15 receptor in cis. There was no significant toxicity associated with Hu-Mikβ1 administration in patients with T-LGL leukemia, but no major clinical responses were observed. One patient who had previously received murine Mikβ1 developed a measurable Ab response to the infused Ab. Nevertheless, the safety profile of this first in-human study of the humanized mAb to IL-2/IL-15Rβ (CD122) supports its evaluation in disorders such as refractory celiac disease, in which IL-15 and its receptor have been proposed to play a critical role in the pathogenesis and maintenance of disease activity. The protocol is registered with www.clinicaltrials.gov as number NCT 00076180.

Clinical Safety and Activity in a Phase 1 Trial of IPI-145, a Potent Inhibitor of Phosphoinositide-3-Kinase-δ,γ, in Patients with Advanced Hematologic Malignancies

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3663-3663 ◽  
Author(s):  
Ian W. Flinn ◽  
Steven M. Horwitz ◽  
Manish Patel ◽  
Anas Younes ◽  
James R. Porter ◽  
...  
Keyword(s):  
T Cell ◽  
Dose Escalation ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Grade 3 ◽  
Expansion Cohort ◽  
Dose Levels

Abstract Abstract 3663 Introduction: Phosphoinositide-3-kinases (PI3Ks) play pivotal roles in cell signaling and regulate a variety of cellular functions relevant to oncogenesis. Impaired development and function of B and T lymphocytes has been demonstrated in PI3K-δ and PI3K-γ isoform knockout mice, supporting the development of PI3K-δ,γ specific inhibitors for B- and T-cell lymphoid malignancies. IPI-145 is a potent PI3K-δ,γ inhibitor in clinical development for patients (pts) with hematologic malignancies. The activity of IPI-145 via PI3K-δ and PI3K-γ isoform inhibition has been characterized in biochemical and cellular assays and demonstrated in preclinical models of B- and T-cell mediated disease. Early results of the Phase 1 study in pts with advanced hematologic malignancies are reported here. Methods and Patients: This Phase 1 dose-escalation study is designed to evaluate the safety, pharmacokinetics (PK) and activity of orally administered IPI-145 in pts with advanced hematologic malignancies, including T-cell lymphomas/leukemias. Sequential cohorts of pts are enrolled at progressively higher dose levels with expansion cohorts of pts with select hematologic malignancies. IPI-145 is administered orally 2 times per day (BID) continuously in 28-day cycles. Tumor response is evaluated based on disease-specific standard criteria. Results: As of 16 July 2012, the study had enrolled 20 pts; 5 pts with chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL), 4 with indolent non-Hodgkin's lymphoma (iNHL), 3 with aggressive B-cell NHL [including diffuse large B-cell lymphoma (DLBCL) n=2 and Richter's transformation n=1], 3 with multiple myeloma (MM), 2 with Hodgkin's lymphoma (HL), 2 with T-cell lymphoma [anaplastic large-cell lymphoma (ALCL) n=2] and 1 with mantle cell lymphoma (MCL). Of these pts, 11 are male and 9 female, with a median [range] age of 63 years [30–81], with 36% <6 month from most recent prior systemic therapy. The median [range] number of prior therapies was 3 [1–8]. IPI-145 doses administered include 8 mg BID (n=1), 15 mg BID (n=6), 25 mg BID (n=7), 35 mg BID (n=3), and 50 mg BID (n=3). The median [range] number of treatment cycles was 2 [1–8], with 12 (60%) pts continuing on treatment. Adverse events (AEs) have occurred in 13 (65%) pts, including 7 (35%) pts with AEs Grade ≥3. Treatment-related AEs occurred in 11 pts (55%) with Grade ≥3 occurring in 5 pts (25%). Grade 4 neutropenia was the one dose limiting toxicity observed to date (15 mg dose cohort). New Grade ≥3 hematological laboratory abnormalities included neutropenia [n= 6 (30%)] and thrombocytopenia [n= 1 (5%)]. Grade 3 ALT/AST elevations occurred in 1 (5%) MM pt with onset 6 weeks after IPI-145 initiation. Preliminary PK show dose-proportional increases in plasma Cmax and AUC over the dose range studied. Further, the PK and initial pharmacodynamic (PD) data from the first 3 cohorts (8–25 mg BID) predict continuous suppression of the PI3K-δ pathway with increasing inhibition of the PI3K-γ pathway with a 25 mg BID dose or greater. In the evaluable pts (n=11), responses were observed at the 8, 15, and 25 mg BID dose levels including 2/3 CLL/SLL pts (0 CR/2 PR/1 SD), 1/2 iNHL pts (1 CR/0 PR/1 SD), and 1/1 in MCL (1 PR). No responses have been observed to date in evaluable pts with MM (0/3) or aggressive NHL (0/2). All pts with at least SD after 2 cycles (n=6) remain on treatment including the first pt dosed. Based on the PK/PD and the preliminary activity observed in pts with CLL, iNHL and MCL, an expansion cohort is enrolling pts in these select hematologic diseases dosed at 25 mg BID to further evaluate the safety and preliminary activity of IPI-145. Dose escalation continues with a focus on pts with T-cell malignancies and DLBCL where increasing suppression of the PI3K-γ isoform may improve the efficacy profile. Additional expansion cohorts in T-cell lymphoma, DLBCL, myeloproliferative neoplasms and the acute leukemias will better define disease specific activity. Conclusions: IPI-145, an oral, potent PI3K-δ,γ inhibitor, appears to be well tolerated and has shown initial clinical activity in pts with iNHL, MCL, and CLL. A dose of 25 mg BID effectively inhibits PI3K-δ, providing a rationale for expansion in CLL/iNHL/MCL. Additional safety and efficacy data from the ongoing dose escalation evaluation in T-cell/aggressive NHL and the CLL/iNHL/MCL expansion cohort will be presented. Disclosures: Flinn: Infinity Pharmaceuticals, Inc.: Research Funding. Horwitz:Seattle Genetics: Consultancy, Research Funding; Allos: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Genzyme: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy; Johnson & Johnson: Consultancy; Infinity Pharmaceuticals, Inc. : Research Funding. Patel:Infinity Pharmaceuticals, Inc. : Research Funding. Younes:Novartis: Honoraria, Research Funding; Celgene: Honoraria; Seattle Genetics: Honoraria, Research Funding; Sanofi-Aventis: Honoraria, Research Funding; MIllenium: Honoraria; Incyte: Honoraria; Genentech: Research Funding; Infinity Pharmaceuticals, Inc. : Research Funding; Gilead: Research Funding. Porter:Infinity Pharmaceuticals, Inc. : Employment. Sweeney:Infinity Pharmaceuticals, Inc. : Employment. Allen:Infinity Pharmaceuticals, Inc. : Employment. Kelly:Infinity Pharmaceuticals, Inc. : Employment. Kahl:Infinity Pharmaceuticals, Inc. : Research Funding.

scholarly journals Phase 1 clinical trial of the PI3Kδ inhibitor YY-20394 in patients with B-cell hematological malignancies

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Bo Jiang ◽  
Junyuan Qi ◽  
Yuqin Song ◽  
Zengjun Li ◽  
Meifeng Tu ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
B Cell ◽  
Phase 1 ◽  
Objective Response ◽  
Human Study ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Lymphocytic Leukemia ◽  
Pharmacokinetic Parameters ◽  
Durable Response

AbstractYY-20394, an oral phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor, was investigated in a first-in-human study of patients with relapsed or refractory B-cell malignancies. During dose escalation, 25 patients received 20–200 mg of YY-20394 daily. The primary outcome measures were tolerability and dose-limiting toxicity (DLT). The secondary outcomes were pharmacokinetic parameters, progression-free survival (PFS) and the objective response rate (ORR). Since no patients experienced DLT, the maximum tolerated dose (MTD) was not reached. The majority (≥ 5%) of drug-related adverse events were ≥ grade III, being neutropenia (44.0%), pneumonia (16.0%), hyperuricemia (12.0%), lymphocythemia (8.0%), leukopenia (8.0%) and pneumonitis (8.0%). The overall ORR was 64.0% (95% confidence interval (CI): 45.2, 82.8%) including 5 patients with complete remission (CR), 11 with partial remission (PR), 2 with stable disease (SD) and 7 with progressive disease (PD), while the disease control rate (DCR) was 72.0% (95% CI: 54.4, 89.6%). The ORR of 10 patients with follicular lymphoma was 90%. The median PFS time was 255 days. One PR patient with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who received 40 mg q.d. had a durable response of around 36 months. The median PFS time of 10 patients with follicular lymphoma was 300 days. A recommended phase 2 dose of 80 mg q.d. was established. Considering that YY-20394 was well-tolerated with promising preliminary efficacy, further development is warranted.Trial registration clinicaltrials.gov, NCT03757000, retrospectively registered, November 28, 2018, https://clinicaltrials.gov/ct2/show/NCT03757000?term=NCT03757000&draw=2&rank=1.

scholarly journals A Phase 1 Study of ACTR087 in Combination with Rituximab, in Subjects with Relapsed or Refractory CD20-Positive B-Cell Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 244-244
Author(s):  
Javier Munoz ◽  
Samantha Jaglowski ◽  
Matthew S. McKinney ◽  
Iris Isufi ◽  
Patrick J. Stiff ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antitumor Activity ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Human Study ◽  
Advisory Board ◽  
Phase 1 Study ◽  
Dose Levels

Background: The Antibody-Coupled T-cell Receptor (ACTR) platform is an autologous engineered T-cell therapy that combines the cell-killing ability of T cells and the tumor-targeting ability of co-administered antibodies to exert potent antitumor immune responses. ACTR087 comprises the extracellular domain of CD16 linked to a CD3ζ-signaling domain and a 4-1BB co-stimulatory domain. Here we present the clinical experience from Study ATTCK-20-2 (NCT02776813), a multicenter, phase 1 study of ACTR087 in combination with rituximab in subjects with relapsed or refractory (R/R) CD20+ NHL. Methods: The main objectives of this first-in-human study were to evaluate the safety and antitumor activity of ACTR087+rituximab. Other objectives included evaluating ACTR T-cell persistence and other correlative biomarkers. Subjects must have had CD20+ NHL that was R/R after prior treatments, which must have included anti-CD20 antibody-containing chemotherapy. Subjects received lymphodepleting chemotherapy (cyclophosphamide and fludarabine) for 3 days, followed by rituximab and a single dose of ACTR087. Additional doses of rituximab were administered q3w until disease progression, unacceptable toxicity, or Investigator decision. The study included a dose escalation phase (increasing doses of ACTR087) and an expansion phase (ACTR087 at the preliminary recommended phase 2 dose [RP2D]); all subjects received rituximab at a fixed dose of 375 mg/m2 q3w. Results: Two dose levels (DL) of ACTR087 were evaluated during dose escalation (n=17). The MTD was exceeded at DL2, with severe cases of cytokine release syndrome (CRS) and neurotoxicity. Statistical analysis of the relationship between non-hematologic toxicity and ACTR+ T-cell doses was retrospectively performed (two-parameter Bayesian logistic regression model) to estimate an RP2D of 35×106 ACTR+ T cells. Nine subjects enrolled in an expansion cohort and received ACTR087 at this RP2D in combination with rituximab. Among all subjects treated (n=26), the majority (69%) were diagnosed with DLBCL. Subjects had received a median of 3 (range 1-9) prior lines of therapy, with 77% having received ≥3 prior lines. ACTR087 showed dose-dependent expansion with peak levels generally observed 7 to 14 days post administration. In subjects with ongoing clinical response (CR), ACTR remained detectable through the last timepoint evaluated. Across all cohorts, Grade ≥3 TEAEs reported in &gt;3 subjects regardless of causality were limited to hematologic events. Potential T cell-mediated toxicities were observed, including 4 serious cases of CRS (Gr 4 in 2 subjects, both with fatal sepsis) and 2 serious cases of neurotoxicity (1 Gr 5, 1 Gr 4 in a subject with fatal septic shock). Elevated baseline inflammatory markers (eg, ferritin, CRP) were observed in patients who developed Gr ≥3 CRS and neurotoxicity post ACTR087. Of note, severe CRS presented without fever and events occurred &gt;7 days post ACTR087. Clinical activity was reported with an ORR of 50% in all dose levels tested, including durable complete responses, with one subject in CR for 869+ days (Table 1). Conclusions: ACTR087+rituximab demonstrated antitumor activity, with observed safety events that are expected with other autologous T-cell products. The time to onset and clinical presentation of severe CRS and neurotoxicity events in this study informed the safety monitoring and adverse reaction management guidance across clinical studies of ACTR T-cell products. Data from this first-in-human study of ACTR087+rituximab confirm the proof of concept and will be used to guide further development for the ACTR platform. Updated clinical data, as well as expanded biomarker correlations to efficacy and safety, will be presented. Disclosures Munoz: Pharmacyclics /Janssen: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy; Fosunkite: Speakers Bureau; AstraZeneca: Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene/Juno: Consultancy, Research Funding; Genentech: Consultancy, Research Funding, Speakers Bureau; Kite/Gilead: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy; Alexion: Consultancy; Portola: Research Funding; Incyte: Research Funding; Bayer: Consultancy, Speakers Bureau; Merck: Consultancy. Jaglowski:Kite: Consultancy, Other: advisory board, Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding; Unum Therapeutics Inc.: Research Funding; Juno: Consultancy, Other: advisory board. Isufi:Celgene: Consultancy; Novartis: Consultancy; Astra Zeneca: Consultancy. Stiff:Gamida-Cell: Research Funding; Incyte: Research Funding; Cellectar: Research Funding; Unum: Research Funding; Gilead/Kite Pharma: Consultancy, Honoraria, Research Funding; Amgen: Research Funding. Sachs:Unum Therapeutics Inc.: Employment. Ranger:Unum Therapeutics Inc.: Employment. Harris:Unum Therapeutics Inc.: Employment. Payumo:Unum Therapeutics Inc.: Employment. Akard:Bristol-Myers Squibb: Speakers Bureau; Gilead: Speakers Bureau; Takeda: Speakers Bureau; Novartis: Speakers Bureau; Celgene: Speakers Bureau.

Latest Advances in the Diagnosis and Treatment of Large Granular Lymphocytic Leukemia

2018 ◽  
pp. 616-625 ◽  
Author(s):  
Aline Moignet ◽  
Thierry Lamy
Keyword(s):  
T Cell ◽  
Natural Killer Cell ◽  
Natural Killer ◽  
Killer Cell ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
World Health ◽  
Necrosis Factor Alpha ◽  
Constitutive Activation ◽  
Lgl Leukemia

Large granular lymphocyte (LGL) leukemia has been recognized in the World Health Organization classifications among mature T cell and natural killer cell neoplasms and is divided into three categories. Chronic T cell leukemia and natural killer cell lymphocytosis can be considered as a similar spectrum of an indolent disease characterized by cytopenias and autoimmune conditions. The last category, aggressive natural killer cell LGL leukemia is very rare, related to Epstein-Barr virus, and seen mainly in young Asian people. Clonal LGL expansion arises from chronic antigenic stimulation sustained by interleukin-15 and platelet-derived growth factor cytokine signal. Those leukemic cells are resistant to apoptosis, mainly because of constitutive activation of survival pathways including Jak/Stat, MapK, Pi3k-Akt, RasRaf-1, MEK1/ERK, sphingolipid, and NFκB. Stat3 constitutive activation is the hallmark of this lymphoproliferative disorder. Socs3 is downregulated, but no mutation could be found to explain this status. However, several somatic mutations, including Stat3, Stat5b, and tumor necrosis factor alpha–induced protein 3, have been demonstrated recently in LGL leukemia; they are identified in half of patients and cannot explain by themselves LGL leukemogenesis. Recurrent infections as a result of chronic neutropenia, anemia, and autoimmune disorders are the main complications related to LGL leukemia. Despite an indolent presentation, 10% of patients die, mainly because of infectious complications. Current treatments are based on immunosuppressive therapies. A better mechanistic understanding of LGL leukemia will allow future consideration of a personalized therapeutic approach perhaps based on Jak/Stat inhibitors, which may offer better results than current immunosuppressive therapy.

Phase 1 trial of drug resistant immunotherapy: A first-in-class combination of MGMT-modified γδ t cells and temozolomide chemotherapy in newly diagnosed glioblastoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2057-2057
Author(s):  
Louis B. Nabors ◽  
Lawrence S. Lamb ◽  
Melissa Jo Beelen ◽  
Thriumaine Pillay ◽  
Mariska ter Haak ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Phase 1 ◽  
Human Study ◽  
Γδ T Cells ◽  
Maintenance Phase ◽  
Fixed Dose ◽  
Drug Resistant ◽  
Newly Diagnosed ◽  
Normal Range

2057 Background: Temozolomide (TMZ) transiently upregulates NKG2D ligands targeted by innate immune effector cells. Lymphodepletion impairs this immune response, however, genetic modification of ex vivo expanded γδ T cells with an MGMT-expressing lentivector confers resistance to TMZ, allowing concurrent chemotherapy and γδ T cell infusion, thereby targeting the tumor when NKG2DL are maximally expressed. This Drug Resistant Immunotherapy (DRI) is currently being evaluated in a Phase 1 first in human study (NCT04165941) and interim safety and biologic correlative analysis are detailed here for the first dosing cohort. Methods: Adults with newly diagnosed, untreated glioblastoma (GBM), adequate organ function, and a KPS≥70% will be enrolled. Subjects undergo subtotal resection and placement of a Rickham reservoir followed 3-4 weeks by apheresis from which γδ T cells are expanded, transduced with an MGMT-expressing lentivector, harvested, and cryopreserved. Standard of care induction TMZ/radiation therapy is initiated followed by 6 cycles of maintenance TMZ. Intravenous TMZ (150mg/m2) and intracranial dosing of 1 x 107 γδ T cells occur on day 1 of each maintenance cycle. Daily oral TMZ 150mg/m2 follows for Days 2-5. Dose level 1 (DL1) subjects receive 1 fixed dose of γδ T cells and DL2 receive 3 doses administered on Day 1 of each of first 3 cycles of TMZ dependent on absence of dose limiting toxicity. Primary endpoint is safety; secondary endpoints include progression free and overall survival. Immunologic and genomic correlative analyses are being conducted at specific time points from peripheral blood and cerebral spinal fluid collected from the Rickham. Results: Six subjects (4 females, 2 males) have been enrolled in DL1. All subjects were IDH1-WT with 5 subjects MGMT unmethylated and 1 methylated. Of these, 1 generated inadequate gd T cells and 2 withdrew consent prior to DRI treatment. For the 3 that received DRI, treatment-related adverse events with maximum CTCAE Grade 3 occurred in 1 subject; UTI, dehydration, and thrombocytopenia. The most common Grade 1/2 events included: fever, leukopenia, nausea, and vomiting which were attributable to TMZ or radiotherapy. Circulating T cells remained below normal range throughout maintenance phase in 2/3 subjects. NK and gd T cell numbers remained within low normal range for 3/3 and 2/3 subjects, respectively. Serum Th1 (IFNg, IL-2, TNFa) and Th2 (IL4, IL5, IL-10) cytokines were within clinical range although TNFa remained elevated from the gdT cell infusion through day +30 in 2 subjects. Conclusions: Administration of MGMT-gene modified gdT cells and TMZ as DRI is feasible in lymphodepleted subjects during TMZ maintenance phase and sufficiently safe to warrant further investigation at additional doses. Clinical trial information: NCT04165941.

IL-6 Production by B-CLL Cells Plays a Critical Role in the Inhibition of T Cell Activation and Proliferation and Promotes a Th2 Response in Normal T Lymphocytes.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2808-2808 ◽  
Author(s):  
Andrea G.S. Buggins ◽  
Piers E.M. Patten ◽  
Julie Richards ◽  
Stephen J. Orr ◽  
Ghulam J. Mufti ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Function ◽  
Critical Role ◽  
Lymphocytic Leukemia ◽  
Th2 Response ◽  
Cytokine Bead Array ◽  
Cd40l Expression

Abstract Immune dysfunction is a hallmark of B-cell chronic lymphocytic leukemia (B-CLL) which occurs through loss of normal cell function as the malignant clone expands, as a result of therapy or because of immunoregulatory properties of the tumor itself. It has previously been shown that B-CLL cells are poor stimulators of the allogeneic mixed lymphocyte reaction (MLR) and we first determined whether this is due to lack of stimulatory activity or active immunosuppression by examining the effect of B-CLL contact and tumor supernatant (TSN) on a 3rd party MLR. Incorporation of B-CLL cells in a 5 day MLR inhibited 3H proliferation by responders in 2/10 cases, whereas TSN inhibited in all 10 cases. Studies in which normal T cells were stimulated by CD3/28 beads for 72 hours in the absence or presence of TSN showed a reduction in cell cycle entry measured by PI and FITC staining with 26+/−4.6% and 13.7+/−4.3% of cells in S +G2M in the absence and presence of TSN respectively (p<0.0001). Studies performed using CFSE labelled normal T cells showed that TSN reduced the number of T cells undergoing one or more cell divisions from a mean of 81.8+/−1.65% to 58.2+/−4.4% (p=0.0072). It is known that T cells in B-CLL have an acquired defect in CD40L expression, which has been ascribed to downregulation by CD40 present on tumor cells. Our experiments confirm that this defect is reversible since purification of B-CLL T cells restores activation induced CD40L upregulation to normal. We further demonstrate that B-CLL TSN from all 17 patients tested inhibits CD40L upregulation by normal T cells in response to PMA and ionomycin or CD3/28 beads (to a mean of 51%+/−5.6%, p<0.0001, of those activated in the absence of TSN) and a parallel inhibition of IL-2 secretion (correlation with CD40L inhibition: p=0.006, r2 = 0.54). In addition to the effects of TSN on T proliferation and activation, B-CLL TSN also induced Th2 polarisation of normal T cells. When activated using CD3/28 beads in control medium, normal T cells show an increase in IL-2, γ-interferon and TNF-α secretion consistent with the expected Th1 response. When incubated in TSN however, 10 and 1000 fold increases in IL-4 and IL6 release were observed respectively consistent with a shift to a Th2 response. B-CLL cells are known to secrete a number of cytokines and in order to determine which might be responsible for the observed effects a number were assayed either by enzyme-linked or cytokine bead array assay. The effects of TSN were not due to TGF-β , IL-10 or soluble CD40 and depletion of soluble CD25 using bead conjugated anti-CD25 had no effect on the immunosuppressive activity. High levels of IL-6 were detected in TSN from all cases studied (n=5). When normal T cell were activated in TSN, a 100 fold further increase in IL-6 level was observed suggesting that this cytokine may be responsible for at least some of the observed effects of TSN. Antibody neutralization of the IL-6 in TSN demonstrated an increase in both Th1 cytokine production and CD40L expression. Furthermore, addition of recombinant IL-6 to T cells activated in media inhibited CD40L upregulation. In summary, B-CLL cells secrete factor(s) which inhibit T cell activation and proliferation and promote Th2 polarisation. These factors might contribute to the disease phenotype by impairing T cell responses to infection, predisposing to autoimmunity and promoting the growth of the malignant clone through the action of IL-6.

scholarly journals 469 A phase 1 first in human study of HMBD-002, an IgG4 monoclonal antibody targeting VISTA, as a monotherapy and combined with pembrolizumab in patients with advanced solid malignancies

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A498-A498
Author(s):  
Leah DiMascio ◽  
Dipti Thakkar ◽  
Siyu Guan ◽  
Eric Rowinsky ◽  
Jordi Rodon ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cell ◽  
Tumor Microenvironment ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immune Cell ◽  
Phase 1 ◽  
Human Study ◽  
Cell Activity ◽  
Myeloid Cells

BackgroundV-domain Ig suppressor of T cell Activation (VISTA), an immune checkpoint regulator predominantly expressed on myeloid cells, represents a promising therapeutic target due to its role in suppressing pro-inflammatory, anti-tumor responses within the tumor microenvironment (TME). Based on VISTA’s broad expression across immune cell subtypes, HMBD-002 has been designed as a non-depleting, IgG4 monoclonal antibody with high affinity and specificity to VISTA across species (human, cynomolgus monkey, and rodent) that has the ability to block a predicted counter-structure binding site. In preclinical studies, HMBD-002 significantly inhibited tumor growth, both as a monotherapy and in combination with pembrolizumab, while decreasing infiltration of suppressive myeloid cells within the TME and increasing T cell activity. While rapid serum clearance and immune toxicities (e.g. cytokine release syndrome) have been reported for IgG1 antibodies, these were not observed preclinically with HMBD-002. In addition to VISTA expression on pro-inflammatory immune cells, examination of VISTA expression across cancer types has revealed that several malignancies, particularly human samples of triple negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC), express high levels of VISTA, thereby providing a rationale for exploring these indications in clinical studies.MethodsThis Phase 1, first in human study is being conducted in two parts and will evaluate multiple doses and schedules of intravenously (IV) administered HMBD-002, with or without pembrolizumab, in patients with advanced solid tumors. Part 1 (dose escalation) seeks to identify the maximum tolerated dose (MTD), or the maximum tested dose, of HMBD-002 as a monotherapy, and separately, in combination with pembrolizumab to define the recommend doses for subsequent disease directed studies (i.e., recommended phase 2 dose [RP2D]). Part 2 (dose expansion) will assess the anti-cancer activity of HMBD-002 as a monotherapy at the RP2D in previously treated patients with TNBC, and NSCLC, and in combination with pembrolizumab in patients with TNBC, NSCLC, and other VISTA-expressing malignancies. The size of the disease-directed cohorts will be determined based on an interim futility analysis conducted upon enrollment of 15 patients. Safety, efficacy, pharmacokinetic, and pharmacodynamic endpoints will be monitored and reported. Correlative studies will assess pre- and post-treatment markers of immune activity in the periphery and the tumor microenvironment.AcknowledgementsThis work was funded in part by the Cancer Prevention and Research Institute of Texas (CPRIT).Ethics ApprovalThe study was approved by each participating Institution’s Institutional Review Board.

scholarly journals Preliminary Clinical Results from a Phase 1 Study of ACTR707 in Combination with Rituximab in Subjects with Relapsed or Refractory CD20+ non-Hodgkin Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1587-1587
Author(s):  
Ian W. Flinn ◽  
Jason R. Westin ◽  
Jonathon B. Cohen ◽  
Luke P. Akard ◽  
Samantha Jaglowski ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Advisory Board ◽  
Phase 1 Study ◽  
Advisory Committees ◽  
Clinical Responses

Background: The Antibody-Coupled T-cell Receptor (ACTR) platform is an autologous engineered T-cell therapy that combines the cell-killing ability of T cells and the tumor-targeting ability of co-administered antibodies to exert potent antitumor immune responses. ACTR707 comprises the extracellular domain of CD16 linked to a CD3ζ signaling domain and a CD28 co-stimulatory domain. ACTR707 is in clinical development in combination with rituximab (NCT03189836) or trastuzumab (NCT03680560). Here we present clinical findings from the dose escalation phase of Study ATTCK-20-03, an ongoing, multicenter, phase 1 study of ACTR707+rituximab in subjects with relapsed or refractory (R/R) CD20+ NHL. Methods: The primary objectives of this first-in-human study are to evaluate the safety of the combination of ACTR707 and rituximab and to determine a recommended phase 2 dose (RP2D). Other objectives include evaluating antitumor activity and ACTR T-cell persistence. Subjects must have CD20+ NHL that is R/R after prior treatments, which must include anti-CD20 antibody-containing chemotherapy. Subjects receive lymphodepleting chemotherapy (cyclophosphamide and fludarabine) for 3 days, followed by rituximab and a single dose of ACTR707. Additional doses of rituximab are administered q3w until disease progression, unacceptable toxicity, or Investigator decision. The study includes a dose escalation phase (increasing doses of ACTR707 with fixed dose of rituximab at 375 mg/m2 q3w) and an expansion phase at the RP2D. Results: Six subjects received ACTR707 at Dose Level 1 (DL1; 23-38×106 ACTR+ T cells), 3 subjects at DL2 (30-50×106 ACTR+ T cells), and 5 subjects at DL3 (45-55×106 ACTR+ T cells). The majority of the subjects were diagnosed with DLBCL (93%) and had refractory disease (71%), defined as progressive disease as the best response to any prior treatment or relapse &lt;1 year post autologous stem cell transplant. In DL1 through DL3, as of 27 May 2019, there were no dose-limiting toxicities, AEs of cytokine release syndrome (CRS), serious or severe neurologic AEs, or AEs leading to deaths on treatment. TEAEs reported in &gt;2 subjects, regardless of causality or grade, included neutropenia, thrombocytopenia, anemia, febrile neutropenia, pyrexia, cough, constipation, diarrhea, nausea, and vomiting. SAEs considered possibly related to ACTR707 were febrile neutropenia (n=2) and cytopenia (n=1). ACTR707 expansion generally reached peak levels within 1 to 2 weeks after administration. All subjects with complete response (CR) up to 1 year had detectable ACTR at the last timepoint evaluated. Higher ACTR707 CD8:CD4 T-cell ratios were associated with clinical responses. Clinical activity was reported across DL1 through DL3, with an overall response rate of 64% including durable complete responses (CRs), with one subject in CR for 387+ days (Table 1). Conclusions: Data available from DL1 through DL3 of ACTR707+rituximab suggest that clinical responses can be achieved without severe T cell-mediated toxicities (eg, CRS and neurotoxicity) that have been reported with other autologous T-cell products. Dose escalation continues at a target dose of 80×106 ACTR+ T cells; enrollment in DL4 (n=6) was recently completed. Updated data, including identified correlates of clinical outcomes, will be presented for DL1 through DL4. Disclosures Flinn: TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding. Westin:Genentech: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Unum: Research Funding; Curis: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; MorphoSys: Other: Advisory Board; 47 Inc: Research Funding; Celgene: Other: Advisory Board, Research Funding; Novartis: Other: Advisory Board, Research Funding. Cohen:Genentech, Inc.: Consultancy, Research Funding; Takeda Pharmaceuticals North America, Inc.: Research Funding; Gilead/Kite: Consultancy; LAM Therapeutics: Research Funding; UNUM: Research Funding; Hutchison: Research Funding; Astra Zeneca: Research Funding; Lymphoma Research Foundation: Research Funding; ASH: Research Funding; Bristol-Meyers Squibb Company: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy. Akard:Celgene: Speakers Bureau; Novartis: Speakers Bureau; Takeda: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Gilead: Speakers Bureau. Jaglowski:Juno: Consultancy, Other: advisory board; Kite: Consultancy, Other: advisory board, Research Funding; Unum Therapeutics Inc.: Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding. Sachs:Unum Therapeutics Inc.: Employment. Ranger:Unum Therapeutics Inc.: Employment. Harris:Unum Therapeutics Inc.: Employment. Payumo:Unum Therapeutics Inc.: Employment. Bachanova:Celgene: Research Funding; Gamida Cell: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; GT Biopharma: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Novartis: Research Funding.

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