scholarly journals 509 A first-in-human phase 1 study of NL-201 in patients with relapsed or refractory cancer

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A540-A540
Author(s):  
Aung Naing ◽  
Margaret Callahan ◽  
Brian Costello ◽  
Carlo Bifulco ◽  
Evan Hall ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Cancer Immunotherapy ◽  
Cd8 T Cells ◽  
Dose Escalation ◽  
Safety Profile ◽  
Phase 1 ◽  
Response To Treatment ◽  
Carcinomatous Meningitis ◽  
Link Type

BackgroundNL-201 is a selective and long-acting computationally designed alpha-independent agonist of the IL-2 and IL-15 receptors, which share beta and gamma signaling subunits. NL-201 is being developed as a potent activator of CD8+ T cells and NK cells for cancer immunotherapy. Binding to the beta and gamma subunits selectively stimulates dose-dependent expansion and tumor infiltration of cytotoxic CD8+ T cells and NK cells, thereby enhancing the immune response in the tumor. The absence of binding to the IL-2 alpha subunit reduces the undesirable effects of traditional IL-2 therapies, such as vascular leak syndrome and expansion of immunosuppressive regulatory T cells. As such, NL-201 is designed to promote the desired immunomodulatory anti-tumor effects of IL-2 with an improved safety profile.MethodsNL201-101 is a Phase 1 first-in-human, open-label, dose-escalation, and cohort expansion study consisting of two parts. Part 1 is an adaptive monotherapy dose escalation study in up to 60 adult patients with advanced and/or refractory solid tumors to determine the safety profile and the recommended phase 2 dose (RP2D) and schedule of NL-201. During dose escalation, two different schedules will be evaluated: dosing every 21 days or on days 1 and 8 of each 21-day cycle. Tumor response to treatment will be assessed by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 and/or RECIST for use in cancer immunotherapy trials (iRECIST). In Part 2, patients with pathologically proven diagnosis of indication-specific cohorts (up to N=30/cohort), who have advanced and/or refractory measurable disease and have failed at least one line of treatment, which may include checkpoint inhibitors, will be enrolled. Key exclusion criteria include history of brain cancer, carcinomatous meningitis, neurologic autoimmune disease, or active central nervous system metastases; patients previously receiving CAR-T or IL-2-based therapies are not eligible. Recruitment of Part 1 began in April 2021, and the trial is actively enrolling. Clinicaltrials.gov identifier: NCT04659629.Trial RegistrationClinicaltrials.gov identifier: NCT04659629.Ethics ApprovalAll relevant documents have been or will be submitted to an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) by the investigator and reviewed and approved by the IRB/IEC before the study is initiated. Site 1001: Belberry HREC, application number 2020–09–925 (Belberry does not provide an approval number); Site 1003: Austin Health HREC, approval number HREC/69340/Austin-2020; Site 2003: MDACC Office of Human Subjects Protection, approval number 2020–0383.

scholarly journals 703 Favorable pre-clinical safety profile of the novel not-alpha IL-2 agonist ANV419 supports first in human clinical development

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A731-A731
Author(s):  
Christoph Huber ◽  
Guzman Alonso ◽  
Elena Gerralda ◽  
Christoph Bucher ◽  
Philippe Jacqmin ◽  
...  
Keyword(s):  
Blood Pressure ◽  
T Cells ◽  
Nk Cells ◽  
Cancer Patients ◽  
Cd8 T Cells ◽  
Dose Escalation ◽  
Safety Profile ◽  
Serum Cytokines ◽  
Dose Dependent Increase ◽  
Dose Dependent

BackgroundANV419 is a novel interleukin-2 (IL-2)/anti-IL-2 fusion protein with preferential signaling through the IL-2 beta/gamma receptor that induces selective proliferation of CD8 T cells and NK cells in vivo for the treatment of cancer. The safety and pharmacodynamic effects of ANV419 were studied in a 4-week cynomolgus monkey GLP study to support the ongoing PhI dose escalation clinical trial.MethodsANV419 was administered by i.v. injection over 1 min at doses of 0.03, 0.1, 0.3 mg/kg, or vehicle control on days 1 and 15 of the 29-day study. Assessments included body weight, blood pressure, hematology, clinical pathology, serum cytokines, immunophenotyping, histopathology, and pharmacokinetics.ResultsThe pharmacokinetics of ANV419 were characterized by target mediated disposition, with a half-life of approximately 24h at concentrations not affected by target mediated clearance. Dose-dependent increases in WBC were observed after each injection, driven by preferential expansion of CD8 T cells and NK cells over Tregs. NK cells were more sensitive to ANV419 than CD8 T cells reaching maximal proliferation in blood at 0.03 mg/kg vs. 0.3 mg/kg for CD8 T cells. Hematological changes included: transient dose-dependent increase in basophils; elevation in eosinophils, up to 2.2-fold above control animals at > 0.03 mg/kg, remaining within the normal range for cynomolgus monkeys (<1.94 G/L); minor decrease in platelets at day 4 after each injection. There were no relevant treatment-related changes in inflammatory serum cytokines (IL-1b, IL-5, IL-6, IL-8, IFNg, TNFa, GM-CSF). A mild systemic inflammatory response was observed at 0.3 mg/kg evidenced by a transient increase of CRP on days 4 and 19, preceded after the first injection by a slight dose dependent increase in IL-1RA at 4h post injection, and an increase in IL-10 at 24h post treatment at 0.3mg/kg. No significant changes in body weights or blood pressure and no signs of capillary leak were observed during the entire study.A multi-part PhI dose-escalation study of ANV419 has been initiated in cancer patients. In the part A single patient escalation cohort, two patients have been dosed Q2W multiple times with 0.003mg/kg and 0.006mg/kg respectively with the expected PD profile and no DLT observed.ConclusionsConsistent findings, relating to expected effects of ANV419 as a not-alpha IL-2 agonist, demonstrated a favorable tolerability and safety profile at pharmacodynamically relevant doses that strongly support its translational development in cancer patients to identify clinical benefits.

scholarly journals ATIM-25. PD-1 INHIBITION CAN BE COMBINED WITH IL-12 IN SUBJECTS WITH RECURRENT GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi6-vi7
Author(s):  
Ennio Chiocca ◽  
Rimas Lukas ◽  
Ganesh Rao ◽  
Jill Buck ◽  
Nathan Demars ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cells ◽  
Dose Escalation ◽  
Safety Profile ◽  
Adverse Reactions ◽  
Phase 1 ◽  
Recurrent Glioblastoma ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
Main Study

Abstract Monotherapy with intratumoral Ad-RTS-hIL-12 (Ad), a novel gene therapeutic conditionally expressing IL-12 under the transcriptional control of oral veledimex (V, 20 mg) acting via the proprietary RheoSwitch Therapeutic System® (RTS®), was shown in a phase 1 Main study (NCT02026271) to elicit a sustained intra-tumoral activated cytotoxic T-cell response with co-expression of PD-1. Additionally, the Main study showed improved median overall survival (mOS), compared to historical controls, in subjects with recurrent glioblastoma (rGBM) receiving Ad + V. Herein, we report updated findings from on an ongoing open label, dose-escalation Phase 1 substudy (NCT03636477) evaluating safety and tolerability of local, controlled IL-12 plus nivolumab in adult subjects with rGBM. Ad was administered by single intratumoral injection (2 x 1011 viral particles) on Day 0 plus V (10 and 20 mg) PO QD x 15 with nivolumab (1 and 3mg/kg) IV on Days -7, 15, then Q2W. Subjects have been accrued into three cohorts and follow-up is ongoing. Data from all three cohorts regarding dose escalation of V and nivolumab will be presented. The initial safety profile during V dosing period was similar to Ad+V monotherapy with adverse reactions being dose-related and rapidly reversible upon discontinuation of V. And those adverse reactions during the follow on nivolumab dosing were tolerable and manageable and consistent with nivolumab labeling, with no synergistic toxicities, and drug-related deaths. In the first two cohorts (where data is available), combination therapy improved the biomarker “cytoindex” (ratio of circulating CD8+ T cells to FoxP3+ regulatory T cells). (In the Main study, cytoindex correlated with overall survival). Controlled IL-12 production using Ad+V with nivolumab is a rational combination with initial data consistent with immune-mediated anti-tumor effects with a favorable safety profile. Further phase 2 investigation of Ad+V plus a checkpoint inhibitor in rGBM is planned.

807 A multicenter open-label phase I/lb study of SO-C101 as monotherapy and in combination with pembrolizumab in patients with selected advanced/metastatic solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A856-A856
Author(s):  
Aurelien Marabelle ◽  
Stephane Champiat ◽  
Elena Garralda ◽  
Alberto Hernando ◽  
Filip Janku ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Dose Escalation ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
Open Label ◽  
Link Type ◽  
Anti Cancer

BackgroundIL-15 is a member of the common y-chain family of cytokines that shares functional activities with IL-2. SO-C101is a superagonist fusion protein of IL-15 and the IL-15 receptor α sushi+ domain. SO-C101 stimulates the proliferation and the cytotoxic activity of NK cells and memory CD8+ T cells.In pre-clinical studies SO-C101 promoted expansion and activation of human, murine and cynomolgus monkey NK and CD8+ T cells. NK and CD8+ T cell activation correlated with potent monotherapy anti-cancer activity of SO-C101 in metastatic and solid tumor models. The combination of an anti-PD-1 or of anti-cancer monoclonal antibodies with SO-C 101 augmented the anti-tumor responses in mouse models. First clinical study was initiated in June 2019 to investigate SO-C101 as monotherapy and in combination with pembrolizumab.MethodsThe phase 1/1 b study currently on-going is a multicenter, open-label, dose escalation study for patients with selected advanced/metastatic solid tumors. The study consists of 2 parts: Part A - dose escalation of SO-C101 as monotherapy; Part B - dose escalation of SO-C101 in combination with pembrolizumab. Study objectives are to define the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of SO-C101 in both parts.ResultsAs of September 22nd, 19 subjects were treated in part A in 6 escalating dose levels, and 3 subjects were treated in part B, at dose level 1.SO-C101 was well tolerated. No DLT was observed, the main AEs related to SO-C101 were injection site reactions, fever, chills, flu-like syndrome, all G1- G2, and transient lymphopenia in 5 subjects, Grade 2 to 4, all resolved within few days.Preliminary PK results showed the PK profile to be dose-proportional, with a Tmax of approx. 5 – 6 hours after administration and T½ approx. 4 hours.Preliminary PD analysis showed dose dependent NK and CD8+ T cell activation.A preliminary efficacy signal has been observed in a patient refractory to anti-PD1 therapy, who showed a RECIST PR with initial 20% shrinkage of target lesions at 6 weeks and 49% shrinkage at 12 weeks on CT-scans.ConclusionsTo date, SO-C101 has been well tolerated, with a manageable toxicity and encouraging signs of clinical activity. The study will proceed to reach a RP2D in both monotherapy and combination with Pembrolizumab. Expansion of the study in selected indications is warranted.Trial Registration https://clinicaltrials.gov/ct2/show/NCT04234113?term=sotio&draw=3&rank=12The study was approved to proceed by FDA – IND 140011 -and by the sites ECs.Ethics ApprovalThe NCT04234113 clinical trial was approved by each investigational site health agency and ethical committee.ConsentWritten informed consent of patients was obtained prior enrollment in the NCT04234113 clinical trial.

PEGylated human IL-10 (AM0010) monotherapy in refractory metastatic colorectal cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3571-3571
Author(s):  
Jeffrey R. Infante ◽  
Kyriakos P. Papadopoulos ◽  
Aung Naing ◽  
Karen A. Autio ◽  
Patrick Alexander Ott ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Dose Escalation ◽  
Stable Disease ◽  
De Novo ◽  
Phase 1 ◽  
Second Line ◽  
Line Of Therapy

3571 Background: Colorectal Cancer (CRC) has been refractory to immune therapies. The clinical benefit of immunotherapy is thought to depend on the expansion of activated, intratumoral, tumor specific cytotoxic CD8+ T cells which are low in most CRCs. AM0010 stimulates the survival, expansion and cytotoxicity of intratumoral CD8+ T cells. Patients with CRC who have progressed on SOC first and second line of therapy have a reported 7.1 months OS with TAS-102 (Meyer et al. NEJM372;20, 2015). In this Phase 1 study the efficacy of AM0010 was studied in refractory metastatic CRC patients. Methods: CRC pts progressing on a median of 4 prior therapies (range 2-7) were treated daily with AM0010 in doses of 1 ug/kg SQ daily to 40 ug/kg in a dose escalation design. Tumor responses were assessed using irRC. Serum cytokines, activation of blood derived T cells and peripheral T cell clonality were analyzed. Pretreatment archival tissue samples were evaluated by IHC for tumor infiltration by CD8+T cells. Results: AM0010 was tolerated with reversible TrAEs. 10 pts (of 27) had a G3/4 TrAE. There were no objective responses. 11 patients were treated in dose escalation cohorts (1-10 ug/kg) and 16 pts were treated at or above RP2D (20 ug/kg or 40 ug/kg). Seven of 25 pts with at least one radiographic response evaluation had stable disease at 8 weeks. One patient had SD for 19.4 months. The mPFS (ITT n = 27 pts) was 1.6 months, mOS was 11.7 (range 2.4 – 32+) months. The median follow-up is 25.2 months (range 13-35). AM0010 increased Th1 cytokines IL-18 and IFNg in the serum of patients, while decreasing mediators of chronic, tumor promoting inflammation (Th17 cytokines) and TGFb. Tumor infiltrating granzyme B+ CD8+ T cells increased during the treatment. AM0010 induced de-novo oligoclonal expansion of T cell clones in patients. Conclusions: AM0010 is well tolerated in patients with refractory CRC. Although objective tumor responses were not seen in this very advanced CRC population, the observed immune activation including clonal T cell expansion, prolonged stable disease, and the mOS of 11.7 months is encouraging in this advanced CRC population. Future study of AM0010 in combination with FOLFOX in a second – line of therapy colorectal cancer patients is being planned. Clinical trial information: NCT02009449.

scholarly journals O82 A phase 1 dose escalation study of PRS-343, a HER2/4–1BB bispecific molecule, in patients with HER2-positive malignancies

2020 ◽  
Vol 8 (Suppl 1) ◽  
pp. A1.2-A2 ◽  
Author(s):  
Sarina Piha-Paul ◽  
Johanna Bendell ◽  
Anthony Tolcher ◽  
Sara Hurvitz ◽  
Amita Patnaik ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Dose Escalation ◽  
Phase 1 ◽  
Cd8 T Cell ◽  
Post Treatment ◽  
Primary Study ◽  
Biomarker Response ◽  
Active Dose

BackgroundAnticalin® proteins are recombinantly engineered human proteins based on lipocalins. PRS-343 is a first-in-class bispecific antibody-Anticalin fusion protein targeting the oncogenic tumor antigen HER2 and the costimulatory immune receptor 4-1BB on T and other immune cells. Here, we report the results of a phase 1 single-agent dose escalation trial in patients with HER2+ solid tumors.MethodsPRS-343 has been evaluated in sequential dose cohorts from 0.0005 to 8 mg/kg i.v. Doses were administered Q3W and the 8 mg/kg dose was also given Q2W. An accelerated titration design was utilized for the initial dose escalation followed by a modified 3+3 design and the option to back-fill cohorts. Dose-limiting toxicities (DLTs) were reported during the first cycle of each schedule. The primary study objectives include the safety profile and RP2D of PRS-343. Secondary objectives include ORR and DCR, PD biomarker response and PK profile. PD response was assessed in tumor biopsies (CD8+ T cell IHC) pre- and post- PRS-343 treatment.Results51 patients (median age 61.2 years, 61% female, 82% caucasian, 57% with more than three lines of prior therapy) with a variety of solid tumor indications [gastric/GEJ (n=19); BC (n=12); gynecological cancer (n=6); CRC (n=5); BTC (n=4); UC (n=2); melanoma, pancreatic and salivary duct (n=1 each)] have been treated with PRS-343. Based on pharmacokinetic analyses and observed kinetics of the CD8+ T cell expansion post-treatment, the low end of the active dose range is considered 2.5 mg/kg. 19 patients treated at active dose levels before the data cut-off on 09-06-2019 were evaluable for response [DCR 58% (11% confirmed PR) as per RECIST 1.1]. At the active doses, we observed significant and pronounced post-treatment expansion of CD8+ T cells particularly in the tumor nests, consistent with the MoA of PRS-343, while there was no increase in the doses below 2.5 mg/kg. The post-treatment expansion of CD8+ T cells was more pronounced in patients with a confirmed PR or prolonged SD. PRS-343 was very well tolerated, with no SAEs reported. The most frequent TRAEs were fatigue (9%), chills (6%) and diarrhea (5%) of mild to moderate severity. None qualified as a DLT.ConclusionsPRS-343 is the first molecule of its kind to demonstrate encouraging evidence of safety and clinical benefit with a correlative PD effect in a heavily pre-treated population. These initial data suggest that PRS-343, the first 4-1BB bispecific to enter clinical development, merits further investigation in clinical trials.Trial RegistrationNCT03330561

801 PRIME™ IL-15 (RPTR-147): Preliminary clinical results and biomarker analysis from a first-in-human Phase 1 study of IL-15 loaded peripherally-derived autologous T cell therapy in solid tumor patients

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A850-A850
Author(s):  
Erika Hamilton ◽  
Sarah Nikiforow ◽  
Philip Bardwell ◽  
Christine McInnis ◽  
Jeffrey Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Metastatic Disease ◽  
Cd8 T Cells ◽  
Dose Escalation ◽  
Phase 1 ◽  
T Cell Clones ◽  
Cell Product ◽  
Cell Clones ◽  
Biomarker Analysis

BackgroundRPTR-147 is a novel autologous non-genetically modified multi-clonal T cell product loaded with an IL15-Fc nanogel. The product was derived from rare peripherally-derived anti-tumor T cell clones that were primed against a multi-antigen cassette containing tumor associated antigens (TAA), known to be over-expressed in specific tumor types. We describe preliminary results from the ongoing first-in-human Phase 1 trial.MethodsAutologous anti-TAA T cells are generated with a proprietary dendritic cell priming process and then loaded with an IL15-Fc nanogel. TAAs used in cassette: PRAME, NY-ESO-1, SSX2, Survivin and WT1. Thawed RPTR-147 is delivered by infusion. Pre- and post-treatment biopsies were collected for biomarker analysis by immunohistochemistry (IHC) and transcriptome sequencing. Serial blood collections were obtained for measuring IL-15 pharmacokinetics and pharmacodynamic parameters including plasma cytokine levels and immunophenotyping by flow cytometry. T cell receptor sequencing (TCRSeq) was used to characterize the T cell repertoire from manufactured T cell product and the patient‘s blood.ResultsInterim clinical and biomarker data from 17 patients with advanced metastatic disease refractory to SOC who received monthly infusions of 20-360 million cells/m², were reviewed (table 1). There were no dose-limiting toxicities and no evidence of cytokine-release syndrome. The 360M/m² dose contained 3X more IL15-Fc than the MTD of systemically administered IL15-Fc,1 but produced less than a tenth of the systemic exposure to free IL15-Fc. Currently, 360M cells/m² is considered safe and well-tolerated. Further dose escalation is planned.Matched evaluable biopsies were obtained in 7 patients. Tumor-infiltrating T cell lymphocytes was observed in 5 cases for CD8 T cells and 4 cases for CD4 T cells. A dose dependent increase in both inflammatory cytokines and NK & CD8+ T cells was observed, consistent with expected MOA and PK. TCRSeq analysis demonstrated that product specific T cell clones could be tracked in both patient‘s blood and tumor over time. Further analysis to decode the specificity of those cells and demonstrate that tumor antigen specific T cells can be found in patient‘s blood and tumor biopsies is ongoing.Of the 17 patients who received RPTR-147 infusions 10 were noted to have stable disease (SD) and in 4 patients SD lasted > 6 months.Abstract 801 Table 1Summary of PatientsTumor types for the 17 patients with advanced metastatic disease included in this clinical trial (NCT0381568)ConclusionsInterim results with RPTR-147 have shown it to be well-tolerated and have a favorable safety profile. Dose-escalation is proceeding. Ongoing biomarker analysis will inform future clinical strategies in matching patients to an optimized PRIME IL-15 T cell product.Trial RegistrationNCT03815682Ethics ApprovalThe study was approved by local institutional IRBs after acceptance of the IND by the FDA.ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.ReferenceRomee R, Cooley S, Berrien-Elliott MM, et al. First-in-human phase 1 clinical study of the IL-15 superagonist complex ALT-803 to treat relapse after transplantation. Blood 2018;131(23):2515-2527.

scholarly journals Large-Scale Mass Cytometry Reveals Significant Activation of Innate and Adaptive Immunity in Bone Marrow Tumor Microenvironment of Iberdomide-Treated Myeloma Patients

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 730-730
Author(s):  
Oliver Van Oekelen ◽  
Michael Amatangelo ◽  
Manman Guo ◽  
Bhaskar Upadhyaya ◽  
Geoffrey Kelly ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Nk Cells ◽  
Cd8 T Cells ◽  
Dose Escalation ◽  
Research Funding ◽  
Large Scale ◽  
Post Treatment ◽  
Publicly Traded ◽  
Heavily Pretreated

Abstract Background: Iberdomide (IBER) is a potent cereblon E3 ligase modulator (CELMoD agent) with direct anti-tumor and immunomodulatory activities in multiple myeloma (MM). An ongoing phase 1b/2a multicenter, open-label, dose-escalation study has reported favorable efficacy and safety of IBER plus low-dose dexamethasone (DEX) in heavily pretreated patients with relapsed/refractory MM (RRMM). While previous studies focused on IMiD/CELMoD agent immune effects in peripheral blood (Amatangelo, ASH 2019), a large-scale characterization of pharmacodynamics in the bone marrow (BM) tumor microenvironment (TME) has not been reported. Here, we present data on BM aspirates (BMAs) of 99 individuals pre-/post-treatment with IBER in the largest study of TME immune dynamics of RRMM patients to date. Methods: A mass cytometry (CyTOF) panel was designed/validated to capture deep and comprehensive immunophenotyping of T, B, and NK cell subpopulations. In all, staining with 37 metal-tagged Abs characterized 110 supervised cell phenotypes. Paired longitudinal assessment was conducted for viably preserved BMAs of IBER±DEX treated patients in dose-escalation of the CC220-MM-001 Ph 1b/2a study pre (SCREEN) and post treatment (cycle 2 day 15, C2D15). For a subset of patients (n=12), samples were available at disease progression (PD) . A training set analysis (n=64, data reported here) collected in North America, was validated against an independent test set (n=35) recruited in Europe. An R-based computational workflow and manual hierarchical gating identified subpopulations of B, T, NK and myeloid cells. In total, more than 5M immune cells were captured (approx. 40K per specimen). Cell populations are expressed as percentage of non-tumor bone marrow mononuclear cells (BMMC, i.e. CD45+CD66b-). P values are by Mann-Whitney U test for unpaired and Wilcoxon test for paired analyses. Results: IBER treatment resulted in profound immune shifts in the TME. B cells decreased (median SCREEN 3.3% vs C2D15 0.7%, p=0.001), with significant reduction of naïve (p=0.001) and regulatory B cells (p&lt;0.001). Decrease occurred in CD4+ T cells (median 15.3% vs 8.9%, p&lt;0.001), whereas CD8+ T cells increased (median 14.9% vs 17.4%). T cell subtypes showed a shift towards cytotoxic effector-memory phenotype (CCR7-CD45RA) (median 67.6% vs 80.9% of CD4+ T cells, p&lt;0.001 and median 78.2% vs 89.2% of CD8+ T cells, p&lt;0.001) with concurrent reduction of naive (CD45RA+CCR7+), central-memory (CD45RA-CCR7+) and EMRA (CD45RA+CCR7-) T cells. The shift towards a cytotoxic TME is confirmed by significant increases of GZMB+, HLA-DR+, ICOS+, Ki-67+, CXCR3+ and CD38+ activated CD8+ T cells (p≤0.001, paired). Conversely, CD8+ T cells expressing inhibitory checkpoints TIGIT and KLRG1 decreased significantly (p≤0.001, paired). Similar changes (with minor deviations) were noted in the CD4+ T cell compartment. NK cells increased (median 4.2% vs 8.7%, p=0.003), with increase of both CD56hi cytokine-producing (median 1.9% vs 4.5%, p&lt;0.001) and CD16+ cytolytic (median 1.8% vs 2.6%, p=0.06) subsets. NKG2A+ and NKG2D+ subsets were increased (p&lt;0.001, paired), as well as subsets expressing markers of activation: GZMB, ICOS, CD38 and PD-1 (p&lt;0.05, paired). TIGIT+ NK cells decreased significantly. NKT cells were also significantly increased (median 1.4% vs 2.2%, p&lt;0.001). Increase of NK and NKT cells expressing the activating receptor NKG2D was limited to patients achieving best response of PR or better. Additional analyses correlating immune phenotypes at baseline/post-treatment with outcomes are ongoing and will be reported at the meeting, as will data on how prior treatment (e.g. with CD38-mAb) shapes the TME at baseline and affects response. Conclusion: Our analysis on a large cohort of RRMM patients provides unique insights into the heterogeneity of the immune TME of heavily pretreated MM patients and how it changes upon treatment with IBER±DEX. We found significant increases of effector T and NK cells in paired analysis, demonstrating innate and adaptive immune enhancement in the MM bone marrow niche as an important mechanism of action. Importantly, these changes were observed throughout dose escalation and in patients previously refractory to lenalidomide/pomalidomide. The presented platform of large-scale immune profiling demonstrates a strategy to design and study rational combinations with (other) immune-enhancing therapies in MM. Figure 1 Figure 1. Disclosures Amatangelo: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Gooding: Bristol Myers Squibb: Research Funding. Jagannath: Legend Biotech: Consultancy; Bristol Myers Squibb: Consultancy; Karyopharm Therapeutics: Consultancy; Janssen Pharmaceuticals: Consultancy; Takeda: Consultancy; Sanofi: Consultancy. Pierceall: BMS: Current Employment, Current equity holder in publicly-traded company. Parekh: Foundation Medicine Inc: Consultancy; Amgen: Research Funding; PFIZER: Research Funding; CELGENE: Research Funding; Karyopharm Inv: Research Funding. Thakurta: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company.

scholarly journals 'First-in-human' phase I dose escalation trial of IL-15N72D/IL-15Rα-Fc superagonist complex (ALT-803) demonstrates immune activation with anti-tumor activity in patients with relapsed hematological malignancy

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1957-1957 ◽  
Author(s):  
Jeffrey S. Miller ◽  
Sarah Cooley ◽  
Shernan Holtan ◽  
Mukta Arora ◽  
Celalettin Ustun ◽  
...  
Keyword(s):  
T Cells ◽  
Phase I ◽  
Nk Cells ◽  
Cd8 T Cells ◽  
Dose Escalation ◽  
Allogeneic Transplantation ◽  
Donor Chimerism ◽  
Grade Ii ◽  
Anti Tumor Activity ◽  
Dose Dependent

Abstract Disease-free survival after allogeneic transplantation for hematological malignancies may be enhanced with post-transplant immunotherapy. IL-15 is a homeostatic cytokine that stimulates both NK cells and CD8+ T cells, but unlike IL-2 it does not stimulate suppressive regulatory T cells. Physiologic IL-15 signaling occurs after trans-presentation with IL-15Rα to IL-15Rβ and IL15Rγ (common chains shared with the IL-2R). ALT-803 (Altor BioSciences) is an IL-15/IL-15Rα-Fc superagonist complex, which includes an activation mutation in IL-15 (N72D), a sushi domain to increase transpresentation, and an IgG1 Fc domain to increase serum half-life and stability. In preclinical mouse models, ALT-803 exhibits potent anti-tumor activity. We therefore performed a 'first-in-human' phase I open label dose escalation trial of ALT-803 in patients with relapsed hematologic malignancy after allogeneic hematopoietic cell transplantation (> 60 days) with no active GVHD and having >10% residual donor chimerism. Sixteen patients (AML, n=10; MDS, n=2; myeloma, n=2; ALL, n=1; NHL, n=1) received escalating doses of intravenous ALT-803 given weekly x 4 doses in 4 cohorts of 1 (n=6), 3 (n=3), 6 (n=4), and 10 (n=3) mcg/kg. Cohort 1 was expanded because of atrial fibrillation (grade 2 toxicity) in an AML subject with a prior history. One unevaluable subject in Cohort 3 who did not receive the minimum 3 doses of ALT-803 was replaced. There was highly reproducible and dose-dependent constitutional symptoms, consistent with immune activation (fevers and tachycardia) that peaked at 5-6 hours after each dose despite pre-medication with acetaminophen & diphenhydramine. Fever ≥103 degrees F was observed in cohorts 3 and 4 in patients receiving 6 and 10 mcg/kg, respectively, but was self-limited with resolution within 12 hours. These side effects correlated with ALT-803 dose-dependent increases in serum IFNγ and IL-6 levels 4 hours after dosing. Grade 2 hypotension (asymptomatic) occurred and responded to saline infusions, resulting in saline bolus prophylaxis in later patients. No patients experienced systemic capillary leak syndrome. Oxygen saturations were normal at all time points except in one patient (6 mcg dose) with an isolated 02 saturation of 88% and 89% five hours after doses 2 and 3, respectively. No dose limiting toxicities were observed. Dose dependent increases in CD8+ T cell and NK proliferation (Ki-67+) were observed at 3 and 5 days after the first dose of ALT-803 (Figure, top) with a slight increase in Ki67+ Treg and CD4+ T cells, but less than NK cells and CD8+ T cells. NK proliferation remained above pre-treatment baseline for 7 days in the 10 mcg/kg cohort, resulting in a sustained increased in absolute NK cells for 28 days (Figure, bottom). Functional studies at the 10 mcg/kg dose showed an increased frequency of NK cells that degranulated against K562 targets and produced IFNγ after IL-12/IL-18 stimulation. Clinical responses occurred in 2 patients with stable disease 1 month after the last dose of ALT-803 and one complete response. This 69 y/o man had recurrent RAEBT (9% blasts) with complex cytogenetics (monosomy 7 with cytogenetic evolution in 5/20 metaphases), relapsing after prior second unrelated donor transplant with 46% donor chimerism at the time of treatment. After 4 doses of ALT-803 at 6 mcg/kg without DLT, he developed a biopsy proven cutaneous grade II GVHD that resolved with topical steroids alone. His follow-up bone marrow biopsy revealed 3% blasts, normal karyotype, 93% donor chimerism with normalization of blood counts (Hgb from 9.6 to 12.5, platelets from 61K to 168K, WBC from 1.7 to 4.2 and ANC from 400 to 1400 from pre-therapy to one month post-therapy). An additional patient had grade II skin GVHD with disease response measures pending. This phase I trial demonstrates that ALT-803 safely induces proliferation of functional NK cell and CD8+ T cells with in vivo cytoxicity. Recent pre-clinical data suggest that subcutaneous dosing of ALT-803 can decrease peak serum concentrations, increase half-life and preferentially distributes to lymphoid tissues potentially optimizing drug delivery. The ongoing trial now utilizes subcutaneous dosing at 6 mcg/kg followed by dose escalation. IL-15N72D /IL-15Rα-Fc superagonist complex is a promising new therapeutic strategy for the treatment of relapse, a major obstacle after allogeneic transplantation for high risk hematologic malignancies. Figure 1. Figure 1. Disclosures Miller: Coronado: Speakers Bureau; BioSciences: Speakers Bureau; Celegene: Speakers Bureau. Jeng:Altor BioScience Corporatoin: Employment. Wong:Altor BioScience Corporation: Employment, Other: stockholder of Altor Bioscience Corporation.

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