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.

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.

A Phase I Study Of An Anti-CD30 x Anti-CD16A Bispecific Tandab Antibody, AFM13, In Patients With Relapsed Or Refractory Hodgkin Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5116-5116 ◽  
Author(s):  
Eugene Zhukovsky ◽  
Achim Rothe ◽  
Bastian von Tresckow ◽  
Max Topp ◽  
Anas Younes ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Nk Cells ◽  
Stable Disease ◽  
Fdg Pet ◽  
Tumor Volume ◽  
Brentuximab Vedotin ◽  
Soluble Cd30 ◽  
Anti Tumor Activity ◽  
Dose Dependent

Abstract Background AFM13 is a bispecific TandAb antibody for the treatment of Hodgkin lymphoma (HL) and other CD30+ malignancies. AFM13 specifically targets both CD30, which is the antigen identifying HL tumor cells, and CD16A, for the recruitment of NK cells. Our preclinical data demonstrate a specific and potent anti-tumor activity mediated by the engagement of NK immune effector cells. Methods AFM13 was investigated in an open-label single-arm phase I dose escalation trial in patients with relapsed/refractory HL. The objective of this study was to evaluate the safety, tolerability, pharmacokinetics, immunogenicity, anti-tumor activity, and maximum tolerated dose (MTD). Each patient received 4 weekly doses of AFM13. Seven dose levels, from 0.01 to 7.0 mg/kg, were escalated in cohorts of 3 patients. In addition, one cohort of 4 patients received AFM13 twice a week at 4.5 mg/kg for 4 weeks. Results Twenty-eight (28) HL patients were enrolled, and these heavily pre-treated patients had a median number of six (6) prior therapies. 14/28 patients were refractory to their most recent therapy. 9/28 patients had a prior therapy with brentuximab vedotin. AFM13 was safe and well-tolerated, and did not reach the MTD. One dose-limiting toxicity (DLT) was observed at 0.5 mg/kg, and this dose cohort was expanded to 6 patients. No further DLTs were observed. The most frequent adverse events were infusion-related reactions (headache, fever, fatigue and myalgia) that often occurred after the first administration. Nearly all adverse events were short-lived. According to the Cheson criteria, 2 patients achieved partial responses and 13 patients achieved stable disease. In addition, AFM13 was active in brentuximab vedotin relapsing/refractory patients, with 7 out of 9 patients achieving stable disease after AFM13 treatment. The responses of the 13 patients who received AFM13 at and above the 1.5 mg/kg dose level were further analyzed for pharmacodynamic/anti-tumor activity correlations. In this group the drug exhibited substantial anti-tumor activity, with 8 out of the 13 patients experiencing a reduction in both tumor volume (as assessed by CT scan) and tumor activity (as assessed by FDG-PET scan imaging). Furthermore, 3 out of the 13 patients (23%) exhibited a reduction in tumor volume of more than 50%. The on-mechanism activity of the drug was further substantiated by the NK cell activation and soluble CD30 clearance pharmacodynamic parameters. Statistically significant correlations between increasing anti-tumor activity parameters (i.e. tumor volume reduction and FDG-PET SUV reduction) and the pharmacodynamic biomarkers were observed as: i) a dose-dependent increase in the activation of NK cells, and ii) a dose-dependent reduction in soluble CD30 levels. Variations in SUV were correlated with the number of activated NK cells (i.e. CD69+ cells) at baseline and 24 hours after the start of therapy with AFM13. The number of activated NK cells peaked 12 hrs after dosing, and dropped after 48 hrs. A decrease in SUV was observed at the highest level of activated NK cells, and was accompanied by a concomitant reduction in soluble CD30 levels. Furthermore, AFM13 exhibited a half-life of 1 day, representing a substantial increase relative to that of the alternative bispecific tandem scFv that is currently in clinical evaluation for hematological malignancies. Conclusions AFM13 has demonstrated good safety and encouraging anti-tumor activity. Furthermore, there is a solid scientific rationale suggesting that during phase I the anti-tumor potential of AFM13 was not fully realized. A compelling hypothesis for further exploration is whether we may detect much stronger activity, in refractory/relapsing HL patients, in a phase II study employing a pK-optimized regimen with an extended duration of therapy. Disclosures: Zhukovsky: Affimed Therapeutics AG: Employment, Equity Ownership. von Tresckow:Novartis: honoraria for acting as a consultant: Consultancy; Takeda Pharma GmbH: reimbursement of congress, travel, and accommodation costs and honoraria for preparation of scientific educational events: Honoraria. Topp:Affimed Therapeutics AG: Consultancy. Ravic:Affimed Therapeutics AG: Consultancy. Hucke:Affimed Therapeutics AG: Consultancy. Engert:Affimed Therapeutics AG: Consultancy.

New Insights into the Mechanism of Action (MoA) of First-in-Class IgG-Based Bcma T-Cell Bispecific Antibody (TCB) for the Treatment of Multiple Myeloma (MM)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2096-2096 ◽  
Author(s):  
Laura Moreno ◽  
Aintzane Zabaleta ◽  
Diego Alignani ◽  
Marta Lasa ◽  
Patricia Maiso ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Research Funding ◽  
Cell Activation ◽  
Rational Combination ◽  
Dose Dependent ◽  
Tumor Cell Lysis

Abstract Novel agents have improved outcomes in MM, but prognosis after patients relapse remains poor and new drugs with novel MoA are needed. The breakthrough of immuno-oncology has rendered new therapeutic options, and most recently we reported on EM801, a novel BCMA-TCB that showed remarkably efficacy when used as single agent in primary bone marrow (BM) samples from MM patients (Seckinger, Blood 2015;126: abstr 117). Because of its novelty, further knowledge about the MoA of BCMA-TCB is of utmost importance to improve its efficacy by designing rational treatment combinations. In order to optimize the in vitro efficacy of the BCMA-TCB, we started by investigating in primary BM samples from 6 MM patients whether longer treatment periods with BCMA-TCB2 (a BCMA-TCB candidate sharing similar "2+1" structure of EM801 but displaying higher affinity to BCMA) would increase MM cell death. Upon treating samples with BCMA-TCB2 for 48h vs 96h, we noted a 2-fold increment in MM tumor cell lysis at 1nM and 10nM concentrations (Panel A). In parallel, the phenotypic profiles of CD4 and CD8 T cells showed that BCMA-TCB2 induced robust activation (ie. dose-dependent increment in CD69, CD25, HLADR after exposure to 100pM, 1nM and 10nM of BCMA-TCB2), but also led to the natural emergence of the checkpoint inhibitor PD-1 in the surface of activated CD4 and CD8 T cells (Panel B). We then investigated if there was a correlation between the percentage of PD-1 positive CD4 and CD8 T cells and the efficacy of BCMA-TCB2; interestingly, those patients with lower frequencies of PD-1 positive CD4 and CD8 T cells prior to treatment showed the highest rates of MM tumor cell lysis after 48h and 96h of BCMA-TCB2 at 10nM of (r=0.6, P=0.04; Panel C). By contrast, upon measuring the concentration of soluble BCMA and APRIL in the supernatants of primary BM samples from 16 MM patients treated with BCMA-TCB, we found no significant differences between responding (n=11) and non-responding (n=5) patients. Similar results were observed upon comparing the density of BCMA in the surface of MM tumor cells from responding vs non-responding patients (1256 vs 1522 SABC units; P=87). Since the efficacy of BCMA-TCB2 was found to be intrinsically related to the phenotype and activation status of T cells, we then investigated whether we could further harness immune cells by combining BCMA-TCB2 with three drugs representing different types of immunotherapy: lenalidomide (IMIDs), anti-PD1 (checkpoint inhibitors) and daratumumab (mAb). H929 MM cells were co-cultured with human leukocytes (n=5) and challenged to suboptimal concentrations of BCMA-TCB2 (10pM) alone, or in combination with standard doses of lenalidomide (1µM), anti-PD1 (10µg/ml) and daratumumab (10µg/ml) (Panel D). Interestingly, we observed that combining BCMA-TCB2 with lenalidomide or daratumumab significantly increased their anti-MM efficacy by 4-fold and 2.5-fold, respectively. Because lenalidomide and daratumumab share in common that they rely, at least in part, on activated NK cells to eradicate MM cells, we hypothesized whether such robust T cell activation induced by BCMA-TCB2 was leading to co-stimulation of NK cells. First, we demonstrated by analyzing the transcriptomes of T cells prior and after treatment exposure (n=3), that BCMA-TCB2 modulated the transcriptomes of CD4 and CD8 T cells (159 and 141 deregulated genes, respectively), consistent with enhanced activation and T-cell mediated inflammatory response (eg. TNFRS18, STAT1, CCL4). Furthermore, we observed a dose-dependent and significant increment of the CD69 (2-fold), CD25 (2.5-fold) and HLADR (4-fold) activation markers in the surface of NK cells from primary BM samples of 11 MM patients treated with BCMA-TCB2 (Panel E), suggesting a functional crosstalk between activated T cells and NK cells. In conclusion, we showed that the promising pre-clinical activity of the first-in-class IgG-based BCMA-TCB can be further enhanced by longer treatment periods followed by robust T cell activation. The observation that the efficacy of BCMA-TCB is intrinsically related to the activation status of T cells suggests its rational combination with IMIDs as demonstrated here. Most interestingly, potential crosstalk between activated T and NK cells could lead to enhanced function of the later immune subset, and provide a rational combination between BCMA-TCB and anti-CD38 antibodies to eradicate MM cells through highly activated T and NK cells. Figure Figure. Disclosures Strein: EngMab: Employment. Vu:EngMab: Employment. Paiva:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Takeda: Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; EngMab: Research Funding; Amgen: Honoraria; Binding Site: Research Funding.

scholarly journals Pharmacokinetic and Pharmacodynamic Study of NKTR-255, a Polymer-Conjugated Human IL-15, in Cynomolgus Monkey

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2952-2952
Author(s):  
Takahiro Miyazaki ◽  
Peiwen Kuo ◽  
Mekhala Maiti ◽  
Palakshi Obalapur ◽  
Murali Addepalli ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
Nk Cells ◽  
Cd8 T Cells ◽  
Cynomolgus Monkey ◽  
Memory T Cells ◽  
Granzyme B ◽  
Employment Equity ◽  
Equity Ownership ◽  
Dose Dependent

Abstract Introduction IL-15 is a common gamma chain cytokine that activates and provides a survival benefit to T-cells and NK cells and has long been recognized as having potential as an immunotherapeutic agent for the treatment of cancer. Therapeutic use of native IL-15 has been challenging due to, for example, its unfavorable pharmacokinetic and safety properties. NKTR-255 is a polymer-conjugated human IL-15 that retains binding affinity to the alpha subunit of IL-15 receptor and exhibits reduced clearance to thereby provide a sustained pharmacodynamics response. Here we investigate the biological effects of NKTR-255 in naïve cynomolgus monkey. Methods In vitro monkey whole blood was treated with NKTR255 and the percentage of pSTAT5 positive populations in each NK, CD4 T and CD8 T cells was determined by flow cytometry. In an PK/PD study, monkeys received single IV doses of 0.001, 0.003, 0.01, 0.03, or 0.1 mg/kg NKTR-255. Blood samples were collected to determine the plasma concentrations of NKTR-255 and to assess the effects of NKTR-255 on NK and CD8 T cells at multiple time points; flow cytometry was used to measure STAT5 phosphorylation, Ki-67 expression and frequency of cell populations. Granzyme B expression was assessed in NK and CD8 T cells by flow cytometry. Results NKTR-255 induced dose-dependent phosphorylation of STAT5 in monkey whole blood (EC50 values NK cells: 6.9 ng/ml, CD8 T cells: 39 ng/ml, CD4 T cells: 53 ng/ml). The half-life and clearance of NKTR-255 were 26x longer and 38x lower, respectively, than IL-15. NKTR-255 engaged the IL-15 signaling pathway, in vivo, demonstrating both robust and sustained STAT5 phosphorylation in lymphocytes. NKTR-255 drove the proliferation of total CD8 T cells and NK cells in a dose-dependent manner, with dramatic and durable increases observed in Ki67 positive population and absolute cell numbers (NK cells: 6.1 fold; CD8 T cells: 7.8 fold from baseline on day 5 at 0.1 mg/kg). These effects were strongly biased towards CD8 T cells and NK cells, with substantially less induction of CD4 T cells. The Ki67 response analyses of the T cell subpopulation revealed a higher response of memory populations than for naive T cells. Among memory T cells, effector memory T cells showed the highest response over stem cell memory T cells and central memory T cells. Finally, NKTR-255 also increased the expression of Granzyme B in both NK and CD8 T cells, concomitant with an enhancement in target cell lysis. Conclusions Nektar has generated a novel and potent molecule in NKTR-255 that not only preserves the relevant biology of IL-15, but additionally provides enhanced PK and PD properties relative to the native IL-15 cytokine. NKTR-255 is being developed as an immune-stimulatory agent to target NK and CD8 T cell biology for the treatment of cancer. Disclosures Miyazaki: Nektar Therapeutics: Employment, Equity Ownership. Kuo:Nektar Therapeutics: Employment, Equity Ownership. Maiti:Nektar Therapeutics: Employment, Equity Ownership. Obalapur:Nektar Therapeutics: Employment, Equity Ownership. Addepalli:Nektar Therapeutics: Employment, Equity Ownership. Rubas:Nektar Therapeutics: Employment, Equity Ownership. Sims:Nektar Therapeutics: Employment, Equity Ownership. Zhang:Nektar Therapeutics: Employment, Equity Ownership. Madakamutil:Nektar Therapeutics: Employment, Equity Ownership. Zalevsky:Nektar Therapeutics: Employment, Equity Ownership.

scholarly journals A Phase I/II Dose-Escalation Multi-Center Study to Evaluate the Safety of Infusion of Natural Killer Cells or Memory T Cells As Adoptive Therapy in Coronavirus Pneumonia and/or Lymphopenia: (RELEASE NCT04578210)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1765-1765
Author(s):  
Antonio Pérez-Martínez ◽  
Alejandro Martín-Quirós ◽  
Cristina Ferreras ◽  
Karima Al-Akioui ◽  
Marta Mora-Rillo ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Adverse Events ◽  
Phase I ◽  
Nk Cells ◽  
Dose Escalation ◽  
Memory T Cells ◽  
Preliminary Evidence ◽  
Specific Memory

Abstract Background: Adoptive cell immunotherapies for opportunistic virus in immunocompromised patients using haploidentical memory T cells have shown to be safe and effective. Since severe cases of COVID-19 present a dysregulated immune system with T cell lymphopenia and a hyper-inflammatory state we have proposed that a similar strategy could be proven to be efficient for COVID-19 patients. This is a study protocol of an open-label, multicenter, double-arm, randomized, dose-finding phase I/II clinical trial to evaluate the feasibility, safety, tolerability, and efficacy of the administration of a single dose of allogenic SARS-CoV-2 specific memory CD45RA - T cells and Natural Killer (NK) cells in COVID-19 patients with lymphopenia and pneumonia. The aim of the study is to find efficient treatments for patients with moderate/severe COVID-19. Identification of Specific memory T cells and NK cells: i)Memory T Cells: we first determined the existence of SARS-CoV-2 specific T cells within the CD45RA - T memory cells of the blood of convalescent donors. Memory T cells can respond quickly to the infection and provide long-term immune protection to reduce the severity of the COVID-19 symptoms without inducing classically T cell alloreactivity. Also, CD45RA - memory T cells confer protection for other pathogens the donors encountered in their life. ii)NK cells: we determined the phenotype of NK cells after COVID-19 and the main characteristic of SARS-CoV-2 specific NK population in the blood of convalescent donors, as it has been shown for cytomegalovirus infections. Also, NK cells confer protection for other pathogens the donors encountered in their life. Pilot Phase I- Safety, feasibility, and dose escalation: Between September and November 2020 a phase 1, dose-escalation, single-center clinical trial was conducted to evaluate the safety and feasibility of the infusion of CD45RA - memory T cells containing SARS-CoV-2 specific T cells as adoptive cell therapy against moderate/severe cases of COVID-19. Nine participants with pneumonia and/or lymphopenia and with at least one human leukocyte antigen (HLA) match with the donor were infused. The first three subjects received the lowest dose (1x10 5 cells/kg), the next three received the intermediate dose (5x10 5 cells/kg) and the last three received the highest dose (1x10 6 cells/kg) of CD45RA - memory T cells. Clinicaltrials.gov registration: NCT04578210. Findings: All participants' clinical status measured by National Early Warning Score (NEWS) and 7-category point ordinal scales showed improvement six days after infusion. No serious adverse events were reported. Inflammatory parameters were stabilized post-infusion and the participants showed lymphocyte recovery two weeks after the procedure. Donor microchimerism was observed at least for three weeks after infusion in all patients. Interpretation: This study provides preliminary evidence supporting the idea that treatment of COVID-19 patients with moderate/severe symptoms using convalescent SARS-CoV-2 specific CD45RA - memory T cells is feasible and safe. We did not find dose-liming toxicity. The Recommended Phase 2 dose was 1x10 6 CD45RA - T cells. Phase II- Efficacy: Between January 2021 and July 2021 patients have been enrolled based on the matched with the HLA genotype of the convalescent donors and following the protocol inclusion/exclusion criteria. The primary outcome is the incidence of patient recovery at day 14, defined as normalization of fever and oxygen saturation or lymphopenia recovery. Secondary outcomes are the time to normal level of lymphocytes, the proportion of patients showing clinical improvement at day 7, time to first negative SARS-CoV-2 PCR, the incidence of treatment-related adverse events, duration of hospitalization, time to discharge, time to improvement by one category a 7-point ordinal scale or NEWS score, the proportion of patients requiring intensive care unit, and all-cause mortality. In addition, lymphocyte recovery by multiparametric flow cytometry and donor chimerism by real-time PCR in the experimental arm was monitored weekly during the first month. This study provides preliminary evidence supporting the idea that treatment of COVID-19 patients with moderate/severe symptoms using convalescent CD45RA - memory T cells is safe and feasible. The phase II clinical trial is ongoing to demonstrate efficacy. Figure 1 Figure 1. Disclosures Soria: Celgene: Other: Fees; Gilead: Other: Fees; AbbVie: Other: Fees.

A phase I/II study of REGN5678 (Anti-PSMAxCD28, a costimulatory bispecific antibody) with cemiplimab (anti–PD-1) in patients with metastatic castration-resistant prostate cancer.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. TPS174-TPS174
Author(s):  
Jingsong Zhang ◽  
Mark N. Stein ◽  
William Kevin Kelly ◽  
Che-Kai Tsao ◽  
Gerald Steven Falchook ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
T Cell ◽  
Phase I ◽  
Dose Escalation ◽  
Prostate Specific Membrane Antigen ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Anti Tumor Activity ◽  
Specific Membrane

TPS174 Background: Bispecific antibodies (bsAbs) are emerging as a protein-based therapeutic strategy for directing T-cell-mediated cytotoxicity in a tumor antigen-specific manner, typically by binding to both tumor antigen and the CD3 receptor on T-cells. REGN5678 is a human IgG4-based, first-in-class costimulatory bsAb designed to target prostate tumors by bridging prostate specific membrane antigen expressing tumor cells with the costimulatory receptor, CD28, on T-cells, and providing amplified T-cell receptor-CD3 complex-mediated T-cell activation within the tumor through the activation of CD28 signaling. At the tumor site, REGN5678 may synergize with PD-1 inhibitors. In mouse models, REGN5678 in combination with a PD-1 antibody has improved anti-tumor activity compared with either therapy alone (Waite JC et al. Sci Transl Med. 2020:12;549). Methods: This is an open label, Phase I/II, first-in-human study evaluating safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of REGN5678 alone and in combination with cemiplimab in patients with metastatic castration resistant prostate cancer (mCRPC) who progressed after prior therapy (NCT03972657). For inclusion, patients must have received at least two prior lines of systemic therapy (in addition to androgen deprivation therapy) approved for metastatic and/or castration-resistant disease including a second-generation anti-androgen therapy. REGN5678 is administered weekly; cemiplimab (350 mg) is administered once every 3 weeks. During dose escalation, a 3-week safety lead-in of REGN5678 monotherapy will be administered prior to addition of cemiplimab. Study therapies are administered until disease progression, intolerable adverse events, withdrawal of consent, or study withdrawal criterion is met. The primary objectives in dose escalation are to evaluate safety, tolerability, and PK of REGN5678 alone and in combination with cemiplimab. Expansion cohort(s) will be enrolled once a maximum-tolerated REGN5678/cemiplimab dose is reached, or if a recommended Phase 2 dose or doses have been determined. During the expansion phase, the primary objective is to assess clinical activity, as measured by objective response rate of REGN5678 in combination with cemiplimab per modified Prostate Cancer Working Group 3 criteria. At selected sites, prostate-specific membrane antigen PET/CT scans are performed at baseline and select time points on study. This study is currently open to enrollment. Clinical trial information: NCT03972657.

Immune activation in first-in-human anti-macrophage antibody (anti-Clever-1 mAb; FP-1305) phase I/II MATINS trial: Part I dose-escalation, safety, and efficacy results.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3097-3097 ◽  
Author(s):  
Petri Bono ◽  
Reetta Virtakoivu ◽  
Felix Vaura ◽  
Panu Jaakkola ◽  
Shishir Shetty ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Phase I ◽  
Dose Escalation ◽  
Colorectal Cancer Patient ◽  
Scavenger Receptor ◽  
Optimal Dose ◽  
Ductal Adenocarcinoma ◽  
Heavily Pretreated ◽  
Anti Tumor Activity

3097 Background: The scavenger receptor CLEVER-1 mediates the clearance of “unwanted” self-components and is highly expressed on tumor associated macrophages (TAMs). CLEVER-1 expression is associated with immunotherapy resistance and poor survival in several cancers. Pre-clinical studies demonstrate that CLEVER-1 inhibition increases TAM pro-inflammatory cytokine secretion and antigen presentation reactivating CD8 T cell responses with robust anti-tumor activity. Targeting CLEVER-1 could therefore overcome the immunosuppressive tumor microenvironment and has led to the development of FP-1305, a humanized anti-CLEVER-1 IgG4-antibody. Methods: The MATINS (Macrophage Antibody To INhibit immune Suppression) trial is a multicenter first-in-human phase I/II study (NCT03733990) to assess the tolerability, safety and preliminary efficacy of FP-1305 in patients (pts) with advanced cancers including immunotherapy-refractory melanoma, cholangiocarcinoma, hepatocellular carcinoma, ovarian cancer, colorectal (CRC), and pancreatic ductal adenocarcinoma. Part 1 consisted of a dose escalation phase; 30 pts (median age 65, range 30-81) were enrolled to examine 5 dose levels (0.1, 0.3, 1.0, 3.0, 10 mg/kg), to determine the optimal dose of FP-1305 for Parts 2 and 3. Two-stage time-to-event continual reassessment method (TITE-CRM) was utilized for the dose escalation in Part 1. Pts received 1-8 cycles (median 3) of FP-1305 Q3w. FP-1305 was well tolerated without dose-limiting toxicities. A consistent increase in blood NK cells, CD8/CD4 T cell ratio, B cells and a decrease in regulatory T cells was demonstrated. FP-1305 dosing led to the activation (CD25+) and Th1 skewing (CXCR3+) of T cell populations including increase in effector CD8 T-cells with downregulation of several inhibitory immune checkpoint molecules (PD-1, PD-L1, CTLA-4, and LAG3). Increased circulating IFNɣ levels were detected, with the highest levels in a heavily pretreated metastatic, microsatellite stable (MSS) colorectal cancer patient leading to a partial tumor response (-52%). FP-1305 is the first macrophage checkpoint inhibitor candidate promoting immune switch with promising tolerability and clinical anti-tumor activity. FP-1305 represents a novel treatment option to provoke immune response especially in non-inflamed tumors. Full safety, pharmacokinetic and efficacy results of MATINS trial (Part 1) will be presented for the first time in a final late breaking abstract. Clinical trial information: 2018-002732-24 .

A phase I/II study of REGN5678 (Anti-PSMAxCD28, a costimulatory bispecific antibody) with cemiplimab (anti-PD-1) in patients with metastatic castration-resistant prostate cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS5592-TPS5592
Author(s):  
Charles G. Drake ◽  
Jingsong Zhang ◽  
Mark N. Stein ◽  
Yuanfang Xu ◽  
Frank A. Seebach ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
T Cell ◽  
Phase I ◽  
Dose Escalation ◽  
Tumor Antigen ◽  
Objective Response ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Anti Tumor Activity

TPS5592 Background: Bispecific antibodies (bsAbs) are emerging as a protein-based therapeutic strategy for directing T-cell-mediated cytotoxicity in a tumor antigen-specific manner, typically by binding to both tumor antigen and the CD3 receptor on T cells. REGN5678 is a human IgG4-based, first-in-class costimulatory bsAb designed to target prostate tumors by bridging prostate specific membrane antigen expressing tumor cells with the costimulatory receptor, CD28, on T cells, and providing amplified T-cell receptor-CD3 complex-mediated T-cell activation within the tumor through the activation of CD28 signaling. At the tumor site, REGN5678 may synergize with PD-1 inhibitors. In mouse models, REGN5678 in combination with PD-1 antibody has improved anti-tumor activity compared with either therapy alone (Skokos et al CRI/CICON 2019; oral, session 3). This study evaluates the safety and anti-tumor activity of REGN5678 alone and in combination with cemiplimab in patients with metastatic castration-resistant prostate cancer (mCRPC) who progressed after prior therapy. Methods: This is an open label, Phase I/II, first-in-human study evaluating safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of REGN5678 alone and in combination with cemiplimab in treatment-experienced mCRPC (NCT03972657). For inclusion, patients must have received at least two approved therapies for metastatic disease, including a second-generation hormonal agent. REGN5678 is administered weekly and cemiplimab (350 mg) is administered once every 3 weeks. During dose escalation, a 3-week safety lead-in of REGN5678 monotherapy will be administered prior to the addition of cemiplimab. Study therapies are administered until disease progression, intolerable adverse events, withdrawal of consent, or study withdrawal criterion is met. The primary objectives in dose escalation are to evaluate safety, tolerability, and PK of REGN5678 alone and in combination with cemiplimab. Expansion cohort(s) will be enrolled once a REGN5678/cemiplimab recommended Phase II dose is determined. During the expansion phase, the primary trial objective is to assess clinical activity, as measured by objective response rate of REGN5678 in combination with cemiplimab per modified Prostate Cancer Working Group 3 criteria. This study is currently open to enrollment. Clinical trial information: NCT03972657 .

A phase I dose-escalation trial of alpha-tocopheryloxyacetic acid and concurrent trastuzumab in patients with treatment refractory HER2+ metastatic breast cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS1103-TPS1103
Author(s):  
William R Gwin ◽  
Jennifer Childs ◽  
Doreen Higgins ◽  
Kellie Ann Burton ◽  
Kristin Kuano ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Phase I ◽  
Clinical Response ◽  
Cd8 T Cells ◽  
Dose Escalation ◽  
Effector Memory ◽  
Practical Consideration ◽  
Her2 Breast Cancer

TPS1103 Background: Metastatic HER2+ breast cancer, while initially responsive to trastuzumab, pertuzumab, and TDM-1, eventually progresses. The FDA recently approved trastuzumab deruxtecan, showing benefit in progression free survival but not in overall survival to date. Thus, additional therapies are needed for patients who progress on these HER2 directed agents. In metastatic HER2+ breast cancer, HER2-specific Th1 immune responses and higher CD4+ Th1 and CD8+ TIL levels are associated with a survival benefit. As this Type 1 immunity occurs in a minority of patients, additional immune modulation is needed. Alpha-tocopheryloxyacetic acid (α-TEA) has been reported to augment Type 1 immunity through increasing activated effector memory CD4+ and CD8+ T cells and decreasing immune suppressive CD4+CD25+ regulatory T cells in the tumor microenvironment. When given concurrently with an anti-HER2 antibody (7.16.4) in a pre-clinical tumor model, α-TEA synergized with 7.16.4 to induce tumor regression. We hypothesize that α-TEA and trastuzumab combination therapy in metastatic HER2+ breast cancer will be well tolerated, induce a clinical response, and augment anti-tumor Th1 immunity. Methods: Trial Design: Phase I dose escalation trial of α-TEA in combination with trastuzumab. Patients with metastatic HER2+ breast cancer will receive one of four doses sequentially of α-TEA: 0.6 mg/kg, 1.2 mg/kg, 2.4 mg/kg, and 4.8 mg/kg. Toxicity is assessed at baseline and through end of study. Blood and tumor tissue will be collected for immunologic monitoring and evaluation. Clinical response will be evaluated according to RECIST 1.1. Eligibility : Patients with progressive metastatic HER2+ breast cancer who have previously progressed on trastuzumab/pertuzumab and TDM-1. Specific Aims: Determine: (1) safety of four escalating doses of α-TEA with concurrent trastuzumab, (2) clinical response rate of α-TEA with concurrent trastuzumab (3) if concurrent α-TEA and trastuzumab increases activated effector memory CD4+ and CD8+ T cells, and (4) if concurrent α-TEA and trastuzumab increase the number of HER2-specific T cells. Statistical Methods: (1) The sample size of 24 and cohort size of 6 are determined by simulation experiments and practical consideration, (2) clinical response will be evaluated; overall PFS and OS will be calculated, (3) activated effector memory CD4+ and CD8+ T-cells will be analyzed (4) HER2-specific IFN-g/IL-10 ratios will be evaluated. Targeted Accrual : Twenty-four (24) patients. Clinical trial information: NCT04120246 .

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.

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