Quilt-3.064: An open-label phase I study of PD-L1 t-haNK in subjects with locally advanced or metastatic solid cancers.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3152-TPS3152
Author(s):  
Tara Elisabeth Seery ◽  
Mira Kistler ◽  
John H. Lee ◽  
Patrick Soon-Shiong
Keyword(s):  
T Cells ◽  
Antitumor Activity ◽  
Nk Cells ◽  
Dose Escalation ◽  
Nk Cell ◽  
Objective Response ◽  
Locally Advanced ◽  
In Vivo Studies ◽  
Severe Toxicity ◽  
Dose Escalation Study

TPS3152 Background: Tumor cells can escape immunosurveillance through upregulation of PD-L1, which inhibits the proliferation and antitumor activity of T cells. T cells genetically altered to express chimeric antigen receptors (CARs) that recognize tumor-associated antigens have mediated potent responses in patients with hematologic cancers, but have shown limited efficacy in solid tumor cancers and can be associated with severe toxicity, ie, cytokine release syndrome (CRS). Like T cells, NK cells can be genetically modified to express CARs that can specifically recognize and lyse cancer cells. Unlike T cells, NK cell cytotoxicity does not require prior sensitization and is not HLA-restricted, making NK cells an attractive choice for clinical immunotherapy. In addition to their innate cytotoxicity, NK cells mediate antibody-dependent cellular cytotoxicity (ADCC) via expression of CD16. PD-L1 t-haNK is an off-the-shelf, human, allogeneic, NK cell line engineered to express a CAR targeting PD-L1. It can be easily and continuously expanded in culture and preclinical in vitro and in vivo studies have demonstrated effective PD-L1 CAR–mediated antitumor activity against PD-L1+ MDSCs. PD-L1 t-haNK has also been engineered to express the high-affinity variant of the Fcγ receptor (FcγRIIIa/CD16a 158V), and thus has enhanced CD16-targeted ADCC capabilities, particularly when combined with a monoclonal antibody. As such, a dual-targeted NK approach may be more effective at potentiating antitumor activity and reversing suppression in multiple cancers that express PD-L1 in the tumor microenvironment. Methods: This is a dose-escalation study of PD-L1 t-haNK in subjects with locally advanced or metastatic solid cancers, regardless of PD-L1 expression. Dose escalation will involve a standard 3 + 3 design. The primary objectives are to determine safety, maximum tolerated dose (MTD), and designate a recommended phase 2 dose. Secondary objectives include estimates of preliminary efficacy by objective response rate, progression-free survival, and overall survival. Subjects in Cohort 1 will receive ~2 × 109 PD-L1 t-haNK cells twice per week and assessed for dose-limiting toxicities (DLTs). If no DLTs occur, the dose may increase to ~4 × 109 cells twice per week in Cohort 2. Dose expansion will occur when the MTD has been determined. PD-L1 t-haNK is administered by IV infusion in an outpatient setting. Enrollment in Cohort 1 has been completed (N = 6, > 100 doses total) without DLTs or CRS. Enrollment into Cohort 2 began December 2019. Clinical trial information: NCT04050709 .

scholarly journals Anti-tumor effects of RTX-240: an engineered red blood cell expressing 4-1BB ligand and interleukin-15

2021 ◽  
Author(s):  
Shannon L. McArdel ◽  
Anne-Sophie Dugast ◽  
Maegan E. Hoover ◽  
Arjun Bollampalli ◽  
Enping Hong ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Blood Cell ◽  
Nk Cells ◽  
Red Blood Cell ◽  
Safety Profile ◽  
Nk Cell ◽  
Cell Activity ◽  
In Vivo Studies

AbstractRecombinant agonists that activate co-stimulatory and cytokine receptors have shown limited clinical anticancer utility, potentially due to narrow therapeutic windows, the need for coordinated activation of co-stimulatory and cytokine pathways and the failure of agonistic antibodies to recapitulate signaling by endogenous ligands. RTX-240 is a genetically engineered red blood cell expressing 4-1BBL and IL-15/IL-15Rα fusion (IL-15TP). RTX-240 is designed to potently and simultaneously stimulate the 4-1BB and IL-15 pathways, thereby activating and expanding T cells and NK cells, while potentially offering an improved safety profile through restricted biodistribution. We assessed the ability of RTX-240 to expand and activate T cells and NK cells and evaluated the in vivo efficacy, pharmacodynamics and tolerability using murine models. Treatment of PBMCs with RTX-240 induced T cell and NK cell activation and proliferation. In vivo studies using mRBC-240, a mouse surrogate for RTX-240, revealed biodistribution predominantly to the red pulp of the spleen, leading to CD8 + T cell and NK cell expansion. mRBC-240 was efficacious in a B16-F10 melanoma model and led to increased NK cell infiltration into the lungs. mRBC-240 significantly inhibited CT26 tumor growth, in association with an increase in tumor-infiltrating proliferating and cytotoxic CD8 + T cells. mRBC-240 was tolerated and showed no evidence of hepatic injury at the highest feasible dose, compared with a 4-1BB agonistic antibody. RTX-240 promotes T cell and NK cell activity in preclinical models and shows efficacy and an improved safety profile. Based on these data, RTX-240 is now being evaluated in a clinical trial.

scholarly journals A phase I study of the safety and activity of K-001 in patients with advanced pancreatic ductal adenocarcinoma

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jiujie Cui ◽  
Haiyan Yang ◽  
Jue Liu ◽  
Donghui Chen ◽  
Jiong Hu ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Dose Escalation ◽  
Objective Response ◽  
Maximum Tolerated Dose ◽  
Ductal Adenocarcinoma ◽  
Marine Microorganisms ◽  
Open Label ◽  
Dose Escalation Study

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that lack of effective therapeutic drugs. K-001 is an oral antitumor drug made from active ingredients of marine microorganisms. The current study aimed to evaluate safety and antitumor activity of K-001 in patients with advanced PDAC. Methods In this phase I, open-label trial, patients with advanced PDAC were recruited to a dose-escalation study in a standard 3 + 3 design. K-001 was administered twice daily in four-week cycles, and dose escalation from 1350 mg to 2160 mg was evaluated twice daily. Physical examination and laboratory tests were done at screening and then weekly. The safety, dose-limiting toxicity (DLT), and maximum tolerated dose (MTD) of K-001 were assessed while tumor response was estimated by Response Evaluation Criteria in Solid Tumor (RECIST). Results Eighteen patients with advanced PDAC were screened, and twelve eligible patients were analyzed in the study. No DLT was observed. Totally, 47 adverse events (AEs) presented, and 14 drug-related AEs were reported in 7 patients, including 8 grade 1 events (57.1%) and 6 grade 2 events (42.9%). There was no grade 3 or 4 drug-related AE. In these 14 drug-related AEs, the most frequent ones were dyspepsia (21.4%), followed by flatulence, constipation, and hemorrhoid bleeding (above 10% of each). Among all 12 patients, 10 patients (83.3%) maintained stable disease (SD), and 2 patients (16.7%) had progressive disease (PD). The objective response rate (ORR) was 0% and the disease control rate (DCR) was 83.3%. Conclusions K-001 manifests satisfactory safety and tolerability, as well as meaningful antitumor activity in advanced PDAC patients. Further evaluation of K-001 in phase II/III appears warranted. Trial registration NCT02720666. Registered 28 Match 2016 - Retrospectively registered.

scholarly journals Sustained effector function of IL-12/15/18–preactivated NK cells against established tumors

2012 ◽  
Vol 209 (13) ◽  
pp. 2351-2365 ◽  
Author(s):  
Jing Ni ◽  
Matthias Miller ◽  
Ana Stojanovic ◽  
Natalio Garbi ◽  
Adelheid Cerwenka
Keyword(s):  
T Cells ◽  
Antitumor Activity ◽  
Nk Cells ◽  
Cd4 T Cells ◽  
Rational Design ◽  
Nk Cell ◽  
Killer Cell ◽  
Effector Function

Natural killer cell (NK cell)–based immunotherapy of cancer is hampered by the transient effector function of NK cells. Recently, mouse IL-12/15/18–preactivated NK cells were shown to persist with sustained effector function in vivo. Our study investigated the antitumor activity of such NK cells. A single injection of syngeneic IL-12/15/18–preactivated NK cells, but neither naive nor IL-15– or IL-2–pretreated NK cells, combined with irradiation substantially reduced growth of established mouse tumors. Radiation therapy (RT) was essential for the antitumor activity of transferred NK cells. IL-12/15/18–preactivated NK cells expressed high levels of IL-2Rα (CD25), and their rapid in vivo proliferation depended on IL-2 produced by CD4+ T cells. IL-12/15/18–preactivated NK cells accumulated in the tumor tissue and persisted at high cell numbers with potent effector function that required the presence of CD4+ T cells. RT greatly increased numbers and function of transferred NK cells. Human IL-12/15/18–preactivated NK cells also displayed sustained effector function in vitro. Our study provides a better understanding for the rational design of immunotherapies of cancer that incorporate NK cells. Moreover, our results reveal an essential role of CD4+ T cell help for sustained antitumor activity by NK cells linking adaptive and innate immunity.

scholarly journals A Phase I Study of K-001 in Patients with Advanced Pancreatic Ductal Adenocarcinoma

2021 ◽  
Author(s):  
Jiujie Cui ◽  
Haiyan Yang ◽  
Jue Liu ◽  
Donghui Chen ◽  
Jiong Hu ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Dose Escalation ◽  
Objective Response ◽  
Maximum Tolerated Dose ◽  
Ductal Adenocarcinoma ◽  
Marine Microorganisms ◽  
Open Label ◽  
Dose Escalation Study

Abstract Background:K-001 is an oral antitumor drug made from active ingredients of marine microorganisms. The current study aimed to evaluate safety and antitumor activity of K-001 in patients with advanced pancreatic ductal adenocarcinoma (PDAC).Methods:In this phase I, open-label trial, patients with advanced PDAC were recruited to a dose-escalation study in a standard 3+3 design. K-001 was administered twice daily in 4-week cycles, and dose escalation from 1350mg to 2160mg twice daily was evaluated. Physical examination and laboratory tests were done at screening and then weekly. The safety, dose-limiting toxicity (DLT), and maximum tolerated dose (MTD) of K-001 were assessed, and tumor response was estimated by Response Evaluation Criteria in Solid Tumor (RECIST).Results:Eighteen patients with advanced PDAC were screened, and twelve eligible patients were analyzed in the study. No DLT was observed. Totally, 47 adverse events (AEs) presented, and 14 drug-related AEs were reported in 7 patients, including 8 grade 1 events (57.1%) and 6 grade 2 events (42.9%). There was no grade 3 or 4 drug-related AE. In these 14 drug-related AEs, the most frequent ones were dyspepsia (21.4%), followed by flatulence, constipation, and haemorrhoids bleeding (above 10% of each). Among all 12 patients, 10 patients (83.3%) maintained stable disease (SD), and 2 patients (16.7%) had progressive disease (PD). The objective response rate (ORR) was 0% and the disease control rate (DCR) was 83.3%.Conclusions:K-001 has satisfactory safety and tolerability, as well as meaningful antitumor activity in advanced PDAC patients. Further evaluation of K-001 in phase II/III appears warranted.Trial registration: NCT02720666. Registered 28 Match 2016 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02720666.

scholarly journals A bispecific antibody agonist of the IL-2 heterodimeric receptor preferentially promotes in vivo expansion of CD8 and NK cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Katherine E. Harris ◽  
Kyle J. Lorentsen ◽  
Harbani K. Malik-Chaudhry ◽  
Kaitlyn Loughlin ◽  
Harish Medlari Basappa ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Bispecific Antibody ◽  
T Regulatory Cells ◽  
Tumor Regression ◽  
Interleukin 2 ◽  
In Vivo Studies ◽  
Preferential Binding

AbstractThe use of recombinant interleukin-2 (IL-2) as a therapeutic protein has been limited by significant toxicities despite its demonstrated ability to induce durable tumor-regression in cancer patients. The adverse events and limited efficacy of IL-2 treatment are due to the preferential binding of IL-2 to cells that express the high-affinity, trimeric receptor, IL-2Rαβγ such as endothelial cells and T-regulatory cells, respectively. Here, we describe a novel bispecific heavy-chain only antibody which binds to and activates signaling through the heterodimeric IL-2Rβγ receptor complex that is expressed on resting T-cells and NK cells. By avoiding binding to IL-2Rα, this molecule circumvents the preferential T-reg activation of native IL-2, while maintaining the robust stimulatory effects on T-cells and NK-cells in vitro. In vivo studies in both mice and cynomolgus monkeys confirm the molecule’s in vivo biological activity, extended pharmacodynamics due to the Fc portion of the molecule, and enhanced safety profile. Together, these results demonstrate that the bispecific antibody is a safe and effective IL-2R agonist that harnesses the benefits of the IL-2 signaling pathway as a potential anti-cancer therapy.

scholarly journals Short-course IL-15 given as a continuous infusion led to a massive expansion of effective NK cells: implications for combination therapy with antitumor antibodies

2021 ◽  
Vol 9 (4) ◽  
pp. e002193
Author(s):  
Sigrid P Dubois ◽  
Milos D Miljkovic ◽  
Thomas A Fleisher ◽  
Stefania Pittaluga ◽  
Jennifer Hsu-Albert ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Intravenous Infusion ◽  
Nk Cell ◽  
Continuous Intravenous Infusion ◽  
Dose Escalation Study ◽  
Link Type ◽  
Best Response ◽  
Antitumor Antibodies ◽  
Interleukin 15

BackgroundFull application of cytokines as oncoimmunotherapeutics requires identification of optimal regimens. Our initial effort with intravenous bolus recombinant human interleukin-15 (rhIL-15) was limited by postinfusional reactions. Subcutaneous injection and continuous intravenous infusion for 10 days (CIV-10) provided rhIL-15 with less toxicity with CIV-10 giving the best increases in CD8+ lymphocytes and natural killer (NK) cells. To ease rhIL-15 administration, we shortened time of infusion. Treatment with rhIL-15 at a dose of 3–5 µg/kg as a 5-day continuous intravenous infusion (CIV-5) had no dose-limiting toxicities while effector cell stimulation was comparable to the CIV-10 regimen.MethodsEleven patients with metastatic cancers were treated with rhIL-15 CIV-5, 3 µg (n=4), 4 µg (n=3), and 5 µg/kg/day (n=4) in a phase I dose-escalation study (April 6, 2012).ResultsImpressive expansions of NK cells were seen at all dose levels (mean 34-fold), including CD56bright NK cells (mean 144-fold for 4 µg/kg), as well as an increase in CD8+ T cells (mean 3.38-fold). At 5 µg/kg/day, there were no dose-limiting toxicities but pulmonary capillary leak and slower patient recovery. This led to our choice of the 4 µg/kg as CIV-5 dose for further testing. Cytolytic capacity of CD56bright and CD56dim NK cells was increased by interleukin-15 assayed by antibody-dependent cellular cytotoxicity (ADCC), natural cytotoxicity and natural killer group 2D-mediated cytotoxicity. The best response was stable disease.ConclusionsIL-15 administered as CIV-5 substantially expanded NK cells with increased cytotoxic functions. Tumor-targeting monoclonal antibodies dependent on ADCC as their mechanism of action including alemtuzumab, obinutuzumab, avelumab, and mogamulizumab could benefit from those NK cell expansions and provide a promising therapeutic strategy.Trial registration numbersNCT01572493, NCT03759184, NCT03905135, NCT04185220 and NCT02689453.

scholarly journals AsCas12a ultra nuclease facilitates the rapid generation of therapeutic cell medicines

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Liyang Zhang ◽  
John A. Zuris ◽  
Ramya Viswanathan ◽  
Jasmine N. Edelstein ◽  
Rolf Turk ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Genome Editing ◽  
Nk Cell ◽  
Basic Research ◽  
Cell Recognition ◽  
Site Specific ◽  
Editing Efficiency ◽  
Rapid Generation ◽  
Therapeutic Cell

AbstractThough AsCas12a fills a crucial gap in the current genome editing toolbox, it exhibits relatively poor editing efficiency, restricting its overall utility. Here we isolate an engineered variant, “AsCas12a Ultra”, that increased editing efficiency to nearly 100% at all sites examined in HSPCs, iPSCs, T cells, and NK cells. We show that AsCas12a Ultra maintains high on-target specificity thereby mitigating the risk for off-target editing and making it ideal for complex therapeutic genome editing applications. We achieved simultaneous targeting of three clinically relevant genes in T cells at >90% efficiency and demonstrated transgene knock-in efficiencies of up to 60%. We demonstrate site-specific knock-in of a CAR in NK cells, which afforded enhanced anti-tumor NK cell recognition, potentially enabling the next generation of allogeneic cell-based therapies in oncology. AsCas12a Ultra is an advanced CRISPR nuclease with significant advantages in basic research and in the production of gene edited cell medicines.

scholarly journals DNAM-1 promotes activation of cytotoxic lymphocytes by nonprofessional antigen-presenting cells and tumors

2008 ◽  
Vol 205 (13) ◽  
pp. 2965-2973 ◽  
Author(s):  
Susan Gilfillan ◽  
Christopher J. Chan ◽  
Marina Cella ◽  
Nicole M. Haynes ◽  
Aaron S. Rapaport ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Adhesion Molecules ◽  
Cd8 T Cells ◽  
Nk Cell ◽  
Cd8 T Cell ◽  
Antigen Presenting

Natural killer (NK) cells and CD8 T cells require adhesion molecules for migration, activation, expansion, differentiation, and effector functions. DNAX accessory molecule 1 (DNAM-1), an adhesion molecule belonging to the immunoglobulin superfamily, promotes many of these functions in vitro. However, because NK cells and CD8 T cells express multiple adhesion molecules, it is unclear whether DNAM-1 has a unique function or is effectively redundant in vivo. To address this question, we generated mice lacking DNAM-1 and evaluated DNAM-1–deficient CD8 T cell and NK cell function in vitro and in vivo. Our results demonstrate that CD8 T cells require DNAM-1 for co-stimulation when recognizing antigen presented by nonprofessional antigen-presenting cells; in contrast, DNAM-1 is dispensable when dendritic cells present the antigen. Similarly, NK cells require DNAM-1 for the elimination of tumor cells that are comparatively resistant to NK cell–mediated cytotoxicity caused by the paucity of other NK cell–activating ligands. We conclude that DNAM-1 serves to extend the range of target cells that can activate CD8 T cell and NK cells and, hence, may be essential for immunosurveillance against tumors and/or viruses that evade recognition by other activating or accessory molecules.

scholarly journals Interferon Alpha Enhances NK Cell Function and the Suppressive Capacity of HIV-Specific CD8+T Cells

2018 ◽  
Vol 93 (3) ◽  
Author(s):  
Abena K. R. Kwaa ◽  
Chloe A. G. Talana ◽  
Joel N. Blankson
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Effector Cell ◽  
Cell Function ◽  
Nk Cell ◽  
Suppressive Capacity ◽  
Short Course ◽  
Shock And Kill ◽  
Hiv 1

ABSTRACTCurrent shock-and-kill strategies for the eradication of the HIV-1 reservoir have resulted in blips of viremia but not in a decrease in the size of the latent reservoir in patients on suppressive antiretroviral therapy (ART). This discrepancy could potentially be explained by an inability of the immune system to kill HIV-1-infected cells following the reversal of latency. Furthermore, some studies have suggested that certain latency-reversing agents (LRAs) may inhibit CD8+T cell and natural killer (NK) cell responses. In this study, we tested the hypothesis that alpha interferon (IFN-α) could improve the function of NK cells from chronic progressors (CP) on ART. We show here that IFN-α treatment enhanced cytokine secretion, polyfunctionality, degranulation, and the cytotoxic potential of NK cells from healthy donors (HD) and CP. We also show that this cytokine enhanced the viral suppressive capacity of NK cells from HD and elite controllers or suppressors. Furthermore, IFN-α enhanced global CP CD8+T cell cytokine responses and the suppressive capacity of ES CD8+T cells. Our data suggest that IFN-α treatment may potentially be used as an immunomodulatory agent in HIV-1 cure strategies.IMPORTANCEData suggest that HIV+individuals unable to control infection fail to do so due to impaired cytokine production and/cytotoxic effector cell function. Consequently, the success of cure agendas such as the shock-and-kill strategy will probably depend on enhancing patient effector cell function. In this regard, NK cells are of particular interest since they complement the function of CD8+T cells. Here, we demonstrate the ability of short-course alpha interferon (IFN-α) treatments to effectively enhance such effector functions in chronic progressor NK cells without inhibiting their general CD8+T cell function. These results point to the possibility of exploring such short-course IFN-α treatments for the enhancement of effector cell function in HIV+patients in future cure strategies.

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