Nonclinical evaluation of the combination of mouse IL-21 and anti- mouse CTLA-4 or PD-1 blocking antibodies in mouse tumor models.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3019-3019 ◽  
Author(s):  
Maria Jure-Kunkel ◽  
Mark Selby ◽  
Katherine Lewis ◽  
Gregg Masters ◽  
Jose Valle ◽  
...  
Keyword(s):  
T Cell ◽  
Antitumor Activity ◽  
Nk Cell ◽  
Phase Iii ◽  
Tumor Growth Inhibition ◽  
Clinical Activity ◽  
Mouse Tumor ◽  
Synergistic Activity ◽  
Tumor Models ◽  
Mouse Tumor Models

3019 Background: Interleukin 21 (IL-21), a γc chain family cytokine, is produced primarily by CD4+ T cells and has many effects on immune cells, including enhancing CD8+ T cell and NK cell proliferation and cytotoxicity. Recombinant IL-21 (rIL-21) therapy resulted in objective responses in ~20% of melanoma and renal cell carcinoma patients. In mouse models, monoclonal antibody (mAb) blockade of CTLA-4 prolongs antigen-specific T cell responses, while blockade of programmed death 1 (PD-1) reverses tumor induced T cell suppression. Ipilimumab, a CTLA-4 blocking mAb, significantly improved overall survival in patients with metastatic melanoma in 2 phase III trials, and in phase I studies a PD-1 blocking mAb (nivolumab) has antitumor activity in various cancers. Side effect profiles for each mAb have been related to their mechanism and are generally manageable. It was hypothesized that combination of IL-21 plus CTLA-4 or PD-1 blockade may enhance antitumor responses, potentially leading to improved clinical activity. Methods: Preclinical studies were conducted to test the antitumor activity of mouse IL-21 (mIL-21) in combination with an anti-mouse PD-1 (mPD-1) mAb (4H2-IgG1) or with an anti-mCTLA-4 blocking mAb (9D9-IgG2b) in syngeneic mouse tumor models, including MC38, CT-26, EMT-6, and B16F10. mIL-21 was tested at doses ranging from 50-200 μg/dose, administered up to 3d/wk. mCTLA-4 mAb or mPD-1 mAb were administered 3-4x total at 200-300 μg/dose. Results: Combination treatments produced enhanced antitumor activity vs. monotherapy. In the MC38 model, mIL-21 treatment led to 30% median tumor growth inhibition (TGI) by d29, while mPD-1 mAb produced 60% median TGI and 1/10 tumor-free mice. Combination of both agents led to synergistic antitumor activity, with complete regressions (CR) in 7/10 mice and 99.9% median TGI (p=0.046). CTLA-4 mAb + mIL-21 also produced synergistic activity in the MC38 model. By d21, mIL-21 monotherapy induced 34% TGI while CTLA-4 mAb resulted in 28% TGI, with no CR in either group. Combination resulted in 6/8 mice with CR and 86% TGI (p<0.05). Conclusions: These results support the use of rIL-21+nivolumab and rIL-21+ipilimumab in recently initiated clinical trials.

Role of the immunoglobulin constant region in the antitumor activity of antibodies to cytotoxic T-lymphocyte antigen-4 (CTLA-4).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 9055-9055
Author(s):  
Alan J. Korman ◽  
John Engelhardt ◽  
Vafa Shahabi ◽  
Roumyana Yordanova ◽  
Karla Henning ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antitumor Activity ◽  
Phase Iii ◽  
Mouse Tumor ◽  
Constant Region ◽  
Tumor Site ◽  
Tumor Models ◽  
Mouse Tumor Models

9055 Background: Anti-CTLA-4 therapy enhances antitumor T-cell responses by both cell-intrinsic and cell-extrinsic mechanisms. Effector T-cell (Teff) activation is increased directly by interfering with CTLA-4-B7 interactions that negatively regulate T cells and by interfering with CTLA-4 expressed on regulatory T cells (Tregs), which function to inhibit immune responses. To analyze in greater detail the mechanism of action of anti-CTLA-4 antibodies (Abs), we examined the role of the immunoglobulin constant region in the antitumor activity of anti-CTLA-4 Abs in mouse tumor models. Methods: The activity of anti-CTLA-4 Abs with different mouse IgG constant regions were compared in several mouse tumor models, and intratumoral and peripheral T cells were analyzed by FACS. DNA samples from 488 patients with metastatic melanoma who received ipilimumab in a phase III clinical trial, MDX010-20, were analyzed for polymorphisms in the IgG fragment c receptor (FcR) at FCGR3A (V158F) and FCGR2A (H131R) loci. Results: In subcutaneous MC38 and CT26 colon tumor models, an anti-CTLA-4 Ab containing the mouse IgG2a constant region exhibited enhanced antitumor activity compared to an anti-CTLA-4 Ab containing the IgG2b constant region, while anti-CTLA-4 Abs containing mouse IgG1 or a mutated mouse IgG1 D265A constant region showed no activity. Anti-CTLA-4-IgG2a caused a dramatic reduction of Tregs at the tumor site that resulted in a greater Teff/Treg ratio. In contrast, all isotypes resulted in expansion of Tregs in the periphery. These results point to an important role for FcR in the action of anti-CTLA-4 Abs. In patients from study MDX010-20, there was no association between the 2 FcR polymorphisms (FCGR3A and FCGR2A) and overall survival. Conclusions: These preclinical studies reveal a novel dual activity of anti-CTLA-4 Abs consisting of intratumoral reduction of Tregs together with activation of Teff cells. This effect is mediated by the constant region and is presumably due to antibody-dependent cellular cytotoxicity. The data suggest that FcR-bearing cells at the tumor site, as well as the presence of intratumoral Tregs, may be important factors in the antitumor activity of anti-CTLA-4 Abs.

scholarly journals PD-1 blockade enhances elotuzumab efficacy in mouse tumor models

2017 ◽  
Vol 1 (12) ◽  
pp. 753-765 ◽  
Author(s):  
Natalie A. Bezman ◽  
Amy Jhatakia ◽  
Alper Y. Kearney ◽  
Ty Brender ◽  
Mark Maurer ◽  
...  
Keyword(s):  
T Cell ◽  
Antitumor Activity ◽  
Mouse Models ◽  
Cell Activity ◽  
Antitumor Efficacy ◽  
Mouse Tumor ◽  
Tumor Models ◽  
Key Points ◽  
Mouse Tumor Models

Key PointsThe combination of elotuzumab and an anti–PD-1 antibody leads to enhanced antitumor efficacy in mouse models. Enhanced antitumor activity is likely due to the promotion of tumor-infiltrating NK and T-cell activity.

scholarly journals 843 Development and engineering of human sialidase for degradation of immunosuppressive sialoglycans to treat cancer

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A884-A884
Author(s):  
Li Peng ◽  
Lizhi Cao ◽  
Sujata Nerle ◽  
Robert LeBlanc ◽  
Abhishek Das ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Cells ◽  
First Generation ◽  
Single Agent ◽  
Mouse Tumor ◽  
Cytokine Release ◽  
Tumor Models ◽  
Cell Immunity ◽  
Mouse Tumor Models

BackgroundSialoglycans, a type of glycans with a terminal sialic acid, have emerged as a critical glyco-immune checkpoint that impairs antitumor response by inhibiting innate and adaptive immunity. Upregulation of sialoglycans on tumors has been observed for decades and correlates with poor clinical outcomes across many tumor types. We previously showed that targeted desialylation of tumors using a bifunctional sialidase x antibody molecule, consisting of sialidase and a tumor-associated antigen (TAA)-targeting antibody, has led to robust single-agent efficacy in mouse tumor models. In addition to tumor cells, most immune cells present substantially more abundant sialoglycans than non-hematological healthy cells, which may also contribute to immunosuppression. Therefore, we studied the impact of immune cell desialylation and evaluated the therapeutic potential of a newly developed sialidase-Fc fusion (Bi-Sialidase), which lacks a TAA-targeting moiety and consists of engineered human neuraminidase 2 (Neu2) and human IgG1 Fc region, in preclinical mouse tumor models.MethodsThe first generation Neu2 variant was further optimized to improve titers and stability to constructed Bi-Sialidase. Bi-Sialidase’s desialylation potency and impact on immune responses were studied in vitro using various human immune functional assays, including T-cell activation, allogeneic mixed lymphocyte reaction, antibody-dependent cellular cytotoxicity, macrophages polarization/activation, neutrophil activation, and peripheral blood mononuclear cell (PBMC) cytokine release assays. We evaluated its antitumor efficacy in mouse tumor models. Bi-Sialidase’s safety profile was characterized by conducting rat and non-human primate (NHP) toxicology studies.ResultsThe optimized Bi-Sialidase achieved a titer of 2.5 g/L from a 15-day fed-batch Chinese hamster ovary cell culture; in contrast, the wild-type and first-generation Neu2 had no production or a low titer (<0.1 g/L) under similar conditions, respectively. We demonstrated that Bi-Sialidase led to dose-dependent desialylation of immune cells and potentiated T-cell immunity, without impacting NK, macrophage, or neutrophil activation by desialylating immune cells. Activated and exhausted T cells upregulated surface sialoglycans and Bi-Sialidase-mediated desialylation reinvigorated exhausted-like T cells as measured by IFNg production. Bi-Sialidase treatment also enhanced DC priming and activation of naïve T cells by desialylating both T cells and DCs. Furthermore, Bi-Sialidase showed single-agent antitumor activity in multiple mouse tumor models, including MC38, CT26, A20, and B16F10. Importantly, Bi-Sialidase did not cause cytokine release in human PBMC assays and was tolerated to up to 100 mg/kg in rats and NHPs, demonstrating a wide safety margin.ConclusionsBi-Sialidase with an optimized Neu2 offers a novel immunomodulatory approach to enhancing T-cell immunity by desialylating immunosuppressive sialoglycans for cancer treatment.

Phase I dose escalation study of recombinant interleukin-21 (rIL-21, BMS-982470) in combination with ipilimumab (Ipi) in patients (pts) with advanced or metastatic melanoma (MM).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS3109-TPS3109 ◽  
Author(s):  
Shailender Bhatia ◽  
Brendan D. Curti ◽  
Michael S. Gordon ◽  
Jason Chesney ◽  
Theodore Logan ◽  
...  
Keyword(s):  
T Cell ◽  
Antitumor Activity ◽  
Phase I ◽  
T Cell Activation ◽  
Dose Escalation ◽  
Cell Activation ◽  
Cell Function ◽  
Nk Cell ◽  
Combined Treatment ◽  
Clinical Activity

TPS3109 Background: Ipilimumab is a monoclonal anti-CTLA-4 antibody that promotes T-cell activation and has been approved for the treatment of pts with advanced melanoma. The cytokine rIL-21 is a T-cell and NK-cell growth factor that has also demonstrated antitumor activity in selected solid tumors including MM. We hypothesize that coordinated stimulation of T and/or NK cell function with rIL-21 in conjunction with T-cell checkpoint inhibitor blockade with Ipi will achieve enhanced biologic and clinical activity compared to either agent alone. Here we describe an ongoing phase Ib study to investigate the clinical and biologic effects of combined treatment with rIL-21 and Ipi in pts with MM. Methods: The phase I study includes dose escalation (Part 1) using a 6 + 6 design and cohort expansion (Part 2). In Part 1 (n=48), successive cohorts of pts with melanoma will be treated with rIL-21 in combination with Ipi as follows: Arm A, rIL-21 (10, 30, or 50 μg/kg daily x 5) + Ipi (3 or 10 mg/kg Q3W) in a 3 week cycle; or Arm B, rIL-21 (30, 100, or 150 μg/kg weekly) + Ipi (3 or 10 mg/kg Q3W) in a 3 week cycle. In Part 1, all subjects will receive an initial cycle with rIL-21 monotherapy (lead-in) for biomarker and PK assessment that will be the same as the dose of rIL-21 specified for the cohort. Four cycles of combination treatment will follow the lead-in with restaging evaluation after 4 combination cycles. Subjects with initial benefit are eligible for retreatment at progression. In Part 2, pts (n=25/arm) will be randomly assigned to one of 3 cohorts: Ipi monotherapy at 3 mg/kg Q3W or Ipi + weekly rIL-21 or Ipi + daily rIL-21 at the MTD determined for each schedule in Part 1. The primary objectives of this study are to evaluate the safety of rIL-21 + Ipi and to define the MTD of the respective rIL-21 + Ipi regimens. Secondary objectives include assessment of the preliminary antitumor activity, pharmacokinetics, and immunogenicity. Exploratory objectives include investigation of the immunologic effects of this combination in peripheral blood and paired tumor biopsy specimens, and the association of these effects with clinical outcome. Clinical trial information: NCT01489059.

scholarly journals A novel, native-format bispecific antibody triggering T-cell killing of B-cells is robustly active in mouse tumor models and cynomolgus monkeys

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Eric J. Smith ◽  
Kara Olson ◽  
Lauric J. Haber ◽  
Bindu Varghese ◽  
Paurene Duramad ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Bispecific Antibody ◽  
Cell Killing ◽  
Mouse Tumor ◽  
Tumor Models ◽  
Cynomolgus Monkeys ◽  
Mouse Tumor Models

scholarly journals 573 FS120, an OX40/CD137 tetravalent bispecific dual agonist antibody, synergistically increases the antitumor activity of anti-PD-1 in preclinical studies

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A602-A602
Author(s):  
Matthew Lakins ◽  
Wenjia Liao ◽  
Emma McConnell ◽  
Quincy Kaka ◽  
Jennifer Ofoedu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Bispecific Antibody ◽  
Cell Activity ◽  
T Cell Proliferation ◽  
Mouse Tumor ◽  
Tumor Models ◽  
Syngeneic Mouse ◽  
Tumor Bearing ◽  
Mouse Tumor Models

BackgroundImmune checkpoint inhibitors have demonstrated durable clinical responses and an increase in overall survival for some patients with cancer. Next generation cancer immunotherapies, such as tumor necrosis factor receptor superfamily (TNFRSF) agonists, have potential to further improve on this success. FS120 is a tetravalent bispecific antibody targeting OX40 and CD137 (4-1BB), currently being evaluated in a Phase I clinical trial (NCT04648202). FS120 activates CD4+ and CD8+ T cells by concurrent binding to both targets via an FcgR-independent mechanism [1]. In preclinical tumor models, FS120 induced T cell proliferation and cytokine production associated with significant tumor regression, better than that observed with a monoclonal antibody combination. Here, we demonstrate the ability of FS120 to improve anti-PD-1 induced T cell activity, increasing tumor growth inhibition and survival, in syngeneic mouse tumor models, compared to monotherapy.MethodsFS120 < i >in vitro</i > activity in combination with anti-PD-1 was assessed by utilizing staphylococcal enterotoxin A (SEA) superantigen assays and mixed leukocyte reaction (MLR) assays. An anti-mouse OX40/CD137 bispecific antibody (FS120 surrogate) was tested in CT26 syngeneic mouse tumor models in combination with an anti-mouse PD-1 antibody to assess efficacy and pharmacodynamic endpoints, including T cell proliferation by < i>ex vivo</i> flow cytometry and serum cytokine levels.ResultsFS120 in combination with anti-PD-1 enhanced primary human T cell activity, when compared to either monotherapy, in both SEA and MLR assays. FS120 surrogate significantly improved survival of CT26 tumor-bearing mice treated with anti-mPD-1 antibody. FS120 surrogate and anti-PD-1 combination significantly enhanced serum interferon-gamma levels and increased proliferating granzyme B+ CD8+ T cells in the blood of tumor-bearing mice, when compared to either monotherapy treatments.ConclusionsFS120 combination with anti-PD-1 enhances T cell activity in multiple human primary immune assays. In combination with anti-PD-1, FS120 surrogate increased the antitumor efficacy with pharmacodynamic changes related specifically to T cell activation, when compared to monotherapies. These data support the development of FS120 in combination with anti-PD-1 in patients with hard-to-treat cancers who may not benefit fully from either treatment as a monotherapy.ReferencesGaspar M, Pravin J, Rodrigues L, Uhlenbroich S, Everett K L, Wollerton F, Morrow M, Tuna M, Brewis N. CD137/OX40 Bispecific Antibody Induces Potent Antitumor Activity that Is Dependent on Target Coengagement. Cancer Immunol Res. 2020; (8) (6) 781–793Ethics ApprovalMurine studies were conducted under a U.K. Home Office License in accordance with the U.K. Animal (Scientific Procedures) Act 1986 and EU Directive EU 2010/63.

scholarly journals CRISPitope: A generic platform to model target antigens for adoptive T cell transfer therapy in mouse tumor models

2022 ◽  
Vol 3 (1) ◽  
pp. 101038
Author(s):  
Maike Effern ◽  
Nicole Glodde ◽  
Emma Bawden ◽  
Jana Liebing ◽  
Daniel Hinze ◽  
...  
Keyword(s):  
T Cell ◽  
Mouse Tumor ◽  
Cell Transfer ◽  
Tumor Models ◽  
Adoptive T Cell Transfer ◽  
T Cell Transfer ◽  
Mouse Tumor Models
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