Phase 2a, open-label, multi-center study of GI-101A or GI-102 (CD80-IgG4 FC-IL2v) in patients with relapsed/refractory diffuse large B-cell lymphoma following anti-CD19 chimeric antigen receptor T-cell therapy (CARNATION)

Start Date31 Jul 2024

Sponsor / Collaborator

Asan Medical Center

NCT04977453 / RecruitingPhase 1/2

A Phase 1/2, Open-label, Dose-escalation, and Expansion Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Therapeutic Activity of GI-101 As a Single Agent and in Combination with Pembrolizumab, Lenvatinib or Local Radiotherapy in Patients with Advanced or Metastatic Solid Tumors (Keynote B59)

The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and therapeutic activity of GI-101/GI-101A as a single agent or in combination with pembrolizumab, lenvatinib or local radiotherapy (RT) over a range of advanced and/or metastatic solid tumors.

Start Date02 Aug 2021

Sponsor / Collaborator

GI Innovation, Inc.

[+1]

100 Clinical Results associated with IL-2R x CTLA4 x CD28

100 Translational Medicine associated with IL-2R x CTLA4 x CD28

0 Patents (Medical) associated with IL-2R x CTLA4 x CD28

Literatures (Medical) associated with IL-2R x CTLA4 x CD28

05 May 2023·bioRxiv : the preprint server for biology

CD28-Selective Inhibition Prolongs Non-Human Primate Kidney Transplant Survival.

Author: Lovasik, Brendan P ; Mathews, David V ; Adams, Andrew B ; Larsen, Christian P ; Breeden, Cynthia ; Farris, Alton B ; Ford, Mandy L ; Higginbotham, Laura ; Kim, Steven C ; Wakwe, Walter ; Nadler, Steven

Costimulation blockade using belatacept results in improved renal function after kidney transplant as well as decreased likelihood of death/graft loss and reduced cardiovascular risk; however, higher rates and grades of acute rejection have prevented its widespread clinical adoption. Treatment with belatacept blocks both positive (CD28) and negative (CTLA-4) T cell signaling. CD28-selective therapies may offer improved potency by blocking CD28-mediated costimulation while leaving CTLA-4 mediated coinhibitory signals intact. Here we test a novel domain antibody directed at CD28 (anti-CD28 dAb (BMS-931699)) in a non-human primate kidney transplant model. Sixteen macaques underwent native nephrectomy and received life-sustaining renal allotransplantation from an MHC-mismatched donor. Animals were treated with belatacept alone, anti-CD28 dAb alone, or anti-CD28 dAb plus clinically relevant maintenance (MMF, Steroids) and induction therapy with either anti-IL-2R or T cell depletion. Treatment with anti-CD28 dAb extended survival compared to belatacept monotherapy (MST 187 vs. 29 days, p=0.07). The combination of anti-CD28 dAb and conventional immunosuppression further prolonged survival to MST ∼270 days. Animals maintained protective immunity with no significant infectious issues. These data demonstrate CD28-directed therapy is a safe and effective next-generation costimulatory blockade strategy with a demonstrated survival benefit and presumed advantage over belatacept by maintaining intact CTLA-4 coinhibitory signaling.

01 Feb 2002·DiabetesQ1 · MEDICINE

Calcineurin Inhibitor–Free CD28 Blockade-Based Protocol Protects Allogeneic Islets in Nonhuman Primates

Q1 · MEDICINE

Article

Author: Adams, Andrew B. ; Blinder, Yelena ; Shirasugi, Nozomu ; Kenyon, Norma S. ; Pearson, Thomas C. ; Cowan, Shannon ; Hollenbaugh, Dianne ; Strobert, Elizabeth ; Anderson, Dan ; Rees, Phyllis ; Cheung, Michael ; Durham, Megan M. ; Larsen, Christian P. ; Xu, Huaying

Recent success using a steroid-free immunosuppressive regimen has renewed enthusiasm for the use of islet transplantation to treat diabetes. Toxicities associated with the continued use of a calcineurin inhibitor may limit the wide-spread application of this therapy. Biological agents that block key T-cell costimulatory signals, in particular the CD28 pathway, have demonstrated extraordinary promise in animal models. LEA29Y (BMS-224818), a mutant CTLA4-Ig molecule with increased binding activity, was evaluated for its potential to replace tacrolimus and protect allogeneic islets in a preclinical primate model. Animals received either the base immunosuppression regimen (rapamycin and anti–IL-2R monoclonal antibody [mAb]) or the base immunosuppression and LEA29Y. Animals receiving the LEA29Y/rapamycin/anti–IL-2R regimen (n = 5) had significantly prolonged islet allograft survival (204, 190, 216, 56, and >220 days). In contrast, those animals receiving the base regimen alone (n = 2) quickly rejected the transplanted islets at 1 week (both at 7 days). The LEA29Y-based regimen prevented the priming of anti-donor T- and B-cell responses, as detected by interferon-γ enzyme-linked immunospot and allo-antibody production, respectively. The results of this study suggest that LEA29Y is a potent immunosuppressant that can effectively prevent rejection in a steroid-free immunosuppressive protocol and produce marked prolongation of islet allograft survival in a preclinical model.

01 Feb 2000·Journal of AutoimmunityQ1 · MEDICINE

CD69, HLA-DR and the IL-2R Identify Persistently Activated T Cells in Psoriasis Vulgaris Lesional Skin: Blood and Skin Comparisons by Flow Cytometry

Q1 · MEDICINE

Article

Author: K Ferenczi ; M Pope ; L Burack ; L.M Austin ; J.G Krueger

Many lymphocyte-activation-associated molecules are observed by immunohistochemistry in psoriasis vulgaris lesional skin. Non-T cells in lesional skin also express these molecules. We quantitatively measured the number of T cells expressing cell surface activation-associated molecules (CD69, CD25, CD122, HLA-DR) and co-stimulatory molecules (CD28, CTLA-4, CD80, CD86), including a Type 2 T cell marker (CD30) and CD11b, by flow cytometry of skin and peripheral blood. T cells in single cell suspensions of psoriatic lesional-epidermis-expressed HLA-DR (86%), CD69 (59%), CD25 (55%), CD122 (44%), and CD28 (91%). Dermal T cells showed similar percentages except for CD69 (17%). CD69 was found directly in lesional skin biopsies by immunohistochemistry. Both CD4 and CD8 subsets from lesional skin contained large populations of CD25+ cells with a bias towards CD8 activation in the epidermis and towards CD4 activation in the dermis. CD86, CD80, CTLA-4, CD30 and CD11b were expressed by less than 23% of the T cell populations from both the epidermis and dermis. CD30+CD4+ cells were found two-fold over CD8+ T cells. These results show that the majority of lesional lymphocytes are persistently activated. We also found the majority of Type 2 associated markers primarily on the CD4+ epidermal T cell population. Psoriatic blood contained elevated levels of T cells expressing CD25, primarily within the CD8+ subset. Thus the majority of lesional T cells expressed the three primary activation markers, while psoriatic blood T cells were distinguished by an increase in CD25, specifically within the CTL population.

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