This study, a single-center, open, single-dose clinical study, was designed to evaluate the safety, tolerability, and pharmacokinetic profile of INS19 CAR-T cells for the treatment of patients with relapsed or refractory acute B lymphoblastic leukemia

Start Date15 Jan 2024

Sponsor / Collaborator

Beijing Imunopharm Technology Co., Ltd.Startup

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100 Clinical Results associated with INS19 CAR-T Cells(Beijing Imunopharm Technology)

100 Translational Medicine associated with INS19 CAR-T Cells(Beijing Imunopharm Technology)

100 Patents (Medical) associated with INS19 CAR-T Cells(Beijing Imunopharm Technology)

Literatures (Medical) associated with INS19 CAR-T Cells(Beijing Imunopharm Technology)

01 May 2024·Journal for ImmunoTherapy of Cancer

Stealth transgenes enable CAR-T cells to evade host immune responses

Article

Author: Silva, Harrison ; Kann, Michael C ; Millar, David ; Larson, Rebecca ; Gallagher, Kathleen ; Leick, Mark B ; Berger, Trisha ; Turtle, Cameron J ; Grauwet, Korneel ; Frigault, Matthew J ; Bailey, Stefanie R ; Maus, Marcela V ; Bouffard, Amanda A

BackgroundAdoptive cell therapy, such as chimeric antigen receptor (CAR)-T cell therapy, has improved patient outcomes for hematological malignancies. Currently, four of the six FDA-approved CAR-T cell products use the FMC63-based αCD19 single-chain variable fragment, derived from a murine monoclonal antibody, as the extracellular binding domain. Clinical studies demonstrate that patients develop humoral and cellular immune responses to the non-self CAR components of autologous CAR-T cells or donor-specific antigens of allogeneic CAR-T cells, which is thought to potentially limit CAR-T cell persistence and the success of repeated dosing.MethodsIn this study, we implemented a one-shot approach to prevent rejection of engineered T cells by simultaneously reducing antigen presentation and the surface expression of both Classes of the major histocompatibility complex (MHC) via expression of the viral inhibitors of transporter associated with antigen processing (TAPi) in combination with a transgene coding for shRNA targeting class II MHC transactivator (CIITA). The optimal combination was screened in vitro by flow cytometric analysis and mixed lymphocyte reaction assays and was validated in vivo in mouse models of leukemia and lymphoma. Functionality was assessed in an autologous setting using patient samples and in an allogeneic setting using an allogeneic mouse model.ResultsThe combination of the Epstein-Barr virus TAPi and an shRNA targeting CIITA was efficient and effective at reducing cell surface MHC classes I and II in αCD19 ‘stealth’ CAR-T cells while retaining in vitro and in vivo antitumor functionality. Mixed lymphocyte reaction assays and IFNγ ELISpot assays performed with T cells from patients previously treated with autologous αCD19 CAR-T cells confirm that CAR T cells expressing the stealth transgenes evade allogeneic and autologous anti-CAR responses, which was further validated in vivo. Importantly, we noted anti-CAR-T cell responses in patients who had received multiple CAR-T cell infusions, and this response was reduced on in vitro restimulation with autologous CARs containing the stealth transgenes.ConclusionsTogether, these data suggest that the proposed stealth transgenes may reduce the immunogenicity of autologous and allogeneic cellular therapeutics. Moreover, patient data indicate that repeated doses of autologous FMC63-based αCD19 CAR-T cells significantly increased the anti-CAR T cell responses in these patients.

01 Apr 2024·Zhongguo shi yan xue ye xue za zhi

[Construction and Optimization of CD19 Chimeric Antigen Receptor T Cells Derived from C57BL/6J Mice].

Article

Author: Chen, Xian-Xian ; Tian, Yu ; Ren, Chun-Xiao ; Zhao, Kai ; Zhao, Li

OBJECTIVETo explore the stimulation conditions, optimal culture time and infection time of C57BL/6J mice CD3⁺ T cells in vitro, so as to improve the infection efficiency of CD19 chimeric antigen receptor T cells (mCD19 CAR-T).METHODSPurified C57BL/6J mice CD3⁺ T cells were cultured in anti-CD3/CD28 coated, anti-CD3 coated+soluble anti-CD28 and anti-CD3 coated, respectively. The cells were stimulated in above three conditions for 12 h and 24 h, following with 24 h, 48 h and 72 h incubation and then the number of cell clones was recorded. C57BL/6J mice CD3⁺ T cells were stimulated for 12 h, 24 h, and 36 h under the above three conditions, then interleukin (IL)-2 (100 U/ml) was added. The number of cell clones was recorded under microscope at 24 h, 48 h, and 72 h of culture. After 24 h of stimulation, CD3⁺ T cells derived from C57BL/6J mice were infected with retrovirus for 48 h to establish mCD19 CAR-T cells, and the percentage of GFP⁺ CAR-T cells was detected by flow cytometry.RESULTSThe infection efficiency of mCD19 CAR-T cells derived from C57BL/6J mice was only 5.23% under the optimized conditions of mCD19 CAR-T cells derived from BALB/c mice. The number of clones of C57BL/6J mice CD3⁺ T cells was the highest in anti-CD3 coated+soluble anti-CD28 group after stimulated for 24 h and followed cultured for 48 h. After 24 hours of stimulation under the above conditions and 48 hours of culture with IL-2, the number of T cell proliferating clones in the anti-CD3 coated+soluble anti-CD28 group was significantly increased compared with the same group without IL-2, and the infection efficiency of CAR-T cells in this group reached 17.63%±4.17%.CONCLUSIONThe optimal conditions for constructing CAR-T cells from C57BL/6J mice CD3⁺ T cells are different from those of BABL/c mice. T cells stimulated by anti-CD3 coated+soluble anti-CD28+IL-2 can obtain mCD19 CAR-T cells with the highest efficiency after retrovirus infection.

30 Nov 2022·Cancer Research Communications

Mechanistic Modeling of the Interplay Between Host Immune System, IL-7 and UCART19 Allogeneic CAR-T Cells in Adult B-cell Acute Lymphoblastic Leukemia

Article

Author: Mager, Donald E. ; Fouliard, Sylvain ; Derippe, Thibaud ; Dupouy, Sandra ; Chenel, Marylore ; Marchiq, Ibtissam ; Almena-Carrasco, Maria ; Declèves, Xavier ; Geronimi, Julia

Chimeric antigen receptor (CAR)-T cell therapies have shown tremendous results against various hematologic cancers. Prior to cell infusion, a host preconditioning regimen is required to achieve lymphodepletion and improve CAR-T cell pharmacokinetic exposure, leading to greater chances of therapeutic success. To better understand and quantify the impact of the preconditioning regimen, we built a population-based mechanistic pharmacokinetic-pharmacodynamic model describing the complex interplay between lymphodepletion, host immune system, homeostatic cytokines, and pharmacokinetics of UCART19, an allogeneic product developed against CD19+ B cells. Data were collected from a phase I clinical trial in adult relapsed/refractory B-cell acute lymphoblastic leukemia and revealed three different UCART19 temporal patterns: (i) expansion and persistence, (ii) transient expansion with subsequent rapid decline, and (iii) absence of observed expansion. On the basis of translational assumptions, the final model was able to capture this variability through the incorporation of IL-7 kinetics, which are thought to be increased owing to lymphodepletion, and through an elimination of UCART19 by host T cells, which is specific to the allogeneic context. Simulations from the final model recapitulated UCART19 expansion rates in the clinical trial, confirmed the need for alemtuzumab to observe UCART19 expansion (along with fludarabine cyclophosphamide), quantified the importance of allogeneic elimination, and suggested a high impact of multipotent memory T-cell subpopulations on UCART19 expansion and persistence. In addition to supporting the role of host cytokines and lymphocytes in CAR-T cell therapy, such a model could help optimizing the preconditioning regimens in future clinical trials.Significance:A mathematical mechanistic pharmacokinetic/pharmacodynamic model supports and captures quantitatively the beneficial impact of lymphodepleting patients before the infusion of an allogeneic CAR-T cell product. Mediation through IL-7 increase and host T lymphocytes decrease is underlined, and the model can be further used to optimize CAR-T cell therapies lymphodepletion regimen.

100 Deals associated with INS19 CAR-T Cells(Beijing Imunopharm Technology)

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Indication	Highest Phase	Country/Location	Organization	Date
B-Cell Leukemia	Phase 1	-	Beijing Imunopharm Technology Co., Ltd.Startup	15 Jan 2024
Pre B-cell acute lymphoblastic leukemia	Phase 1	-	Beijing Imunopharm Technology Co., Ltd.Startup	15 Jan 2024

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