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Modified cell expansion and uses thereof

A technology of cells and cell groups, which is applied in the field of expansion of modified cells and its application, and can solve the problems of slow progress in the treatment of solid tumors

Pending Publication Date: 2021-11-19
斯丹赛控股有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, progress in the treatment of solid tumors has been relatively slow

Method used

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  • Modified cell expansion and uses thereof
  • Modified cell expansion and uses thereof
  • Modified cell expansion and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0474] Example 1. Bispecific CAR

[0475] Lentiviral vectors encoding the individual CAR molecules were generated and transfected with T cells as detailed below. For technologies related to cell culture and cytotoxic T lymphocyte assay construction, please refer to "Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains", PNAS, March 3, 2009, Volume 106, Issue 9 , pp. 3360-3365 and "Chimeric Receptors Containing CD137 Signal Transduction Domains Mediate Enhanced Survival of TCells and Increased Antileukemic Efficacy In Vivo," Molecular Therapy, 2009, Vol. 17 No. 8, pp. 1453-1464, cited by reference method is incorporated into this article as a whole.

[0476] On day 0, peripheral blood was drawn from healthy volunteers and sorted to collect CD3+ T cells. CD3 / CD28 Dynabeads were added to collected CD3+ T cells at a ratio of 1:1. On day 1, a vector comprising CD19 CAR (MOI=15; the binding domain of CAR is SEQ...

Embodiment 2

[0503] Example 2. CAR T cell expansion and antitumor activity in patients

[0504] The clinical study was designed to assess the safety and efficacy of infusion into patients of autologous T cells modified to express CAR / 4-1BB / CD3-ζ specific for several solid tumor markers. In the first arm (arm) of the study, patients received only solid tumor marker-specific CAR T cells. Solid tumor markers include TSHR and tMUC1. In the second cohort, patients received CAR T cells directed against CD19 and solid tumor antigens (eg, TSHR, tMUC1, or GUCY2C). T cells from the patient are obtained, modified and infused into the patient. T cell responses of patients from the first and second groups were measured and compared using the following protocol approved by the hospital conducting the trial. Written informed consent was provided to all patients. Information on these patients is provided in Table 9 below (SD: stable disease; PD: progressive disease; PR: partial response; CR: complete ...

Embodiment 3

[0533] Example 3. Activation of coupled / mixed T cells

[0534] Mixed CAR T cells (coupled CAR T cells) were divided into three groups for activation assays: CD19 CAR and tMUC1 CAR (group 1), anti-CD19 CAR and ACPP CAR (group 2), and CD19 and CLDN18.2 CAR (group 2). Group 3). Peripheral blood was collected from healthy volunteers. CD3+ T cells were sorted with Pan T kit and added to CD3 / CD28 Dynabead at a ratio of 1:1. CD3+ T cells were then transfected with lentivirus. Remove lentivirus and Dynabead and add fresh medium. Determine CAR ratio and cell phenotype. CAR expression in these three groups of cells was measured. CD19 CAR T cells, tMUC1 CAR T cells and target cells were selected and mixed for 24 hours or 48 hours. The expression of various markers in the corresponding cells was measured. Will 20x10 4 CAR T cells and 20x 10 4 Substrate cells were co-cultured for 24 hours. The expression of molecules such as hCAR (humanized scFv), mCAR (murine scFv), CD25 and CD1...

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Abstract

The present disclosure relates to compositions and methods for enhancing T cell response and / or CAR cell expansion and / or maintenance in vivo and / or in vitro. For example, a method of enhancing T cell-based therapy comprises administering a mixed population of T cells comprising modified T cells comprising a first chimeric antigen receptor (CAR) and modified T cells comprising a second CAR, wherein a binding domain of the first CAR binds a first antigen, and a binding domain of the second CAR binds a second antigen. The first antigen is different from the second antigen. In embodiments, the first CAR binds a surface molecule or antigen of a white blood cell.

Description

[0001] Cross References to Related Applications [0002] This application is a continuation-in-part of US Application 16 / 445,965, filed June 19, 2019, and US Application 16 / 387,166, filed April 17, 2019. This application also claims U.S. Provisional Application 62 / 932,587, filed November 8, 2019; U.S. Provisional Application 62 / 902,766, filed September 19, 2019; U.S. Provisional Application 62 / 891,131, filed August 23, 2019; 2019 U.S. Provisional Application 62 / 889,926, filed August 21, 2019; U.S. Provisional Application 62 / 848,961, filed May 16, 2019; U.S. Provisional Application 62 / 846,563, filed May 10, 2019; March 12, 2019 U.S. Provisional Application 62 / 817,322, filed March 11, 2019; U.S. Provisional Application 62 / 799,462, filed January 31, 2019; and U.S. Provisional Application 62 / 799,462, filed January 10, 2019 The benefit of application 62 / 790,783, said US provisional application is hereby incorporated by reference in its entirety. [0003] Sequence Listing Informatio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K35/17C12N5/0783A61K39/00C07K16/28C07K16/30C07K19/00
CPCC12N5/0636C07K14/7051C07K16/2803C07K16/2878C07K16/30C07K14/5412C07K14/5434C07K14/57A61K39/001112A61K39/001113A61K39/001117A61K39/00114A61K39/001141A61P35/00C12N2510/00C07K2319/33A61K2039/5158C07K2319/03C07K2317/31C07K2317/622C07K16/2869C07K2317/24C07K2317/73C07K14/4748C12N2740/16043C12N5/0635C12N2501/515C12N2501/599A61K2039/836A61K2039/82A61K2039/812A61K2039/852A61K39/46447A61K39/4611A61K39/464412A61K39/464488A61K39/4631A61K39/464444A61K2239/50A61K39/464481A61K2239/30A61K38/204A61K38/217C07K16/28A61K2039/585A61K2039/804A61K2300/00C12N2740/15041A61K39/0011A61K35/17A61K2039/5156A61K2039/505C07K14/70521C07K14/70578C07K2319/02C07K2319/30
Inventor 肖磊蒲程飞曹志远
Owner 斯丹赛控股有限公司
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