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Combination immune therapy and cytokine control therapy for cancer treatment

A pro-inflammatory cytokine and cell technology, applied in the fields of proliferation rate composition and efficacy composition, can solve problems such as tissue damage

Pending Publication Date: 2018-12-21
恩立夫克治疗RDO有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

If CAR-targeted tumor-associated antigens are expressed in normal tissues, as normal B cells are depleted by anti-CD19 CAR T cells, these tissues may be damaged

Method used

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  • Combination immune therapy and cytokine control therapy for cancer treatment
  • Combination immune therapy and cytokine control therapy for cancer treatment
  • Combination immune therapy and cytokine control therapy for cancer treatment

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0554] Example 1: Apoptotic cell generation process

[0555] Purpose: To generate early apoptotic cells for use in the methods described herein.

[0556] method:

[0557] Methods for preparing early apoptotic cell populations are described in detail in WO2014 / 087408 International Publication and US2015 / 0275175-A1 US Application Publication, see, for example, the previous examples of "ApoCell Preparation" and "Apoptotic Cell Generation" The Methods section (paragraphs [0223] to [0288]), as well as Examples 11, 12, 13 and 14, are incorporated herein in their entirety.

[0558] figure 1 The flow chart shown provides an overview of one embodiment of the steps used in the production of an early apoptotic cell population, where an anticoagulant is included in the preparation step. The time point of adding anticoagulant during the production process is indicated in the flowchart. As described in detail in Example 14 of International Publication No. WO2014 / 087408 and U.S. Applicat...

Embodiment 2

[0567] Example 2: Effect of apoptotic cells on cytokine release in an in vitro cytokine storm model

[0568]Objective: To detect the cytokine storm markers (cytokines IL-6, IL-10, MIP-1α, IL-8, TNF-α, MIP-1β, MCP-1 and IL-9) levels.

[0569] method:

[0570] Cell Lines and Culture Reagents

[0571] Human lymphoma cell line Raji (eCACC, UK, accession number 85011429), human cervical cancer cell line HeLa (ATCC, US, number CCL-2) and HeLa-CD19 (ProMab, US, catalog number PM-Hela-CD19) Be cultured in supplemented with 10% FBS (Gibco, Thermo Fisher Scientific Company, South America, catalog number 12657-029), 2mM GlutaMAX (Gibco, Thermo Fisher Scientific Company, USA, catalog number 35050-038) And in RPMI 1640 (Gibco, Thermo Fisher Scientific, USA, catalog number 31870-025) of 100U / ml penicillin+100U / ml streptomycin (Gibco, ThermoFisher Scientific, USA, catalog number 15140-122), This RPMI 1640 is hereinafter referred to as "complete medium". The HeLa-CD19 medium was further ...

Embodiment 3

[0581] Example 3: Effect of apoptotic cells on cytokine storm without negative impact on CAR T cell efficacy

[0582] Objective: To detect the effect of apoptotic cells or supernatants derived from apoptotic cells on cytokine storm marker cytokines and the efficacy of CAR T cells on tumor cells.

[0583] method:

[0584] T4+CAR T cells

[0585] A solid tumor model reported to induce a cytokine storm in mice was utilized (van der Stegen et al., 2013 supra). In this model, T cells (T4 + CAR-T cells), these ErbB dimers are often highly upregulated in specific solid tumors such as head and neck tumors and ovarian cancer. T cells were isolated from PBMC isolated from peripheral blood using CD3 microbeads. Construct containing chimeric T4 + recipient vector and transduce it into isolated T cells to obtain T4 + CAR T cells. For the experiments carried out in this paper, T4 + CAR T cells were purchased from Creative Biolabs (New York, USA) or Promab Biotechnologies (California...

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Abstract

Compositions disclosed herein, and methods of use thereof included those for inhibiting or reducing the incidence of cytokine release syndrome or cytokine storm in a subject undergoing CAR T-cell therapy, wherein the subjects are administered compositions comprising apoptotic cells or apoptotic cell supernatants. In certain instances compositions and methods of use thereof disclosed herein do notreduce the efficacy of the CAR T-cell cancer therapy. Disclosed herein are also compositions and methods of use thereof for decreasing or inhibiting cytokine production in a subject experiencing cytokine release syndrome or cytokine storm comprising administration of a composition comprising apoptotic cells or an apoptotic cell supernatant.

Description

technical field [0001] Disclosed herein are compositions and methods thereof for maintaining or increasing the proliferation rate of chimeric antigen receptor expressing T cells during CAR T cell cancer therapy. In addition, disclosed herein are compositions and methods for increasing the efficacy of chimeric antigen receptor T cell cancer therapy, wherein the incidence of a subject experiencing cytokine release syndrome or cytokine storm is reduced or inhibited. The method disclosed herein includes: a method comprising administering CAR T cells and an additional agent, the additional agent comprising apoptotic cells, apoptotic cell supernatant, CTLA-4 blocking agent, α-1 antitrypsin or a fragment thereof or analogs, tellurium-based compounds or immunomodulators, or any combination thereof. Background technique [0002] While the standard treatments for cancer are surgery, chemotherapy and radiation therapy, improved approaches, such as targeted immunotherapy, are currently...

Claims

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Application Information

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IPC IPC(8): A61K35/17A61P35/00
CPCC12N5/0636C12N2510/00C07K16/2803C07K2317/622C07K2319/03C07K2319/33A61P35/00A61K2239/59A61K39/464406C12N5/0638A61K2239/31A61K39/464412A61K39/4631A61K2239/48A61K2239/38A61K39/4611A61K39/464419C12N5/0646C12N5/0634A61K45/06C12N2502/11A61K2039/5158A61K39/0011A61K35/17
Inventor S·诺维克D·梅沃拉克
Owner 恩立夫克治疗RDO有限责任公司
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