Toxicity Management for Anti-Tumor Activity of CARs

a technology of toxic management and car, which is applied in the field of toxic management of car antitumor activity, can solve the problems of insufficient investigation of car t cells on all blasts, more immature leukemia with a more rapid progression, and insufficient investigation of cytokine secretion and disorders associated with in vivo chimeric antigen recept t-cell expansion, so as to reduce or avoid an adverse effect

Inactive Publication Date: 2015-07-23
THE CHILDRENS HOSPITAL OF PHILADELPHIA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0012]The invention provides a method of reducing or avoiding an adverse effect associated with the administration of a cell genetically modified to express a CAR, wherein the CAR comprises an antigen binding domain, a transmembrane domain, and an intr

Problems solved by technology

However, the effects of CAR T cells on ALL blasts, a more immature leukemia with a more rapid progression, have not been fully investigated.
However

Method used

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  • Toxicity Management for Anti-Tumor Activity of CARs
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  • Toxicity Management for Anti-Tumor Activity of CARs

Examples

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experimental examples

[0160]The invention is further described in detail by reference to the following experimental examples. These examples are provided for purposes of illustration only, and are not intended to be limiting unless otherwise specified. Thus, the invention should in no way be construed as being limited to the following examples, but rather, should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.

[0161]Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the compounds of the present invention and practice the claimed methods. The following working examples therefore, specifically point out the preferred embodiments of the present invention, and are not to be construed as limiting in any way the remainder of the disclosure.

example 1

Cytokine Therapy in Combination with CAR T Cell Infusion

[0162]The results presented herein demonstrate that patients following infusion of CART cells exhibit differential expression levels of various cytokines. In some instances, the elevated levels of some cytokines are a result of the toxicity of the infused CAR T cells (FIG. 1). It was observed that tocilizumab (anti-IL6) can ameliorate the toxicity of CARs and seemingly preserve antitumor effects in 2 of 2 patients (FIG. 2). Without wishing to be bound by any particular theory, it is believed that anakinra and other reagents that block IL-1 may also be useful in this regard. The data presented herein also demonstrates that IL-1 is elevated in patients, and this may lead to the later rise in IL-6. Anakinra is an IL-1Ra recombinant protein which binds to the IL1 receptors and blocks both IL-1 alpha and beta signaling. Anakinra has a short ½ life. There is an advantage to use Anakinra to start treating patients since both IL-1 alph...

example 2

CD19-Redirected Chimeric Antigen Receptor T (CART19) Cells Induce a Cytokine Release Syndrome (CRS) and Induction of Treatable Macrophage Activation Syndrome (MAS) that can be Managed by the IL-6 Antagonist Tocilizumab (Toc)

[0164]Infusion of CART19 cells results in 100 to 100,000× in vivo proliferation, tumor lysis syndrome followed by durable antitumor activity, and prolonged persistence in patients with B cell tumors. The results presented herein demonstrate that in vivo proliferation of CART19 cells and potent anti-tumor activity therefrom is associated with CRS, leading to hemophagocytic lymphohistiocytosis (HLH), also termed MAS. Without wishing to be bound by any particular theory, it is believed that MAS / HLH is a unique biomarker that is associated with and may be required for potent anti-tumor activity.

[0165]Autologous T cells were lentivirally transduced with a CAR composed of anti-CD19 scFv / 4-1BB / CD3-zeta, activated / expanded ex-vivo with anti-CD3 / anti-CD28 beads, and then ...

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Abstract

The present invention provides compositions and methods for treating cancer in a patient. In one embodiment, the method comprises a first-line therapy comprising administering to a patient in need thereof a genetically modified T cell expressing a CAR wherein the CAR comprises an antigen binding domain, a transmembrane domain, a costimulatory signaling region, and a CD3 zeta signaling domain and monitoring the levels of cytokines in the patient post T cell infusion to determine the type of second-line of therapy appropriate for treating the patient as a consequence of the presence of the CAR T cell in the patient.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application claims priority to U.S. Provisional Patent Application No. 61 / 671,482, filed on Jul. 13, 2012 and U.S. Provisional Patent Application No. 61 / 782,982, filed on Mar. 14, 2013, each of which application is hereby incorporated herein by reference in its entirety.BACKGROUND OF THE INVENTION[0002]Patients with relapsed and chemotherapy-refractory acute lymphocytic leukemia (ALL) have a poor prognosis despite the use of aggressive therapies such as allogeneic hematopoietic stem cell transplantation (Barrett et al., 1994, N Engl J Med 331:1253-8; Gokbuget et al., 2012, Blood 120:2032-41) and bi-specific CD19 antibody fragments (Bargou et al., 2008, Science 321:974-7). Chimeric antigen receptor modified T cells targeting lineage-specific antigens CD19 and CD20 have been reported to be effective in adults with CLL and B-cell lymphomas (Till et al., 2008, Blood 112:2261-71; Kochenderfer et al., 2010, Blood 116:4099-102; Brentjens et ...

Claims

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Application Information

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IPC IPC(8): A61K39/395C12Q1/68G01N33/68A61K35/00A61K45/06
CPCA61K39/3955A61K35/00A61K45/06G01N2800/52C12Q1/6886A61K2039/505A61K2039/515G01N33/6803A61K31/7088A61K31/713G01N2333/52A61K48/0083A61P35/02A61P37/06A61P39/02A61K35/17A61K2300/00G01N33/6863
Inventor JUNE, CARL H.LEVINE, BRUCE L.KALOS, MICHAEL D.GRUPP, STEPHAN
Owner THE CHILDRENS HOSPITAL OF PHILADELPHIA
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