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Cd20 therapies, cd22 therapies, and combination therapies with cd19 chimeric antigen receptor (CAR)-expressing cell

A CD22 and cell technology, applied in the direction of receptor/cell surface antigen/cell surface determinant, anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, animal cells, etc., can solve incurable and clinically effective Sexual difficulties, side effects, etc.

Active Publication Date: 2018-07-31
NOVARTIS AG +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Many patients with B-cell malignancies are incurable with standard treatments
In addition, traditional treatment options often have severe side effects
Attempts have been made in cancer immunotherapy, but several obstacles make achieving clinical effectiveness a very difficult goal
Although hundreds of so-called tumor antigens have been identified, they are usually self-derived and thus poorly immunogenic

Method used

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  • Cd20 therapies, cd22 therapies, and combination therapies with cd19 chimeric antigen receptor (CAR)-expressing cell
  • Cd20 therapies, cd22 therapies, and combination therapies with cd19 chimeric antigen receptor (CAR)-expressing cell
  • Cd20 therapies, cd22 therapies, and combination therapies with cd19 chimeric antigen receptor (CAR)-expressing cell

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[1827] Example 1: CD19 CAR T cells for the treatment of multiple myeloma

[1828] Even with current chemotherapy regimens targeted therapy and autologous stem cell transplantation, myeloma is considered incurable. This example describes the treatment of multiple myeloma (MM) with CD19-directed autologous T cells with a chimeric antigen receptor (lentivirus / CD19:4-1BB:CD3zeta; also known as "CART19" or CTL019). This example demonstrates that CAR therapy targeting CD19 has the potential to establish deep long-term durable responses based on targeting myeloma stem cells and / or tumor cells expressing very low (undetectable by most methods) levels of CD19.

[1829] In treating patients with aggressive secondary plasma cell leukemia, we found that CART19 administered two days after salvage autologous stem cell transplantation resulted in rapid clearance of plasma cell leukemia, with a very good fraction in patients undergoing multiple lines of chemotherapy reaction. The patient wa...

Embodiment 2

[1915] Example 2: CAR19T cell therapy for Hodgkin's lymphoma

[1916] CAR19T cell therapy can also be used to treat Hodgkin's lymphoma (HL). Hodgkin's lymphoma is characterized by the presence of malignant Hodgkin Reed-Sternberg (HRS) cells derived from clonal germinal center B cells. Several factors suggest the efficacy of CAR19T cell therapy for HL. CD19 staining of HL tumors revealed CD19-expressing (CD19+) cells within the tumor and tumor microenvironment ( figure 2 ). A study showed that clonal B cell populations expressing CD19 (CD20 + CD27 + ALDH + ) is responsible for the generation and maintenance of Hodgkin's lymphoma cell lines and also circulates in the blood of most HL patients (Jones et al., Blood, 2009, 113(23):5920-5926). This clonal B cell population is also thought to cause or contribute to the generation of malignant HRS cells. Thus, CART19 treatment will deplete the B cell population that contributes to tumorigenesis or maintenance of tumor cells. ...

Embodiment 3

[1922] Example 3: A Subset of Non-Responders in CLL Patients Shows Increased Expression of Immune Checkpoint Inhibitor Molecules

[1923] In the present study, the expression of immune checkpoint inhibitor molecules such as PD-1, LAG3 and TIM3 was assessed in clinically manufactured CART19 cells from 34 CLL patients. The response of this cohort to CART19 is known, so the correlation between response and biomarker expression patterns can be assessed.

[1924] Prepared CART19 cells from CLL patients with different responses to CART therapy were analyzed by flow cytometry to determine the expression of CAR and immune checkpoint inhibitor molecules PD-1, LAG3 and TIM3. CART19 cells were derived from: healthy donors (HD) (n=2); CLL patients (n=5) who responded to CART therapy (CR); CLL patients who partially responded to CART therapy (PR) (n=8); did not respond to CART CLL patients treated (NR) (n=21). Cells were stained with fluorescently labeled antibodies that specifically rec...

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PUM

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Abstract

The invention provides compositions and methods for treating diseases associated with expression of CD19, e.g., by administering a recombinant T cell comprising the CD19 CAR as described herein, in combination with one or more B-cell inhibitors, e.g., inhibitors of one or more of CD1O, CD20, CD22, CD34, CD123, FLT-3, ROR1, CD79b, CD179b, or CD79a. The disclosure additionally features novel antigenbinding domains and CAR molecules directed to CD20 and CD22, and uses, e.g., as monotherapies or in combination therapies. The invention also provides kits and compositions described herein.

Description

[0001] This application claims U.S. Serial No. 62 / 144,615 filed April 8, 2015, U.S. Serial No. 62 / 144,497 filed April 8, 2015, U.S. Serial No. 62 / 144,639 filed April 8, 2015, 2015 Priority of US Serial No. 62 / 207,255 filed August 19, US Serial No. 62 / 263,423 filed December 4, 2015, the contents of which are hereby incorporated by reference in their entirety. technical field [0002] The invention generally relates to T cells engineered to express a chimeric antigen receptor (CAR), optionally with a B cell inhibitor, such as CD10, CD19, CD20, CD22, CD34, CD123, FLT-3, ROR1, CD79b, CD179b Or the use of one or more combinations of CD79a to treat diseases related to the expression of cluster of differentiation 19 protein (CD19). Background technique [0003] Many patients with B-cell malignancies are incurable with standard treatments. In addition, traditional treatment options often have serious side effects. Attempts have been made in cancer immunotherapy, but several obstac...

Claims

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Application Information

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IPC IPC(8): C07K14/725C07K16/28C12N5/0783A61K39/00
CPCC12N5/0636C12N5/0646C12N15/85C07K16/2803C07K16/2866C07K14/7051A61P35/02A61P35/00A61K45/06C12N2510/00C12N2800/107C07K2319/03C07K2319/33C07K2317/565C07K2317/569A61K39/464419A61K2239/38A61K39/4611A61K39/464424A61K39/464412A61K2239/48A61K39/464413A61K39/4631A61K39/4636C07K2317/24C07K2317/622C07K2319/00A61K2039/70A61K38/00A61P43/00C07K14/70596C07K16/28A61K39/0011C07K16/2851C07K19/00C12N5/10C12N15/63A61K2039/5156A61K2039/5158A61K39/001112A61K39/001113A61K39/001124
Inventor H·比特J·M·波尔多B·布拉尼迪J·布罗格顿N·K·达卡帕加里S·吉尔S·海菲尔L·黄C·H·琼J·Y·金姆M·雷N·李A·洛E·奥兰多M·鲁艾拉T·德兰J·张L·周
Owner NOVARTIS AG
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