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Use of cd2/5/7 knock-out Anti-cd2/5/7 chimeric antigen receptor t cells against t cell lymphomas and leukemias

A chimeric antigen receptor, leukemia technology, applied to anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, receptor/cell surface antigen/cell surface determinant, NGF-receptor/TNF-receptor It can solve the problems of T-cell lymphoma and leukemia, such as poor prognosis, few treatment methods, and CART cells cannibalism.

Pending Publication Date: 2021-09-28
THE TRUSTEES OF THE UNIV OF PENNSYLVANIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

T-cell lymphomas and leukemias have a poor prognosis and few treatments are available
Chimeric antigen receptor T-cell (CART) therapy has proven effective against B-cell neoplasms, but successful expansion of CAR T-cells to T-cell malignancies is problematic because most target antigens are between normal and malignant cells shared, causing CAR T cells to kill each other

Method used

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  • Use of cd2/5/7 knock-out Anti-cd2/5/7 chimeric antigen receptor t cells against t cell lymphomas and leukemias
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  • Use of cd2/5/7 knock-out Anti-cd2/5/7 chimeric antigen receptor t cells against t cell lymphomas and leukemias

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0478] Example 1: A new approach to targeting T-cell lymphoma and leukemia without causing T-cell toxicity

[0479] The overall prognosis of T-cell lymphomas and leukemias is very poor, and few treatment options are available for these patients. Chimeric antigen receptor T-cell (CART) immunotherapy has achieved unprecedented results in CD 19+ B-cell non-Hodgkin's lymphoma (B-NHL). Herein, another successful "CART19-like" product was designed to target T-NHL. Since CD19 is not expressed in T-NHL, other targets such as CD2, CD5, CD7, etc. were evaluated for CART therapy. However, all of these targets are also expressed by normal T cells, leading to unacceptable clinical toxicity (T cell agenesis-immunodeficiency) ( figure 1 ). Herein, a safe and effective CART strategy for the treatment of T-cell lymphoma was developed by editing normal T cells resistant to CART killing ( figure 2 ). CART therapy against T-cell lymphomas and leukemias is feasible when CART targets (CD2, ...

Embodiment 2

[0480] Example 2: Anti-CD5 CAR T cells (CART5) and CD5 knockout (KO) normal T cells

[0481] This paper discloses a two-pronged immunotherapy comprising anti-CD5 CAR T cells (CART5) and CD5 knockout (KO) normal T cells ( image 3 ). CART5 destroys T-cell lymphoma (such as T-NHL) or T-cell leukemia cells, but also kills normal T cells. Infusion of CD5 KO normal T cells provides CART resistant T cell immunity until CART5 cells are depleted, in some cases by use of suicide genes (eg iCasp9, CD20 / rituximab or others).

[0482]CD5 was chosen as a T-NHL target due to its high expression on T-NHL cells and its lack of expression in tissues other than T cells and a small subset of B cells. Single chain variable fragments (scFv) with different affinities (#17, #34, #9 with high, medium and low affinity respectively (Klitgaard JL, et al. (2013) British journal of haematology 163:182-93)) were used ) generated six anti-CD5 CAR constructs and expressed them in T cells ( Figure 4-5 ...

Embodiment 3

[0503] Example 3: Anti-CD2 CAR T cells (CART2) and CD2 knockout (KO) normal T cells

[0504] This paper discloses a two-pronged approach to immunotherapy comprising anti-CD2 CAR T cells (CART2) and CD2 knockout (KO) normal T cells ( image 3 ). CART2 destroys T-cell lymphoma (such as T-NHL) or T-cell leukemia cells, but also kills normal T cells. Infusion of CD2 KO normal T cells provided CART-resistant T cell immunity until CART2 cells were depleted, in some cases through the use of suicide genes (eg iCasp9).

[0505] Guide RNAs were designed to knock down the CD2 gene (and CD5) using the CRISPR / Cas9 system. CD2 was efficiently knocked out in 78% of the T cell population. Second-generation anti-CD2 and anti-CD5 CARs (CART2 and CART5, respectively) were generated ( Figure 4 ). Knockout cells (CD2KO and CD5KO) were incubated with their corresponding CART cells (CART2 and CART5, respectively), stimulated and measured for population doubling ( Figure 7 ). Mock electrop...

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Abstract

The present invention includes compositions and methods for treating T cell lymphomas and leukemias. In certain aspects, the compositions and methods include CAR T cells targeting CD2, CD5, or CD7 and modified cells, wherein CD2, CD5, or CD7 has been knocked-out.

Description

[0001] Cross References to Related Applications [0002] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 62 / 782,131, filed December 19, 2018, which is hereby incorporated by reference in its entirety. Background technique [0003] T cell lymphomas and leukemias are aggressive neoplasms derived from T cell progenitors or differentiated T cells. Mature or peripheral T-cell lymphomas account for 10%-15% of all non-Hodgkin lymphomas, or approximately 7,000 to 10,000 cases per year in the United States. T-cell lymphomas and leukemias have a poor prognosis and few treatments are available. Chimeric antigen receptor T-cell (CART) therapy has proven effective against B-cell neoplasms, but successful expansion of CAR T-cells to T-cell malignancies is problematic because most target antigens are between normal and malignant cells shared, causing CAR T cells to kill each other. [0004] There is a need for compositions and methods f...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28C12N5/00C12N9/22
CPCC12N9/22C07K16/2896C07K16/2806C07K16/2803C07K2317/522C07K2317/31C07K2319/33C07K2319/03C07K2317/92C07K14/70507C07K14/7051A61K2039/804C12N2310/20C12N15/1138C12N5/0636C12N2501/515C12N2510/00C12N2501/53C12N2501/599A61K39/4611A61K39/4631A61K2239/38A61K39/464429A61K2239/48A61P35/00C07K14/705C12N9/641C07K2319/02C07K2317/622A61K39/001129A61K2039/5156A61P35/02A61K38/00A61K2039/505C07K14/70578C07K14/70596C07K2317/565C07K2319/30C07K14/4748
Inventor M·鲁埃拉S·吉尔C·H·祝恩A·D·波西D·J·鲍威尔
Owner THE TRUSTEES OF THE UNIV OF PENNSYLVANIA
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