Treatment of cancer using Anti-cd19 chimeric antigen receptor

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 a kinase inhibitor, e.g., a kinase inhibitor described herein. The invention also provides kits and compositions described herein.

Description

[0001]This application is a divisional of U.S. Ser. No. 14 / 680,860, filed Apr. 7, 2015, which claims priority to U.S. Ser. No. 61 / 976,396 filed Apr. 7, 2014, U.S. Ser. No. 62 / 007,309 filed Jun. 3, 2014, U.S. Ser. No. 62 / 036,493 filed Aug. 12, 2014, U.S. Ser. No. 62 / 076,238 filed Nov. 6, 2014, U.S. Ser. No. 62 / 087,888 filed Dec. 5, 2014, and U.S. Ser. No. 62 / 097,278 filed Dec. 29, 2014, the contents of which are incorporated herein by reference in their entireties. International Application Number PCT / US15 / 24671, filed Apr. 7, 2015, is also incorporated herein by reference in its entirety.SEQUENCE LISTING[0002]The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Apr. 6, 2015, is named N2067-7051US_SL.txt and is 249,332 bytes in size.FIELD OF THE INVENTION[0003]The present invention relates generally to the use of T cells engineered to express a C...

AI Technical Summary

Benefits of technology

[0031]In another embodiment, the cell expressing the CAR molecule, e.g., as described herein, can further express another agent, e.g., an agent which enhances the activity of a CAR-expressing cell.

[0051]In one embodiment, the cell expressing a CAR molecule, e.g., a CAR molecule described herein, is administered in combination with an agent that increases the efficacy of a cell expressing a CAR molecule, e.g., an agent described herein.

[0055]In an embodiment this approach can be used to optimize the performance of a CAR cell described herein in the subject. While not wishing to be bound by theory, it is believed that, in an embodiment, the performance of endogenous, non-modified immune effector cells, e.g., T cells, is improved. While not wishing to be bound by theory, it is believed that, in an embodiment, the performance of a CD19 CAR expressing cell is improved. In other embodiments, cells, e.g., T cells, which have, or will be engineered to express a CAR, can be treated ex vivo by contact with an amount of an mTOR inhibitor that increases the number of PD1 negative immune effector cells, e.g., T cells or increases the ratio of PD1 negative immune effector cells, e.g., T cells / PD1 positive immune effector cells, e.g., T cells.

[0056]In an embodiment, administration of a low, immune enhancing, dose of an mTOR inhibitor, e.g., an allosteric inhibitor, e.g., RAD001, or a catalytic inhibitor, is initiated prior to administration of an CAR expressing cell described herein, e.g., T cells. In an embodiment, the mTOR inhibitor is RAD001 or rapamycin. In an embodiment, the CAR cells are administered after a sufficient time, or sufficient dosing, of an mTOR inhibitor, such that the level of PD1 negative immune effector cells, e.g., T cells, or the ratio of PD1 negative immune effector cells, e.g., T cells / PD1 positive immune effector cells, e.g., T cells, has been, at least transiently, increased.

Problems solved by technology

In addition, traditional treatment options often have serious side effects.

Attempts have been made in cancer immunotherapy, however, several obstacles render this a very difficult goal to achieve clinical effectiveness.

Although hundreds of so-called tumor antigens have been identified, these are generally derived from self and thus are poorly immunogenic.

Furthermore, tumors use several mechanisms to render themselves hostile to the initiation and propagation of immune attack.

The variable quality of T cells whether it's a result of anergy, suppression or exhaustion will have effects on CAR-transformed T cells' performance but for which skilled practitioners have limited control over at this time.

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