Chimeric antigen receptor-expressing t cells as Anti-cancer therapeutics

Abstract

Cytotoxic lymphocytes expressing chimeric antigen receptors (CAR) that target and bind small conjugate molecules (SCM) are disclosed, as well as methods of using the cells and the SCMs in the treatment of cancer.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation application of U.S. application Ser. No. 14 / 654,227, filed on Jun. 19, 2015, which is a national stage entry under 35 U.S.C. §371(b) of PCT International Application No. PCT / US2013 / 076986, filed on Dec. 20, 2013, which claims priority under 35 U.S.C §119(e) to U.S. Provisional Application Ser. No. 61 / 740,384, filed on Dec. 20, 2012, each of which is incorporated herein by reference.BACKGROUND OF INVENTION[0002]Immunotherapy based on adoptive transfer of lymphocytes (e.g., T cells) into a patient can play an important role in eliminating cancer. Among many different types of immunotherapeutic agents, one of the most promising therapeutic methods being developed is T cells expressing Chimeric Antigen Receptors (CAR). CARs are genetically engineered receptors that are designed to target a specific antigen of a selected tumor [1]. For example, T cells that have cytotoxic activity are transfected with and gro...

AI Technical Summary

Benefits of technology

[0008]The invention relates to a Chimeric Antigen Receptor (CAR) system and methods for using the system in the treatment of subjects with cancer. The CAR system of the present invention includes cytotoxic lymphocytes expressing CARs that target a moiety that is not produced or expressed by cells of the subject being treated. This CAR system thus allows for focused targeting of the cytotoxic lymphocytes to target cells, such as cancer cells. The targeted moiety is part of a small conjugate molecule (SCM) that also comprises a ligand of a tumor cell receptor. Administration of a SCM along with the CAR-expressing cytotoxic lymphocytes results in the targeting of the cytotoxic lymphocyte response to only those cells expressing the tumor receptor to which the SCM is bound.

Problems solved by technology

Although T cells transduced to express such constructs showed positive results in vitro, they have been found to have limited performance in eliminating tumor cells in clinical trials.

The main limitation has been the relative inability to prolong and expand the T cells population and achieve sustained antitumor effects in vivo.

First, ‘off-target’ toxicities may result due to the fact that it is difficult to target only cancer cells via tumor-associated antigens because in many cases normal cells also express the tumor-associated antigen.

Second, ‘unregulated CAR activity’ may be found where the rapid eradication of cancer cells by CARs induces a constellation of metabolic disturbances, called tumor lysis syndrome or a cytokine storm, which can be a fatal consequence to patients [1, 4, 6].

This is a result because transduced T cells expressing CARs cannot be easily regulated.

Once transduced T cells are infused to patients, it is currently very difficult to regulate or control the activation of the cells.

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