Veterans Affairs

CCR4 directed chimeric antigen receptor to treat a spectrum of T-cell malignancies

Cellular therapy approach for T-cell malignancies in which ex-vivo engineered T-cells can be utilized to abate several cancers

Medical & Biotechnology

A healthy T-cell. Image Credit: NIAID/NIH

Scientists at the VA have recently identified a chimeric antigen receptor (CAR) that targets chemokine receptor CCR4 for use in treating various cancers. The patented technology is available via patent license agreement to companies that would make, use, or sell it commercially.

Given the emerging success of treating CD19 expressing B-cell malignancies with ex vivo modified, autologous T-cells that express CD19‐directed CAR, there is intense interest in expanding this evolving technology to develop effective modalities to treat other malignancies including solid tumors.

Exploiting this approach to develop a therapeutic modality for T-cell malignancies for which the available regimens are neither curative, nor confer long term survival, VA researchers generated a lentivirus‐based CAR gene transfer system to target the chemokine receptor CCR4 that is over‐expressed in many T-cell malignancies as well as in CD4+CD25+Foxp3+T regulatory cells that accumulate in the tumor microenvironment constituting a barrier against anti‐tumor immunity.

The ex vivo modified, donor‐derived T-cells that express CCR4 directed CAR display antigen‐dependent potent cytotoxicity against patient‐derived cell lines representing adult T-cell lymphoma (ATL), cutaneous T-cell lymphoma, and anaplastic large cell lymphoma. These CAR T-cells eradicated leukemia in a mouse xenograft model of ATL illustrating the potential utility of this modality in the treatment of a wide spectrum of T-cell malignancies.

The invention represents a gene transfer system used to genetically engineer autologous T-cells to express a CAR that targets CCR4 using humanized variable heavy and kappa light chain moieties derived from an anti-CCR4 antibody. The CAR is introduced into T-cells, which were documented to target cells of several malignancies, specifically lymphoid malignancies. Donor T cells modified ex-vivo with the CCR4 targeting CAR efficiently lyse patient-derived tumor cell lines that express CCR4 in an antigen-specific manner and in vivo efficacy has been demonstrated in a model of adult T cell leukemia.

The technology includes a method of identifying lymphoid or solid tumors that produce CCR4 mRNA and then utilizing CD3+ T-cells or NK cells to generate genetically modified T-cells and/or NK cells (autologous or allogeneic) that express the CCR4 directed CAR. The identified malignancy can then be treated with the infusion of genetically modified T/NK cells.

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