eCommons

 

Interleukin 12-Secreting Chimeric Antigen Receptor T Cells And Cancer Immunotherapy

Other Titles

Abstract

For an adoptive T cell immunotherapy to successfully treat cancer, T cells must be able to recognize tumor antigen, expand and persist in the tumor microenvironment, and deliver its effector function. Treatment of B cell acute lymphoblastic leukemia (B-ALL) using human T cells modified to express a “second generation” CD19-targeted chimeric antigen receptor (CAR), which includes the CD28 co-stimulatory signaling domain (19-28z) along with the CD3 zeta chain signaling domain, has been successfully demonstrated in both the pre-clinical and clinical settings. However, application of CAR therapy for the treatment of B cell chronic lymphocytic leukemia (B-CLL) and solid tumors remains a challenge. Here, we present preclinical studies demonstrating that further modifying 19-28z CAR T cells to additionally secrete a recombinant fusion protein of the pro-inflammatory interleukin 12 (IL-12) (19-28z/mIL-12 CAR T cells) enhances the potency of adoptive T cell immunotherapy. We demonstrate that these 19-28z/mIL-12 “armored” CAR T cells display increased proliferation, up-regulation of perforin and granzyme B, as well as a central memory-like phenotype when compared to T cells transduced to express the 19-28z CAR alone. In vivo, treatment of systemic NALM-6 B-ALL tumor-bearing SCID-Beige mice with 19-28z/mIL-12 CAR T cells significantly improved survival when compared to mice treated with T cells modified to express the 19-28z CAR alone. Furthermore, in contrast to T cells modified to express the 19-28z CAR alone, 19-28z/mIL-12 CAR T cells resist CD4+CD25hiFOXP3+ Treg-mediated immunosuppression in vitro and successfully eradicate Raji Burkitt’s lymphoma tumor in SCID-Beige tumor-bearing mice previously infused with CD19-targeted CAR modified Tregs. These findings have important implications for future clinical trials with CAR T cells designed to enhance the clinical outcomes of relapsed B-CLL as well as solid tumor malignancies.

Journal / Series

Volume & Issue

Description

Sponsorship

Date Issued

2016

Publisher

Keywords

cancer; CAR; IL-12; immunotherapy; T cell; Treg

Location

Effective Date

Expiration Date

Sector

Employer

Union

Union Local

NAICS

Number of Workers

Committee Chair

Committee Co-Chair

Committee Member

Degree Discipline

Immunology & Microbial Pathogenesis

Degree Name

Degree Level

Doctor of Philosophy

Related Version

Related DOI

Related To

Related Part

Based on Related Item

Has Other Format(s)

Part of Related Item

Related To

Related Publication(s)

Link(s) to Related Publication(s)

References

Link(s) to Reference(s)

Previously Published As

Government Document

ISBN

ISMN

ISSN

Other Identifiers

Rights

Attribution-NonCommercial-NoDerivatives 4.0 International

Types

dissertation or thesis

Accessibility Feature

Accessibility Hazard

Accessibility Summary

Link(s) to Catalog Record