Chimeric antigen receptors (CAR) are recombinant receptors that provide both antigen-binding and T-cell–activating functions. A multitude of CARs has been reported over the past decade, targeting an array of cell surface tumor antigens. Their biologic functions have dramatically changed following the introduction of tripartite receptors comprising a costimulatory domain, termed second-generation CARs. These have recently shown clinical benefit in patients treated with CD19-targeted autologous T cells. CARs may be combined with costimulatory ligands, chimeric costimulatory receptors, or cytokines to further enhance T-cell potency, specificity, and safety. CARs represent a new class of drugs with exciting potential for cancer immunotherapy.

Significance: CARs are a new class of drugs with great potential for cancer immunotherapy. Upon their expression in T lymphocytes, CARs direct potent, targeted immune responses that have recently shown encouraging clinical outcomes in a subset of patients with B-cell malignancies. This review focuses on the design of CARs, including the requirements for optimal antigen recognition and different modalities to provide costimulatory support to targeted T cells, which include the use of second- and third-generation CARs, costimulatory ligands, chimeric costimulatory receptors, and cytokines. Cancer Discov; 3(4); 388–98. ©2013 AACR.

https://cancerdiscovery.aacrjournals.org/content/candisc/early/2013/04/02/2159-8290.CD-12-0548.full.pdf

The Basic Principles of Chimeric Antigen Receptor Design

To increase the tumor specificity of engineered T cells, Kloss et al. design an approach that relies on T cell recognition of two, rather than one, antigens.

/pdf/combinatorial-antigen-recognition-with-balanced-signaling-2jvv1rlqly.pdf

Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells

Structural Design of Engineered Costimulation Determines Tumor Rejection Kinetics and Persistence of CAR T Cells

The present invention provides compositions and methods for treating cancer in a human. The invention includes relates to administering a genetically modified T cell to express a CAR wherein the CAR comprises an antigen binding domain, a transmembrane domain, a costimulatory signaling region, and a CD3 zeta signaling domain.

Use of chimeric antigen receptor-modified t cells to treat cancer

The promise and potential pitfalls of chimeric antigen receptors

Gene Transfer Efficiency and Genome-Wide Integration Profiling of Sleeping Beauty, Tol2, and PiggyBac Transposons in Human Primary T Cells

Umbilical cord blood (UCB) T cells can be redirected to kill leukemia and lymphoma cells by engineering with a single-chain chimeric antigen receptor (CAR) and thus may have general applications in adoptive cell therapy. However, the role of costimulatory molecules in UCB T-cell activation and effector functions in context with CAR remains elusive. To investigate the effect of costimulatory molecules (4-1BB and CD28) on UCB T cells, we transduced UCB T cells with lentiviral vectors expressing Green Fluorescent Protein (GFP) and CAR for CD19 containing an intracellular domain of the CD3ζ chain and either a 4-1BB (UCB-19BBζ) or a CD28 intracellular domain (UCB-1928ζ), both (UCB-1928BBζ), or neither (UCB-19ζ). We found that UCB-19BBζ and UCB-28BBζ T cells exhibited more cytotoxicity to CD19+ leukemia and lymphoma cell lines than UCB-19ζ and UCB-1928ζ, although differences in secretion of interleukin-2 and interferon-γ by these T cells were not evident. In vivo adoptive transfer of these T cells into...

/pdf/4-1bb-and-cd28-signaling-plays-a-synergistic-role-in-4zbvm2679r.pdf

4-1BB and CD28 signaling plays a synergistic role in redirecting umbilical cord blood T cells against B-cell malignancies.

Sleeping Beauty Transposon‐mediated Engineering of Human Primary T Cells for Therapy of CD19+ Lymphoid Malignancies

Erratum: Gene transfer efficiency and genome-wide integration profiling of sleeping beauty, tol2, and piggyBac transposons in human primary t cells (Molecular Therapy (2010) 18 (1803-1813) DOI:10.1038/mt.2010.141)

Syam Tammana

Papers

Gene Transfer Efficiency and Genome-Wide Integration Profiling of Sleeping Beauty, Tol2, and PiggyBac Transposons in Human Primary T Cells

4-1BB and CD28 signaling plays a synergistic role in redirecting umbilical cord blood T cells against B-cell malignancies.

Sleeping Beauty Transposon‐mediated Engineering of Human Primary T Cells for Therapy of CD19+ Lymphoid Malignancies

Erratum: Gene transfer efficiency and genome-wide integration profiling of sleeping beauty, tol2, and piggyBac transposons in human primary t cells (Molecular Therapy (2010) 18 (1803-1813) DOI:10.1038/mt.2010.141)