Cancer Immune Therapy Edited by G. Stuhler and P. Walden ...

288 14 The T-Body Approach: Towards Cancer Immuno-Gene Therapy
14.2
CRs with Antitumor Specificity
14.2.1
Optimizing the CR Design
14.2.1.1 The single-chain CR
The original chimeric TCR configuration did not comply with the practical requirements
for its application in tumor therapy. In order to express it in the patient's lymphocytes,
one has to deliver two genes ± each encoding one of the two TCR chains.
Such an undertaking was very inefficient considering the state of the art of gene delivery
in the early 1990s. We therefore introduced and developed the single-chain
CR, where we tookadvantage of the ability to express the antibody binding in the
form of single-chain Fv (scFv) [5, 6]. Here we joined the scFv to receptor chains, such
as the CD3 z chain or FcR g chain, which are capable of directly triggering T cell activation
[7]. Such a single-chain configuration now enabled the expression of the CR
following only one gene transfer. This innovation opened a new era in the development
of T-bodies towards the adoptive immunotherapy of cancer. It was indeed reflected
by the many research groups that joined the effort and many CRs were developed
to cancers of various histologies (see Tab. 14.2 below). Combined with the advent
in gene transfer into lymphocytes it became a valid option for clinical trials. The
single-chain configuration also expanded the choice of T cell triggering molecules
that could be used in the CR context, thereby extending the repertoire of effector
cells whose specificity could be redirected by this genetic manipulation (Tab. 14.1).
We have shown, for example, that the CR can redirect the specificity of a natural
killer (NK)-like cell line [8].
14.2.1.2 Direct recruitment of intracellular triggering molecules
In the clinic the CRs will have to be expressed in lymphocytes of tumor patients and
it is likely that the first clinical trials will be performed in patients with advanced disease
that has resisted common therapeutic treatments. It has been known for a while
now that lymphocytes derived from patients with a heavy tumor burden are often defective
in their signaling pathway due to impaired protein tyrosine kinases (PTKs)
Tab. 14.1 Molecules and cells employed in the scFcR context
Receptor Subunit chain Cells
TCR a, b, g, d T cells
CD3 z, Z, g T cells
FcgRIII CD16a, g NK, lymphokine-activated killer
(LAK) cells
IL-2R a, b, g lymphocytes
IL-nR various chains lymphocytes
Cytoplasmic + transmembrane PTK lymphocytes