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

290 14 The T-Body Approach: Towards Cancer Immuno-Gene Therapy
14.2.2
Anticancer Specificities of CRs
14.2.2.1 Cancer-specific antibodies
Since the development of the single-chain CR in 1993 [7], many anticancer antibodies
have served to generate T-bodies specific to a broad variety of tumors. Table 14.2
lists the various specificities employed by different groups.
Our group has focused on targeting the erbB2 molecule, a member of the erbB
growth factor receptors. Like others, we believe that the erbB2 is an excellent target
for immunotherapy, not only because of its over-expression, but also because it
serves, for certain tumors, as an oncoreceptor on which the transformed phenotype
is dependent [20]. This implies a growth disadvantage for tumor variants that will escape
immunotherapy by not expressing erbB2. The principal anti-erbB2 antibody we
used throughout these studies was N29, generated in Professor Yarden's laboratory
and was found to inhibit the growth of human cancer cell lines in nude mice [21].
Using erbB2-specific scFv±g or ±z CRs we [22] and others [23] have shown that Tcell
lines and hybridomas, as well as NK cells, could specifically kill a variety of erb-expressing
human cells and undergo stimulation for interleukin production following
in vitro interaction with these tumors. Moreover, Groner's group was the first to report
that erbB2-specific T-bodies could prevent the growth of syngeneic erbB2-transfected
NIH 3T3 tumors in mice [23, 24]. We demonstrated in a human prostate cancer
xenograft model in SCID mice that human lymphocytes, expressing the erbB2specific
tripartite receptor, could slow the progression of the human tumors and
even cure a significant number of mice (detailed in Section 14.2.3). Several other tumor-specific
T-body systems have been thoroughly studied in vitro, some of which
have been tested in vivo (see Tab. 14.2) and a few have reached the stage of clinical
trials and are discussed in Sections 14.2.3 and 14.2.4.
14.2.2.2 Ligands and receptors recognition units
In the previous section we have focused on the anticancer activities of lymphocytes
redirected with CRs with antibody specificity. Other molecules, such as receptors
whose ligands are selectively expressed on tumor cells, or ligands to receptors overexpressed
on certain cancers, can even serve as the specific recognition unit of CR.
In fact, the first single-chain CRs used to activate lymphocytes employed ectodomains
of the CD16 [25] and CD4 [26] (which was later used to target HIV infected
cells [27]). Certain groups have reported on CRs made of TCR [28]; however, only recently
a single-chain CR made with scFv of TCR specific to tumor peptide was expressed
on cancer cells. We have collaborated with the group of Professor Bolhuis in
designing the first of such single-chain CRs specific to the human melanoma
MAGE-1 peptide in association with HLA.A2 [29]. Further configurations of this
TCR-based CR were also shown to be functionally expressed in human T cells [29].
The advantage of this CR with TCR specificity is that such a recognition unit has
been naturally selected in terms of affinity and specificity to function in the T cell
milieu. However, since the repertoire of tumor-specific-defined TCRs is limited and
their scope of function is restricted to a certain HLA haplotype, it is likely to target