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

292 14 The T-Body Approach: Towards Cancer Immuno-Gene Therapy
only those tumor cells which express the given HLA peptide, which is often not expressed
in tumors that escape the host immune system.
As to ligand-based CR,we have developed CRs using the erbB ligand Heregulin [also
known as Neuregulin differentiation factor (NDF)] (Feigelson et al., submitted). We
and others [30] used NDF to target adenocarcinoma cells over-expressing the erbB family
of oncogenic receptors. NDF is known to bind to homodimers of erbB3 and
erbB4, and with higher affinity to heterodimers of these molecules with the erbB2
[20]. In our study the CR was made of the EGF (epidermal growth factor), cysteinerich
domain of NDF that encompasses all the binding ability of NDF. T cells expressing
such NDF-based CR indeed demonstrated functional specificity of NDF ± they
underwent activation by human breast and ovarian carcinoma cells expressing
erbB3 and erB4, with and without erbB2, and not with targets expressing only the
erbB2. These results suggest a different targeting specificity than the anti-erbB antibodies,
which may be advantageous towards certain types of cancers and may provide
a higher level of selectivity over normal tissue, and as such may serve as a valid
option for therapy.
14.2.3.
Pre-Clinical Experimental Models
In vitro, the CR approach has proved helpful in conferring antitumor specificity to effector
lymphocytes, stimulating these cells for cytokines production and target cell
killing. However, although promising, the information derived under such conditions
is not sufficient to provide us with important information as to the potential
therapeutic potential of T-bodies. Without entering into the legitimate argument
whether there is an appropriate in vivo experimental system that can equal or mimic
with high fidelity the human situation, we strongly believe that some critical elements
related to the T-body therapy can be tested and evaluated in experimental animal
models, provided that the artificial conditions are controlled and taken into account.
Several in vivo models have been employed to evaluate the anticancer potential of the
T-body approach. In the first one [23], mouse T cells expressing erbB2-specific CR
were injected (together with its target transfected with the human erbB2 gene) subcutaneously
(s.c.) into nude mice. In such a model it was observed that the tumor development
was significantly delayed. In a more recent study by the same group [24],
it was shown that erbB2-specific splenic T cells directly and repeatedly administered
into erbB2-expressing mouse mammary tumors resulted in a total tumor regression.
Using carcinoembryonic antigen (CEA)-specific CR-expressing cytotoxic T lymphocytes
(CTLs) from different mice [31], Smith's group showed an in vivo anticolon carcinoma
effect. The CTLs used in this study required perforin and interferon (IFN)-g
and were independent of Fas ligand or tumor necrosis factor. In a more clinically relevant
experiment [32], Hwu, in collaboration with us, used murine tumor-infiltrating
lymphocytes transduced with the folate binding protein (FBP)-specific CR. The
tumor target was a syngeneic metastatic sarcoma, transduced with the human FBP
gene. When injected intravenously into mice, with a systemic daily supply of IL-2, it
was clearly shown that the only group of mice that developed a significantly lower