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

294 14 The T-Body Approach: Towards Cancer Immuno-Gene Therapy
opment of anti-idiotypic antibodies in the patients' sera that caused misleading interpretation
of the results. Junghans' group applied 24 doses of CEA-specific R-bearing
lymphocytes, totaling to up to 10 11 per patient. The treatment was reported to be adequately
tolerated with only two minor responses observed in two patients [42]. Hwu
and colleagues at the NCI are conducting a phase I clinical trial in ovarian patients
using T-bodies made of the FBP-specific CR described below. Escalated doses of the
modified cells are infused into the patients together with controlled administration
of IL-2. So far no adverse side effects have been seen, neither was there any improvement
in the patient status. In some of the patients' sera neutralizing antibodies were
found, specific to the murine MoV18 mAb from which the scFv was derived.
Although not unexpected in the category of patients in which these trials were carried
out, some warning signals emerge that need our attention in further developing
this approach to effective therapy. These are related in part to the formation of neutralizing
antibodies (following either murine or humanized scFv CR administration),
to the low number of engineered cells that eventually reach the tumor and to
the relative short survival of the patients, reflecting their end-stage disease.
Altogether these results are encouraging with respect to the lackof adverse effects related
to the T-body administration.
14.3
Conclusions and Perspectives
As described in this chapter, great progress has been already accomplished along the
road of application of the T-body approach to cancer immunotherapy. We have at our
disposal a large repertoire of antibodies that can selectively recognize tumor-associated
antigens in human cancer, we know how to optimally design the CR configuration
to fit a certain disease or cell, and the advent of gene delivery and lymphocyte
culture technologies allows us to obtain very large quantities of genetically engineered,
designer lymphocytes, stably expressing functional receptors. In the few
clinical trials done so far, these lymphocytes appear safe even after the administration
of 10 11 cells per patient. Yet, we lacksufficient information to optimize the effect
of these lymphocytes in the patient. From the classical adoptive immunotherapy
using unarmed lymphocytes such as tumor-infiltrating lymphocytes or LAK cells,
and from more recent pre-clinical studies using T-bodies in experimental systems,
we know that continuous supply of IL-2 supports the effector function of T cells. We
are now starting to understand the contribution of supplementing CR-bearing CD4 +
cells to the redirected, CR-bearing CD8 + CTLs. Apparently, the PBL-derived T cells,
following to their activation, transduction and prolonged propagation in vitro, alter
their homing properties and do not behave like the good ªoldº splenocytes that can
faithfully transfer T cell immunity to their syngeneic mouse host.
We want the T-bodies to home to the tumor site after their systemic administration,
and, upon interaction with the target antigen, to kill the tumor and undergo activation
and induce local inflammation that will result in complete tumor elimination.
Apparently, not too many CR bearing lymphocytes reach the tumor after their ad-