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

ministration and most of them appear to be stuckin the lungs and liver. To obtain efficient
antitumor activity, we believe that more research should be focused on two issues.
How to bring more T-bodies to the tumor, and how to maintain the ones that
get stuckin the reticulo-endothelial system so that they will leave the liver and lungs
and seektheir tumor targets. Lessons learned from lymphocyte migration should be
adopted and may prove useful here. In the meantime, we may elect to focus on clinical
conditions where direct, intralesional administration of the engineered lymphocytes
is clinically reasonable and feasible, and may prove helpful as a neoadjuvant or
adjuvant treatment modality. The intratumoral administration of T-bodies into localized
prostate cancer, as we have practiced in the pre-clinical model described above,
is one of the favorable targets for such treatment.
Another issue that has been considered as crucial for optimal therapeutic performance
of the T bodies is to prolong their survival as functional cells in the patient.
We believe that the issue of immunogenicity of the scFv can be solved and the accumulated
experience in obtaining fully human or optimally humanized mAb will answer
the problem. Alternatively, a supply of moderate immunosuppressants can decrease
the tendency of generating anti-idiotypic antibodies in the patients. The issue
of antigen-induced cell death and the lackof long-term expansion of pre-activated T
cells can be solved by using tripartite CR that provides the CD28 co-stimulatory signal
to the programmed cells. Again, external cytokines such as IL-2 or optimal mixtures
of antigen-specific CD4 + and CD8 + cells can contribute to sustain and prolong
the survival of functional lymphocytes.
Altogether, we believe that the optimization of the T-body preparation and administration,
along the lines discussed above, combined with the experience that will be
acquired in phase I and II clinical trials, will allow the testing of the therapeutic effect
of T bodies in more realistic situations (in contrast to end-stage cases as currently applied)
and will put the T-body approach amongst the modalities for cancer therapy.
Acknowledgments
We are indebted to a group of devoted past and present members of our group and
colleagues who contributed to the studies described in this chapter. Recent studies
from our group were supported by the US Army Breast and Prostate Cancer Fellowships,
the European Union Life Science program, and CaP-CURE Israel.
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