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

number of lung metastasis was the one treated with the FBP-specific T cells plus
IL-2. Another in vivo study by the same group [33] evaluated the potency of bone marrow
stem cells, transduced with FBP-specific CR gene, to differentiate and mature
into specific effector cells. Indeed, in mice whose hematopoietic system was reconstituted
by FBP-expressing bone marrow a retardation of the growth of FBP-expressing
tumor was observed. Interestingly, T cells were not directly involved in this process.
Depletion of CD4 and CD8 cells did not diminish the antitumor activity, and it was
suggested that NK cells and/or macrophages expressing the anti-FBP CR are responsible
for this effect. These experiments highlighted an extension of the T-body approach
by the administration of effector cells into patients undergoing systemic cytoablative
therapy. Immediate possible candidates for such a treatment are leukemic
patients receiving stem cells grafts. The tripartite CR is the construct of choice for
such treatment because of the support of the built-in co-stimulatory signaling function
to the priming and activation of naive T cells to mature specific effector cells.
Recently we have evaluated the therapeutic efficacy of anti-erbB2 CR-bearing human
lymphocytes on human prostate cancer xenografts in a SCID mouse model (Pinthus
et al., submitted). Local delivery of erbB2-specific human lymphocytes to well-established
subcutaneously and orthotopic tumors resulted in retardation of tumor
growth and prostate-specific antigen (PSA) secretion, prolongation of survival and,
importantly, tumor elimination in a significant number of mice. Concurrent administration
of IL-2 was required for effective rejection of the prostate cancer xenograft.
We believe that prostate cancer is an excellent candidate for T-body therapy not only
because it expresses a variety of tissue- and tumor-specific antigens that can serve as
targets (e.g. PSMA [34], PSCA [35], STEAP [36], PCTA-1 [37] and erbB2 [38, 39]) and
for monitoring disease progression (such as PSA), but also because direct trans-rectal
ultrasound guided intratumoral administration of the T-bodies into localized tumors
is a valid therapeutic option.
14.2.4.
Clinical Trials
14.2 CRs with Antitumor Specificity
The T-body approach has already been used in clinical trials. So far, several phase I
trials have been initiated. Because of the lackof published information it is impossible
to objectively evaluate these trials. Therefore, most of the information provided
below is based on a recent review by Junghans [4] who has also conducted one of
these trials. The most documented phase I trial was conducted in HIV-infected subjects
receiving 3 × 10 10 autologous lymphocytes bearing the CD4 z CR [40]. Out of 24
patients, 11 also received concurrent 6 × 10 7 IU/24 h IL-2 infusions for 5 days. The
treatment was well tolerated with grade 3 or 4 adverse events predominantly associated
with the IL-2 infusion. In some patients a transient decrease of the viral load
was observed in the plasma and the rectal mucosa, the tissue reservoir for HIV. All
24 subjects tested negative for replication-competent retrovirus for up to 1 year after
infusion. Cell Genesys, the company which carried out this study, also conducted
phase I clinical trials in colorectal patients using the anti-TAG72-z CR made from
the humanized CC49 mAb [41]. However, this trial was terminated due to the devel-
293