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

192 9 Dendritic Cells and Cancer: Prospects for Cancer Vaccination
after autologous stem cell transplant for multiple myeloma. A remarkable nine out
of 18 clinical responses [ five complete responses (CRs) and four partial responses
(PRs)] were seen in this context (F. H. Valone, personal communication)
It is perhaps in melanoma that greatest interest was aroused and there are a plethora
of trials in progress. Few have been formally reported, but the follow-up from the
first description of the use of Mo-DCs and melanoma peptides/tumor lysates [132]
shows two CRs and three PRs in 21 patients with metastatic disease, indicating an
ongoing control of disease in the proportion of patients who responded with a mean
survival of over 47 months in responder patients. This protocol induced peptide-specific
T cell responses in 10 out of 10 HLA-A2 patients. A second trial [141] used Mo-
DCs matured in monocyte-conditioned medium s.c. and i.d. induced specific CTL
expansion in eight out of 11 HLA/A1 patients, but notably these responses declined
after further i.v. injections. Regression of metastases occurred in six out of 11 patients.
Notably, the same group has reported poor clinical results (no regressions in
eight evaluable patients) in a third study involving HLA-A2 individuals, but using
the same MAGE-3 antigen. Curiously, the later patient group had active melanoma
peptide-specific IFN-g effector CD8 + T cells (confirmatory cytotoxic studies were not
performed) present and received DCs by the possibly more optimal s.c. protocol.
However, a fourth published study [76] using immature Mo-DCs administered i.d.
produced poor cytotoxic responses and had only one partial clinical response in seven
patients evaluated. A protocol which used CD34 + -derived DCs administered s.c.
enhanced immunity in at least one assay (ELISPOT or proliferation) in 16 of 18 patients
± DTH responses were independent of blood assay results [91]. During a 10week
evaluation, four patients with multiple lesions experience regression at one or
more disease sites and three with limited disease cleared evidence of the disease. In
broad terms, immunological responses predicted for disease response. Another trial
made use of CD34 + -derived DCs but gave them i.v. ± the monitoring of immunological
responses was limited, but these patients had a lesser clinical response, again
suggesting that perhaps the i.v. route is less effective [89].
A consensus (including unpublished studies) is emerging despite the different approaches
that in advanced melanoma some 20±30% of patients have a significant clinical
response. The use of immature Mo-DCs may be associated with a lesser outcome
[89, 142] in melanoma unless their preparation and antigen loading involves activation,
as may have occurred in the first trial. Immunological tests may predict for the
group with some clinical response [143]. A formal comparison of immature versus
mature Mo-DCs used different DCs preparations and antigens in the same patients
[144]; it was not possible to allocate the positive clinical outcomes to a particular preparation
although, as commented earlier, differences in Tcell responses were seen.
Other most encouraging results have been obtained in renal cell carcinoma [145±
147]. The use of allogeneic tumor cell±DC hybrids was pioneered in this area [117] ±
the excellent results are being investigated further. Again, it is perhaps relevant that
this is a disease in which immune responses are known to occur, e.g. following IL-
2/LAK therapy.
There has been a large cohort of prostate cancer patients studied by two groups [72,
148±157], perhaps in part because prostate organ-specific antigens [e.g. prostate-spe-