In a phase I study, ten
ovarian cancer patients with extensive metastatic disease despite
chemotherapy were immunized three to eight times subcutaneously with the synthetic form of the immunodominant
disaccharide (beta Gal1----3 alpha GalNAc) of the
Thomsen-Friedenreich antigen conjugated to KLH (TF alpha-KLH) plus
DETOX adjuvant. Six patients were given a "low" dose of TF alpha-KLH (100 micrograms/injection) and four patients were given a "high" dose (500 micrograms/injection). All patients received a single low-dose
cyclophosphamide treatment (200 mg/m2 i.v.) 3 days prior to commencement of the series of immunizations. Immunizations were 2 weeks apart. Little or no toxicity was noted. As expected, all patients (prior to immunization) had naturally occurring
IgM antibodies against the synthetic TF alpha
hapten. None of the patients had detectable pre-existing
IgG or
IgA antibodies against synthetic TF alpha
hapten. Nine of the ten
ovarian cancer patients showed a significant increase in
IgM titer above pre-existing levels following immunizations with TF alpha-KLH plus
DETOX adjuvant. These same patients also produced
IgG anti-TF alpha and eight of these also produced
IgA anti-TF alpha, although the
IgA responses were weaker. Most of the
IgG responses followed the
IgM responses by 2-4 weeks. Two patients produced a vigorous
IgG response after their first TF alpha-KLH injection, suggesting a recall response. Both direct ELISAs on various solid-phase synthetic
carbohydrate antigens and
hapten inhibition experiments confirmed the TF alpha
hapten specificity of the
antibodies.
IgM and
IgG anti-TF alpha-specific
antibodies reacted with natural
TF antigen, by ELISA and FACS analysis, although the titers were generally lower than the titers against the immunizing TF alpha
hapten. Increased levels of cytotoxic
antibodies against TF-expressing
tumor cell targets were detected in eight of the ten patients following immunization. One patient who had no detectable cytotoxic
antibodies prior to immunization developed increasingly strong cytotoxic
antibodies as a function of the number of immunizations. The low
antigen dose patients showed as good or better humoral immune responses than the high
antigen dose patients. All four high-dose and four of six low-dose patients developed moderate to strong DTH reactions at the vaccination sites. Our results demonstrate that KLH is an acceptable carrier for
carbohydrate haptens in humans and that DETOX is an appropriate nontoxic adjuvant for the generation of high-titer specific anti-
carbohydrate responses in human
cancer patients.(ABSTRACT TRUNCATED AT 400 WORDS)