Activation of cellular immunity after intracavitary monoclonal antibody therapy of ovarian cancer.
BACKGROUND
Murine monoclonal antibodies (MoAbs) are now used for targeted tumor therapy. A major obstacle in their successful application is the development of a humoral antiglobulin response, which limits the use of repeated cycles of therapy. The cellular aspects of that response are not well understood.


METHODS
Fifteen patients who had one (12 patients) or two (3 patients) courses of MoAb treatment, 13 age-matched patients with the same histologic types of tumors who had not received MoAbs, and 4 healthy control subjects were studied. Peripheral blood mononuclear cells (PBMCs) were obtained and tested for the ability of T-cells to proliferate in vitro in the presence of the MoAb administered for therapy (HMFG1), a control antibody (11.4.1), and, in some cases, their F(ab')2 fragments. In addition, PBMCs from these patients were phenotyped after in vitro MoAb stimulation with antibodies against CD2, CD3, CD4, CD8, CD16, CD20, CD25 (interleukin-2 receptor [IL-2R]), CD45RA, and UCHL1, and the production of interleukin-2 (IL-2) was evaluated by the CTLL-2 bioassay.


RESULTS
A dose-dependent in vitro T-cell proliferation was observed in 13 of the 15 patients after MoAb therapy. This was not observed in the pretherapy group of patients or healthy control subjects. The mean stimulation index (SI) in the posttherapy group was significantly higher than that of the pretherapy patients and that of healthy control subjects (P = 0.007). When the in vitro T-cell proliferative responses of these patients were measured in the presence of HMFG1 MoAb (IgG1) and 11.4.1 MoAb, there was no significant difference in the mean SI for HMFG1 versus 11.4.1 for the whole group of treated patients (P = 0.67). A significant increase in the mean SI was observed in the presence of HMFG1 over 11.4.1 and their F(ab')2 fragments (P = 0.02) in patients treated twice. A significant increase in the percentage of cells expressing IL-2R was observed after in vitro MoAb stimulation. CD4+ lymphocytes, particularly the CD4+/UCHL1+ memory, the CD4+/IL-2R+ subpopulation, and the CD4/CD8 ratio, increased in all the cases studied after MoAb stimulation, where B-cell and natural killer-cell numbers remained relatively constant (< 2-3%). A sixfold increase was found in the production of IL-2 in PBMC supernatants after MoAb stimulation.


CONCLUSIONS
Mouse MoAbs administered to patients with cancer can lead to the generation of T-cells, which can recognize these MoAbs as antigens and therefore refocus the host's cellular immune response against the targeted tumor. The main proliferating population appears to be CD4+ T-lymphocytes, which after stimulation can release IL-2. Multiple treatments may lead to the generation of T-cells with specificity for the idiotypic component of the administered MoAb.
Kosmas
C
C
Department of Clinical Oncology, Royal Postgraduate Medical School, Hammersmith Hospital, London, England.
Epenetos
A A
AA
Courtenay-Luck
N S
NS
D000230:Adenocarcinoma / Q000276:immunology / Q000628:therapy; D000368:Aged; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007263:Infusions, Parenteral; D007376:Interleukin-2 / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology*
D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D007376:Interleukin-2