Bispecific antibody targeted T cell therapy of ovarian cancer: clinical results and future directions.
The high frequency of relapse after induction chemotherapy in advanced ovarian carcinoma patients calls for new therapeutic modalities. Retargeted T cell-mediated lysis can be achieved using the bispecific antibody (BsmAb) OCTR, directed to CD3 on T cells and to the folate receptor on ovarian carcinoma cells. Twenty-eight patients with limited intraperitoneal disease after first-line therapy entered a phase II study. They received two i.p. 5 day cycles of activated PBMC retargeted with OCTR. Despite unfavorable tumor characteristics, 7 of 26 patients (27%) showed complete or partial intraperitoneal responses with strict surgicopathologic evaluation. In most cases, the disease relapsed outside the peritoneal cavity, and in 1 case complete intraperitoneal response was accompanied by progression in retroperitoneal lymph nodes. The morbidity was mild to moderate and transient. Combination of i.v. and i.p. administration of OCTR-retargeted lymphocytes will possibly lead to extraperitoneal cure. Ongoing clinical studies indicate that the i.v. infusion of up to 8 x 10(8) OCTR-retargeted T lymphocytes does not induce a higher toxicity than the i.p. treatment. To avoid PBMC preactivation, new approaches for delivering accessory signals are under investigation. Preliminary results indicate that nonactivated PBMC retargeted by OCTR in the presence of an anti-CD28 monoclonal antibody (mAb) are able to significantly inhibit tumor growth.
Canevari
S
S
Division of Experimental Oncology E, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
Mezzanzanica
D
D
Mazzoni
A
A
Negri
D R
DR
Ramakrishna
V
V
Bolhuis
R L
RL
Colnaghi
M I
MI
Bolis
G
G
D018033:Antibodies, Bispecific / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D000918:Antibody Specificity; D002352:Carrier Proteins / Q000276:immunology*; D003131:Combined Modality Therapy; D003602:Cytotoxicity, Immunologic; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D006801:Humans; D007116:Immunization, Passive; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D008207:Lymphatic Metastasis; D008213:Lymphocyte Activation; D016853:Muromonab-CD3 / Q000276:immunology / Q000627:therapeutic use*; D009363:Neoplasm Proteins / Q000276:immunology*; D010051:Ovarian Neoplasms / Q000276:immunology / Q000473:pathology / Q000601:surgery / Q000628:therapy*; D010534:Peritoneal Neoplasms / Q000276:immunology / Q000556:secondary* / Q000628:therapy; D011956:Receptors, Cell Surface; D012186:Retroperitoneal Neoplasms / Q000556:secondary; D013601:T-Lymphocytes / Q000276:immunology*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D018033:Antibodies, Bispecific; D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D016853:Muromonab-CD3; D009363:Neoplasm Proteins; D011956:Receptors, Cell Surface