Local antitumour treatment in carcinoma patients with bispecific-monoclonal-antibody-redirected T cells

Abstract

In a pilot clinical study carcinoma patients with malignant ascites or pleural exudates have been treated locally with autologous lymphocytes activated ex vivo and redirected towards tumour cells with bispecific monoclonal antibodies. BIS-1, the bispecific monoclonal antibody used in this study, combines specificity against a tumour-associated antigen, AMOC-31, present on carcinomas, with a specificity against the CD3 complex on T lymphocytes. Patients selected for treatment had malignant pleural or peritoneal effusions. Treatment consisted of isolating autologous peripheral blood lymphocytes, ex vivo activation, incubation with bispecific monoclonal antibodies and injection at the effusion site of these BIS-1-redirected lymphocytes. To evaluate the effects of the bispecific monoclonal antibody, five patients received treatments with activated lymphocytes without bispecific antibodies. Effusion samples taken before and at various times after treatment were analysed by immunocytology and for the presence of the soluble factors carcinoembryonic antigen (CEA), interleukin-6 (IL-6), tumour necrosis factor (TNF), C-reactive protein and soluble CD8. In this way both immune activation and anti-tumour activity could be monitored. Conjugate formation between tumour cells and activated lymphocytes was seen as soon as 4 h after injection of BIS-1-redirected activated lymphocytes, followed by a disappearance or reduction of tumour cells after 24-48 h. In parallel with this, the soluble tumour marker CEA decreased in the effusion fluid following injection with the BIS-1-redirected lymphocytes. Furthermore, a steep increase in local granulocyte numbers was observed in the effusion fluid, which reached a maximum 24-48 h after the start of the treatment. Also levels of IL-6 and TNF were greatly elevated. The data suggest that the treatment induces both antitumour activity and a strong local inflammatory reaction. This is accompanied by no or only minor local and systemic toxicity, i.e. mild fever, which disappeared as the local inflammatory reaction diminished 48-72 h after treatment.

Immunotherapy of malignant ascites with trifunctional antibodies

“…28 Two studies have already reported encouraging results with bispecific antibodies in combination with pre-activated PBL in patients with ovarian cancer. 29,30 These approaches induced local inflammatory reactions and even tumor regression, but were lim- ited by the need for in vitro stimulation of effector cells. A study was published recently demonstrating that effector lymphocytes within malignant ascites, without prior stimulation, can be used together with i.p.…”

A novel bispecific antibody for EGFR-directed blockade of the PD-1/PD-L1 immune checkpoint

“…BIS is an EpCAM-directed CD3-agonistic bsAb. 38 This modification allows for redirecting the Jurkat.PD1-NFAT-luc T cells towards EpCAM + A431 carcinoma cells. In short, Jurkat.PD1-NFAT-luc T cells were mixed BIS-1-pretreated A431 cells at a cell ratio of 5 to 1 and then cultured for 18 h in the presence of PD-L1xEGFR or appropriate control antibodies.…”

A quantitative reverse transcriptase polymerase chain reaction-based assay to detect carcinoma cells in peripheral blood

“…EGP2 (also known as hEGP314, GA733-2 antigen, KSA, EGP40) is a 38-kDa transmembrane glycoprotein expressed on the surface of most simple epithelial cells and the majority of carcinomas such as colorectal, lung and breast carcinomas . MAbs directed against EGP-2, such as C017-lA, KS1/4 and MOC3 1, have been studied extensively in diagnostic and therapeutic approaches in cancer (Lobuglio et al, 1986;Elias et al, 1990; Kroesen et al, 1993;Herlyn et al, 1994;Kosterink et al, 1995). The human EGP2 cDNA was independently cloned by different research groups (Bumol et al, 1988;Strnad et al, 1989;Szala et al, 1990) and, more recently, its gene structure on chromosome 4q has been partly determined.…”