Immunotherapy of human colon cancer by antibody-targeted superantigens

Abstract

T lymphocytes generally fail to recognize human colon carcinomas, suggesting that the tumour is beyond reach of immunotherapy. Bacterial superantigens are the most potent known activators of human T lymphocytes and induce T cell cytotoxicity and cytokine production. In order to develop a T-cell-based therapy for colon cancer, the superantigen staphylococcal enterotoxin A (SEA) was given tumour reactivity by genetic fusion with a Fab fragment of the monoclonal antibody C242 reacting with human colon carcinomas. The C242Fab-SEA fusion protein targeted SEA-reactive T cells against MHC-class-II-negative human colon carcinoma cells in vitro at nanomolar concentrations. Treatment of disseminated human colon carcinomas growing in humanized SCID mice resulted in marked inhibition of tumour growth and the apparent cure of the animals. Therapeutic efficiency was dependent on the tumour specificity of the fusion protein and human T cells. Immunohistochemistry demonstrated massive infiltration of human T cells in C242Fab-SEA-treated tumours. The results merit further evaluation of C242Fab-SEA fusion proteins as immunotherapy in patients suffering from colon carcinoma.

Therapy of human non-small-cell lung carcinoma using antibody targeting of a modified superantigen

“…There is an intense focus on other antibodies in the preclinical or early clinical phase, but there are also activities ongoing to further potentiate the successful antibodies using radioisotopes, cytotoxic fusion partners or by making the antibodies bispecific. Targeting of superantigens has previously been described for colon cancer therapy (Dohlsten et al, 1994(Dohlsten et al, , 1995b. This therapy leads to infiltration of T-cells in the tumour tissue (Dohlsten et al, 1995a, Litton et al, 1996.…”

“…There is a correlation between the systemic cytokine levels and systemic toxicity for Fab-SEA constructs in both mice and humans (Dohlsten et al, 1995b;Alpaugh et al, 1998). Repeated injections of Fab-SEA resulted in strong production of IL-2, IFN-γ, TNF-α and IL-6 (Figure 4).…”

“…Most studies of antibody targeted superantigens, e.g. staphylococcal enterotoxin A, SEA, have been for the treatment of human colorectal cancer (Dohlsten et al, 1995b). However, to decrease the reactivity of the superantigen with MHC class IIbearing cells, the Asp227Ala replacement were introduced to destroy the site having the highest affinity for MHC class II in SEA (Abrahmsén et al, 1995).…”

Gene therapy by membrane-expressed superantigen for α-fetoprotein-producing hepatocellular carcinoma

“…31 In addition, cytokines can induce LAK activity, activate natural killer cells and macrophages, [32][33][34] facilitate penetration of high molecular weight proteins and upregulate cell adhesion molecules and MHC class II expression on tumor cells. These factors favor additional fusion protein interactions with subsequent SADCC 30,35 and recruit peripheral blood cells into this inflammatory milieu. 35 In this study, the results of intratumoral treatment of recombinant virus induced systemic and local antitumor immunity.…”

“…These factors favor additional fusion protein interactions with subsequent SADCC 30,35 and recruit peripheral blood cells into this inflammatory milieu. 35 In this study, the results of intratumoral treatment of recombinant virus induced systemic and local antitumor immunity. The antitumor immune mechanisms may be similar to mAb-SEA fusion protein.…”