Repeated treatment with antibody-targeted superantigens strongly inhibits tumor growth

Abstract

Superantigens (SAg) are microbial proteins with the capacity to activate a large proportion of T cells. We have developed a novel approach for cancer immunotherapy by genetically fusing the SAg staphylococcal enterotoxin A (SEA) to a Fab‐fragment of a tumor‐specific antibody. Repeated exposure to SEA induces a state of unresponsiveness including cell deletion and functional hyporesponsiveness, i.e., anergy. In this study we have developed improved therapeutic schedules to allow repeated injections of Fab‐SEA, limit development of immunological unresponsiveness and promote maximal anti‐tumor response. Four daily injections of Fab‐SEA to mice carrying B16‐C215 lung metastases resulted in 90–95% reduction in the number of metastases. However, the animals did retain a minimal residual tumor disease. The immune system was in a hyporesponsive state after 4 daily Fab‐SEA injections, and further injections did not improve therapy. Two repeated cycles, each comprising 4 daily injections of Fab‐SEA, significantly prolonged the survival and resulted in complete cure of a fraction of the animals. A rest period of 10 days between the cycles was required to mount an efficient secondary anti‐tumor response. This secondary immune response was characterized by partial recovery of cytokine production i.e., interleukin‐2, interferon‐γ and tumor necrosis factor‐α. Strong CTL activity was detected in animals that had rested for 8 weeks between the 2 cycles. Interestingly, irrespective of the resting period, the CD4+ SEA‐reactive T cells expanded in response to all 4 additional Fab‐SEA injections both locally and in spleen. In contrast, only marginal expansion of CD8+ T cells was seen if restimulation was given within 1 month. Our data show that potent anti‐tumor effector functions can be induced after repeated stimulation cycles with a SAg‐monoclonal antibody fusion protein resulting in a CD4+ T cell‐dependent cytokine release, prolonged survival and induction of complete cures. Int. J. Cancer 76:274‐283, 1998.© 1998 Wiley‐Liss, Inc.

Phase I Dose Escalation, Pharmacokinetic and Pharmacodynamic Study of Naptumomab Estafenatox Alone in Patients With Advanced Cancer and With Docetaxel in Patients With Advanced Non–Small-Cell Lung Cancer

“…15, 16 Furthermore, clinical results with the predecessor ABR-214936 using a similar schedule showed promising efficacy. 13 Premedications included acetaminophen, indomethacin, or sulindac, and as needed medication for nausea, vomiting, and rigors.…”

Monotherapeutically Nonactive CTLA-4 Blockade Results in Greatly Enhanced Antitumor Effects When Combined With Tumor-targeted Superantigens in a B16 Melanoma Model

“…10 We have previously demonstrated that repeated injections of the C215Fab-SEA fusion protein eliminate a large number of tumors in mice carrying established B16-EpCAM melanoma metastases in the lung. 10,13 However, important antitumor effector functions, such as IFN-g secretion and CTL activity, gradually decline during therapy. 14 Various immunoregulatory mechanisms have been implicated in this process including T-cell deletion, anergy, and induction of regulatory cell subsets.…”

The distinct role of CD4+ and CD8+ T-cells during the anti-tumour effects of targeted superantigens

“…SAg have, in contrast to conventional peptide antigens, a unique capacity of activating both subsets of Tcells (Herrmann et al, 1990;Dohlsten et al, 1990). In fact, it has been demonstrated previously that both CD4 + and CD8 + T-cells are recruited to the tumour area in response to antibody-targeted SAg tumour therapy (Dohlsten et al, 1995a;Litton et al, 1996Litton et al, , 1997Rosendahl et al, 1998a). However, both subsets have the potential to regulate helper activity as well as cytotoxic functions.…”