Repeated treatment with antibody-targeted superantigens strongly inhibits tumor growth.
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 B 16-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-gamma and tumor necrosis factor-alpha. 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.
Rosendahl
A
A
Pharmacia and Upjohn, Lund Research Center, Sweden. alexander.rosendahl@eu.pnu.com
Kristensson
K
K
Hansson
J
J
Ohlsson
L
L
Kalland
T
T
Dohlsten
M
M
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002455:Cell Division / Q000187:drug effects; D016207:Cytokines / Q000097:blood; D004334:Drug Administration Schedule; D004768:Enterotoxins / Q000494:pharmacology*; D005260:Female; D007128:Immunoglobulin Fragments / Q000494:pharmacology*; D000922:Immunotoxins / Q000494:pharmacology*; D007369:Interferon Inducers / Q000494:pharmacology*; D007371:Interferon-gamma / Q000096:biosynthesis; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000276:immunology; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018089:Superantigens / Q000276:immunology / Q000494:pharmacology*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D016207:Cytokines; D004768:Enterotoxins; D007128:Immunoglobulin Fragments; D000922:Immunotoxins; D007369:Interferon Inducers; D018089:Superantigens; D014409:Tumor Necrosis Factor-alpha; C026066:enterotoxin A, Staphylococcal; D007371:Interferon-gamma