Long-term survival and complete cures of B16 melanoma-carrying animals after therapy with tumor-targeted IL-2 and SEA

Rosendahl, Alexander; Kristensson, Karin; Carlsson, Mats; Skartved, Niels Jørgen Østergaard; Riesbeck, Kristian; Søgaard, Morten; Dohlsten, Mikael

doi:10.1002/(sici)1097-0215(19990331)81:1<156::aid-ijc25>3.0.co;2-h

Cited by 19 publications

(17 citation statements)

References 32 publications

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“…Furthermore, a phase of immune exhaustion including failure to produce IL-2 and the tumor-suppressive cytokines IFN-␥ and TNF-␣ as well as failure to induce potent CTL activity followed after the Fab-SEA treatment. 18 This hyporesponsiveness directly limited the therapeutic efficacy of Fab-SEA immunotherapy. Hyporesponsive T cells have a defect in the activation of P21 ras following TCR occupancy, which translates to a down-regulation of the AP-1 transcription factor.…”

Section: Discussionmentioning

confidence: 99%

“…Early studies have shown that SAg-induced IL-2 hyporesponsiveness in vivo correlates with down-regulation of the AP-1 and p50/p65 Rel transcription factors, suggesting an intrinsic defect in anergic T cells. Exogenous IL-2 has been demonstrated to restore responsiveness 36 Rosendahl et al 18 reported that antitumor effect of Fab-SEA immunotherapy was potentiated by Fab-IL-2 co-administration. Fab-SEA combined with Fab-IL-2 augmented the production of IFN-␥, restored the responsiveness of T cells, prolonged the immune response in vivo, so limiting the development of immunological hyporesponsiveness.…”

Section: Discussionmentioning

confidence: 99%

“…8 Furthermore, a state of hyporesponsiveness characterized by sub-optimal production of IFN-␥, IL-2 and marginal CTL activity was induced after repeated treatment with Fab-SEA. 18 This hyporesponsiveness state may due to the functional anergy and the ultimate death of a large number of the responding T cells, which directly limited the therapeutic efficacy, and long-term survival was noted only in a small fraction of the tumor-bearing animals. 18 How to circumvent these problems and enhance the antitumor effect of Fab-SEA immunotherapy more efficiently?…”

Section: Introductionmentioning

confidence: 99%

“…18 This hyporesponsiveness state may due to the functional anergy and the ultimate death of a large number of the responding T cells, which directly limited the therapeutic efficacy, and long-term survival was noted only in a small fraction of the tumor-bearing animals. 18 How to circumvent these problems and enhance the antitumor effect of Fab-SEA immunotherapy more efficiently? Rosendahl et al 16 reported that antitumor effect of Fab-SEA immunotherapy was potentiated by co-administration of fusion protein of Fab and IL-2 (Fab-IL-2).…”

Section: Introductionmentioning

confidence: 99%

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Intratumoral IL-18 gene transfer improves therapeutic efficacy of antibody-targeted superantigen in established murine melanoma

Wang

et al. 2001

Gene Ther

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Antibody-targeted superantigen C215Fab-SEA is a fusion protein of staphylococcal enterotoxin A (SEA) and the Fab region of the tumor-reactive C215 mAb. It can trigger CTL against C215 antigen-positive tumor cells and induce tumorsuppressive cytokines. However, the antitumor effect of C215Fab-SEA is not satisfactory because of suboptimal production of Th1 cytokines after repeated administration. Interleukin 18 (IL-18) is a novel cytokine with profound effects on Th1 cellular response. In this study, we showed that adenovirus-mediated intratumoral IL-18 gene transfer strongly improved the therapeutic efficacy of C215Fab-SEA in the pre-established C215 antigen-expressing B16 melanoma murine model. More significant tumor inhibition and

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Intratumoral IL-18 gene transfer improves therapeutic efficacy of antibody-targeted superantigen in established murine melanoma

Wang

et al. 2001

Gene Ther

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“…In vivo, the application leads to transient expansion and subsequent death of T cells with the appropriate V b s. [7][8][9] The characteristics of superantigens can be exploited in diseases where strong immunologic responses are required. This effect has been evaluated in several preclinical [10][11][12][13][14][15][16][17][18][19][20][21][22] and clinical [23][24][25][26] studies of immunotherapeutic approaches in the treatment of cancer where superantigens were used as adjuvant or in fusion molecules with specific antibodies to enhance or maintain the immunologic response. Superantigen administration significantly enhances ineffective antitumor immune responses, resulting in potent and long-lived protective antitumor immunity.…”

mentioning

confidence: 99%

Preclinical evaluation of superantigen (staphylococcal enterotoxin B) in the intravesical immunotherapy of superficial bladder cancer

Perabo

Willert

Wirger

et al. 2005

Intl Journal of Cancer

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Superantigens are potent activators of T lymphocytes; therefore, their characteristics can be exploited in diseases where immunomodulation is known to be effective. In this study, we evaluated a new approach for the intravesical therapy of superficial bladder cancer. We investigated in coculture experiments if staphylococcal enterotoxin B (SEB)-activated PBMCs are able to induce apoptosis in human transitional cell carcinoma (TCC) cells. Additionally, we tested the toxicity and efficacy of SEB dissolved in NaCl 0.9% administered intravesically once weekly for 6 weeks in a rat bladder cancer model. To validate the coculture in vitro findings, we evaluated tumor stage, grade, apoptotic cells in the urothelium and stroma of the bladder and infiltration of the bladder wall by lymphocytes, macrophages and mononuclear cells. Coculture experiments revealed that SEB-activated PBMCs are able to kill TCC cells by inducing apoptosis. The intravesical toxicity study with a maximum dose of 100 mg/ml SEB demonstrated no side effects. In the intravesically SEB-treated animals (10 mg/ml), only 3 tumors remained vs. 15 persisting tumors in the control group. The remaining tumors of the therapy group showed a significant amount of apoptosis and granulocytes, mainly in the urothelium, whereas no relevant apoptosis or infiltration of the bladder with lymphocytes or macrophages was found in the control group. These preclinical findings suggest that SEB might be an interesting candidate for further clinical evaluation. ' 2005 Wiley-Liss, Inc.Key words: bladder cancer; superantigen; staphylococcal enterotoxin B; apoptosis; Fas ligand At initial presentation, approximately 50-70% of all bladder tumors are superficial, stage Tis (carcinoma in situ) or Ta (papillary) and T1 tumors confined to the mucosa or submucosa. 1 In the majority of these patients, tumors can be resected but have a high risk of recurrence, thus requiring adjuvant treatment. 2 The objective of intravesical therapy is to reduce recurrence or to eradicate Tis in patients when it is not possible to resect completely. The most common immunotherapeutic agent used is BCG, an attenuated strain of Mycobacterium bovis. The exact mechanism by which BCG exerts its antitumor effect remains unknown. However, cytotoxic activity of activated T lymphocytes within a complex local immune response against bladder cancer cells and secretion of several cytokines involved in the local immune response were demonstrated in in vitro cultures and in the urothelium of BCG-treated patients. [3][4][5][6] Other extremely potent activators of T lymphocytes are superantigens. Superantigens are proteins or peptide factors produced by various microorganisms like bacteria, mycoplasma or viruses. Staphylococcal enterotoxins are a family of structurally related proteins produced by Staphylococcus aureus. These compounds, m.w. 24-30 kDa, include the classical groups (A-E), the recently discovered enterotoxins G-Q and TSST-1. Streptococcal superantigens include the pyrogenic exotoxins A (and antigenic va...

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A3—a novel colon and pancreatic cancer reactive antibody from a primate phage library selected using intact tumour cells

et al. 2000

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Long-term survival and complete cures of B16 melanoma-carrying animals after therapy with tumor-targeted IL-2 and SEA

Cited by 19 publications

References 32 publications

Intratumoral IL-18 gene transfer improves therapeutic efficacy of antibody-targeted superantigen in established murine melanoma

Intratumoral IL-18 gene transfer improves therapeutic efficacy of antibody-targeted superantigen in established murine melanoma

Preclinical evaluation of superantigen (staphylococcal enterotoxin B) in the intravesical immunotherapy of superficial bladder cancer

A3—a novel colon and pancreatic cancer reactive antibody from a primate phage library selected using intact tumour cells

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