Superantigen-based immunotherapy: a phase I trial of PNU-214565, a monoclonal antibody-staphylococcal enterotoxin A recombinant fusion protein, in advanced pancreatic and colorectal cancer.

Giantonio, Bruce J.; Alpaugh, R. Katherine; Schultz, Josephine; McAleer, Cecilia; Newton, Duane W.; Shannon, B. J.; Guedez, Y.; Kotb, Malak; Vítek, L; Persson, Robert; Gunnarsson, Per Olov; Kalland, Terje; Dohlsten, Mikael; Persson, Bengt; Weiner, Louis M.

doi:10.1200/jco.1997.15.5.1994

Cited by 76 publications

(41 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[2][3][4][5] There are several reports that have demonstrated the effectiveness of some targeted strategies involving monoclonal antibodies or immunotoxins to treat pancreatic cancer. 3,42 These approaches were limited because expression of the target antigens was insufficient to deliver targeting agents in sufficient quantity to eliminate all cancer cells. 43 Our approach overcomes this problem as gene transfer of only one chain of a cytokine receptor system binds significant molecules of cytotoxin to cause profound antitumor activity.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Potent antitumor activity of IL-13 cytotoxin in human pancreatic tumors engineered to express IL-13 receptor α2 chain in vivo

Kawakami

Husain

et al. 2003

Gene Ther

View full text Add to dashboard Cite

Interleukin-13 receptor (IL-13R) a2 chain plays a key role in ligand binding and internalization. We have recently demonstrated that this cytokine receptor chain has unique characteristics in tumor biology: it inhibits tumorigenicity of breast and pancreatic cancer in animal models. In this study, we have exploited IL-13Ra2 chain and established a novel approach for pancreatic cancer therapy. For this, a plasmid encoding the IL-13Ra2 chain gene was mixed with liposomes and injected into subcutaneously or orthotopically xenografted human pancreatic tumors in immunodeficient mice, followed by systemic or local therapy by a recombinant IL-13 cytotoxin. Only tumors forced to express IL-13Ra2 chain acquired extreme susceptibility to the antitumor effect of IL-13 cytotoxin. There was a dominant infiltration of cells including macrophages and natural killer cells in the regressing tumors. Since macrophages were found to produce nitric oxide, IL-13Ra2-targeted cancer therapy involved not only a direct tumor cell killing by IL-13 cytotoxin but also activation of innate immune response at the tumor site. Therefore, this approach may be a new powerful tool for pancreatic cancer or other localized cancer therapy.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Although many approaches are employed to treat this malignancy including surgery and chemotherapy, median survival following diagnosis is only 6 months, which has not improved in the past 30 years. [2][3][4][5] An effective new approach against this disease is desperately needed.…”

Section: Introductionmentioning

confidence: 99%

Potent antitumor activity of IL-13 cytotoxin in human pancreatic tumors engineered to express IL-13 receptor α2 chain in vivo

Kawakami

Husain

et al. 2003

Gene Ther

View full text Add to dashboard Cite

show abstract

“…8 Recombinant fusion protein of the tumor-reactive mAb and SEA (Fab-SEA) expressed a 100-fold stronger affinity for the tumor antigen than MHC class II molecules. 9 In vitro and in vivo studies have shown that Fab-SEA could target cytotoxic T cells against MHC class II − tumor cells bearing the proper tumor antigen in the absence of obvious systemic side-effects, [10][11][12][13][14][15][16][17] which demonstrated functional substitution of the MHC class II-dependent presentation of SEA with tumor specificity.…”

Section: Introductionmentioning

confidence: 99%

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

Wang

et al. 2001

Gene Ther

View full text Add to dashboard Cite

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

show abstract

“…Synthetic fusion proteins, MHC class II-independent and tumor-specific, have been evaluated successfully. 23,24,[51][52][53][54][55] In summary, the preclinical findings indicate that SEB could be a useful agent for treatment of bladder cancer and that a clinical phase I evaluation appears warranted. …”

Section: Discussionmentioning

confidence: 97%

“…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

View full text Add to dashboard Cite

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...

show abstract

Superantigen-based immunotherapy: a phase I trial of PNU-214565, a monoclonal antibody-staphylococcal enterotoxin A recombinant fusion protein, in advanced pancreatic and colorectal cancer.

Cited by 76 publications

References 54 publications

Potent antitumor activity of IL-13 cytotoxin in human pancreatic tumors engineered to express IL-13 receptor α2 chain in vivo

Potent antitumor activity of IL-13 cytotoxin in human pancreatic tumors engineered to express IL-13 receptor α2 chain in vivo

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

Contact Info

Product

Resources

About