Phase II Study of Anti–Gastrin-17 Antibodies, Raised to G17DT, in Advanced Pancreatic Cancer

Brett, Bernard; Smith, Stacey; Bouvier, Corinne; Michaeli, D; Hochhauser, Daniel; Davidson, BR; Kurzawinski, Tom; Watkinson, Anthony; Someren, N van; Pounder, RE; Caplin, Martyn

doi:10.1200/jco.2002.11.151

Cited by 101 publications

(49 citation statements)

References 24 publications

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“…Early human studies of G17DT in patients with other forms of cancer demonstrated that G17DT was safe and well tolerated [58]. In a phase II study of G17DT in advanced pancreatic cancer, 67% of 30 patients produced an antibody response [59]. The 250-g dose resulted in a significantly greater antibody response rate of 82%, compared with 46% for the 100-g group (p ϭ .018).…”

Section: Immunotherapy: Gemcitabine Plus Gastrin Vaccinementioning

confidence: 99%

Metastatic Pancreatic Cancer 2008: Is the Glass Less Empty?

2008

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Pancreatic cancer is the fourth most common cause of adult cancer death in the U.S. The high mortality rate from pancreatic cancer is a result of the high incidence of metastatic disease at the time of diagnosis, an often fulminant clinical course, and the lack of adequate systemic therapies. Unfortunately, only 5%-25% of patients present with tumors amenable to resection. The median diseasefree survival interval following resection for operable pancreatic cancer is 13.4 months for patients treated with adjuvant gemcitabine and 6.9 months for untreated patients. A much higher percentage of patients present with metastatic disease (40%-45%) or locally advanced disease (40%), and have median survival times of 3-6 months or 8 -12 months, respectively. The frustrating lack of significant clinical advancements in the treatment of metastatic pancreatic cancer remains one of medical oncology's biggest disappointments. The past decade-long frustration has resulted in regulators, investigators, and practicing oncologists gradually lowering their standards/expectations with regard to interpreting clinical trials. Two of the more important examples of this include the approval of gemcitabine plus erlotinib and the use of a progressionfree survival advantage to defend the use of gemcitabine plus oxaliplatin. Given the marginal benefit of systemic antineoplastics, a scholarly review inclusive of other palliative strategies will help oncologists optimize the care of pancreatic cancer patients. This article examines the existing evidence in support of a role for palliative therapy in metastatic pancreatic cancer, describes recent developments with newer chemotherapeutic and molecular-targeted agents, and explores future study designs. The Oncologist 2008;13:562-576

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Section: Immunotherapy: Gemcitabine Plus Gastrin Vaccinementioning

confidence: 99%

Metastatic Pancreatic Cancer 2008: Is the Glass Less Empty?

2008

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“…These antigastrin antibodies can inhibit the proliferation of pancreatic cancer cells. In a phase II study of 30 patients with pancreatic cancer, 67% of patients were shown to mount an immune response to the vaccine [89]. Eighty-two percent of patients given the highest dose of the vaccine (250 µg) achieved a response.…”

Section: G17dtmentioning

confidence: 99%

“…G17DT (Gastrimmune™; Aphton Corp.; Miami, FL) is an immunoconjugate of the amino-terminal sequence of gastrin-17 (G-17) linked by means of a spacer peptide to diphtheria toxoid. Given as an intramuscular vaccination, it has been shown to induce the formation of antibodies that can neutralize endogenous G-17 and precursor glycine-extended G-17 [89]. These antigastrin antibodies can inhibit the proliferation of pancreatic cancer cells.…”

Section: G17dtmentioning

confidence: 99%

New Chemotherapeutic Advances in Pancreatic, Colorectal, and Gastric Cancers

Díaz-Rubio

2004

The Oncologist

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Pancreatic, gastric, and colorectal cancers are major causes of morbidity and mortality worldwide. When curative surgical resection is not an option, these malignancies tend to respond very poorly to chemotherapy and carry a dismal prognosis. There is, therefore, an urgent need for novel treatment strategies for these cancers. Great strides have been made in colon cancer treatment with the recent introduction of several novel agents, including capecitabine, irinotecan, and oxaliplatin either alone or in combination regimens. Treatment of advanced colon cancer, however, remains essentially palliative, and treatmentrelated toxicity remains a significant problem. The treatment of advanced gastric and pancreatic cancer has also seen the introduction of new agents, such as gemcitabine and irinotecan; however, the impact of these agents on survival has been small, and toxicity continues to be a major obstacle. The search for new chemotherapeutic agents and treatment strategies will need to focus on improving outcomes and safety and tolerability profiles. To date, several new agents have shown promise, including pemetrexed, G17DT, bevacizumab, and other targeted agents. Further research into their optimal use either alone or in combination regimens should be a priority.

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“…Gastrin is expressed early in the development of gastrointestinal carcinomas (6,7), and it is being tested as a therapeutic target in pancreatic, gastric, and colorectal cancer (6,8,9). An anti-gastrin vaccine is currently in phase III clinical trials (9) for pancreatic cancer.…”

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confidence: 99%

Affinity maturation of antibodies assisted by in silico modeling

Barderas

Desmet²,

Timmerman³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

126

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Rational engineering methods can be applied with reasonable success to optimize physicochemical characteristics of proteins, in particular, antibodies. Here, we describe a combined CDR3 walking randomization and rational design-based approach to enhance the affinity of the human anti-gastrin TA4 scFv. The application of this methodology to TA4 scFv, displaying only a weak overall affinity for gastrin17 (K D ‫؍‬ 6 M), resulted in a set of nine affinity-matured scFv variants with near-nanomolar affinity (KD ‫؍‬ 13.2 nM for scFv TA4.112). First, CDR-H3 and CDR-L3 randomization resulted in three scFvs with an overall affinity improvement of 15-to 35-fold over the parental. Then, the modeling of two scFv constructs selected from the previous step (TA4.11 and TA4.13) was followed by a combination of manual and molecular dynamics-based docking of gastrin17 into the respective binding sites, analysis of apparent packing defects, and selection of residues for mutagenesis through phage display. Nine scFv mutants were obtained from the second maturation step. A final 454-fold improvement in affinity compared with TA4 was obtained. These scFvs showed an enhanced potency to inhibit gastrin-induced proliferation in Colo 320 WT and BxPc3 tumoral cells. In conclusion, we propose a structure-based rational method to accelerate the development of affinity-matured antibody constructs with enhanced potential for therapeutic use.antibody engineering ͉ gastrin ͉ in vitro affinity maturation ͉ pancreatic cancer

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Phase II Study of Anti–Gastrin-17 Antibodies, Raised to G17DT, in Advanced Pancreatic Cancer

Cited by 101 publications

References 24 publications

Metastatic Pancreatic Cancer 2008: Is the Glass Less Empty?

Metastatic Pancreatic Cancer 2008: Is the Glass Less Empty?

New Chemotherapeutic Advances in Pancreatic, Colorectal, and Gastric Cancers

Affinity maturation of antibodies assisted by in silico modeling

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