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a timely medical meeting newsletter
T-CELL ACTIVATION AS CANCER TREATMENT
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S.E. Nielsen, MD, Copenhagen University Hospital, Denmark,
studied the safety and potential efficacy of a novel fusion
protein (NFP) in 20 cancer patients. Activation of T-cells by
NFP leads to cytokines toxic to tumor cells. Patient baseline
antibody titers to a portion of NFP correlated with induced
systemic concentrations of interleukin (IL)-2 and tumor necrosis
factor (TNF) beta. Additional studies are planned with NFP also
known as PNU-214565.
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| T-cell activation by NFP |
Genetic fusion of superantigen staphylococcal enterotoxin A
(SEA) with the Fab fragment of the monoclonal antibody C242
produces NFP. The protein targets gastrointestinal
adenocarcinomas. Activated T-cells release cytokines such as
IL-2, IL-6, IL-10, gamma interferon and TNF -- all toxic to
tumor cells.
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| Demography of study patients |
Eleven males and 9 females having a median age of 60.5 years
entered this Phase I dose-ranging safety study. Primary tumor
sites consisted of 11 colorectum, 5 pancreas, and 4 others of
gastrointestinal origin. Prior therapy included surgery, 17;
chemotherapy, 2; and radiotherapy, 2. At baseline, all patients
showed a WHO performance status of 0 or 1.
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| Dose-ranging safety protocol |
The study used an intravenous infusion of NFP at 2 mL/hr for
3 hours on 4 consecutive days. Initially, 2 or 3 patients per
group received doses of 0.5, 1.5, or 4.0 ng/kg. Later, the
dose was 2.75 ng/kg for 12 patients. Vital signs, routine
clinical laboratory tests, and cytokine estimates were
performed during treatment with NFP. Patients left the
hospital on Day 5 and returned as outpatients for follow-up
on Day 7 and 28.
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| Toxicity with NFP |
All patients in the 0.5 and 1.5 ng/kg groups experienced
mild adverse reactions. The maximally tolerated dose (MTD)
was 2.75 ng/kg. At this dose, only 1 of 12 patients developed
dose-limiting toxicity (DLT) of grade 4 hypotension which was
easily managed with dopamine, according to Nielsen.
The 4.0 ng/kg dose of NFP led to DLT in both patients in this group. One patient developed transient grade 4 vomiting, thrombocytopenia, leukopenia, hyperbilirubinemia, and acute renal failure requiring dialysis. The other patient showed a grade 4 hepatotoxicity and thrombocytopenia which lasted 5 days.
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| Predicting a safe dose of NFP |
Nielsen found a significant correlation between baseline
anti-SEA antibody titers and systemic cytokines such as IL-1
and TNF beta following NFP infusions (p<0.05). Is it possible
to assign a safe dose of NFP that will produce an increase in
cytokines? Additional data from Phase I studies are needed to
define the MTD of the fusion protein and refine the predictive
value of baseline anti-SEA titers.
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| Investigator conclusions | NFP was generally well-tolerated with transient toxicities. The estimated MTD was 2.75 ng/kg following repeated infusions. Pretreatment concentrations of anti-SEA antibodies correlated with NFP dosage, systemic cytokine release, and dose-limiting toxicity |
For professional correspondence, please contact Dr. Nielsen by Fax at: 45 35 456 966
Presented at The European Cancer Conference (ECCO 9), September
14-18, 1997
Copyright © 1997 Conrad Group, Inc. All Rights Reserved
Eugene A. Conrad, PhD, MPH / ISSN 1078-2230 / November 1997
Send comments to: ConradNote@aol.com
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