ANTIBODY-TOXIN CONJUGATES FOR THE TREATMENT OF HUMAN BRAIN TUMORS

鞘内治疗的I期剂量递增研究

A phase I dose-escalation study of intrathecal therapy with the immunotoxin 454A12-RTA for leptomeningeal neoplasia has been completed. This compound is a conjugate of a monoclonal antibody against the human transferrin receptor and the recombinant ricin A chain protein toxin. Eight patients with leptomeningeal spread of systemic neoplasia were treated with a total of 10 different doses of intrathecal immunotoxin covering a 1,000-fold increase in drug dose (1.2 - 1,200 micrograms). No toxicity was detected until the highest doses were reached. Acute toxicity consisted of transient headache, vomiting and decreased mental status with elevated intracranial pressure which was responsive to steroids and cerebrospinal fluid (CSF) drainage. Bioassays of serial CSF samples from these patients against tumor cell lines in vitro revealed that patients CSF retained cytotoxic activity against tumor cells for approximately 48 hours after intraventricular administration of immunotoxin. In addition, in vitro testing of 454A12-RTA against tumor cells harvested from the CSF in 3 study patients revealed tumor cell sensitivity to the drug before and after treatment at concentrations of drug much lower than the concentration achieved in CSF. Four patients had decreased lumbar CSF tumor cell counts, the most dramatic (>95%) occurring at the highest dose given. These results indicate that immunotoxin can be safely administered intrathecally in humans, retain bioactivity in the CSF, are cytotoxic to tumor cells from patients, and can reduce tumor burden after only a single dose. A new clinical trial of a genetically engineered immunotoxin, Tfn-CRM107, discovered within the branch has begun for treatment of parenchymal brain tumors.