Hi Marc,
an addendum to my prior post;
biospace.com
Some details about Gelsinger's death revealed at the meeting were surprising, disturbing, and unexpected, and they raise many more questions than have been answered so far. First, the vector was found throughout his body, in especially high concentrations in the spleen, bone marrow,lymphatic tissue and gonads. Second, his bone marrow was completely depleted of precursor cells, which some believe could not have occurred in the few days following vector infusion. There was evidence of parvovirus, of unknown origin, which French Anderson believes could have caused the bone marrow to become depleted and possibly to have pushed Gelsinger's immune system into overdrive. In addition, unlike other patients given the vector, Gelsinger's IL-6 levels rose but never declined, and his IL-10 levels never rose sufficiently. This might have been a result of his fever, parvo infection, or both--the cause remains unclear.
Despite the "unusually narrow window of toxicity" Gelsinger experienced,Wilson maintains that he was "comfortable" with the dose he gave Gelsinger. Since the death, the FDA has suspended Schering-Plough's liver cancer
trials at the same high dose, using the same route of administration.
.............
In general, Verma believes that gene therapy vectors need to be better matched to the tissues they are to treat. He has also calls vectors gene therapy's "Achilles heel," and has said that adenovirus vectors like the one used in the OTC trial may well soon be abandoned in favor of improved ones like Merck's "gutless" versions--except perhaps in cancer, where the damage caused by current vectors may actually benefit treatment. Onyx' results with its adenoviral vector in head and neck cancer were the only clearly efficacious results discussed at the meeting.
These and other data concerning the use of adenoviral vectors to deliver chemotherapeutics directly into tumors by local injection "were very encouraging," says GenVec's Fischer. Trials by Onyx, Schering-Plough and RPR Gencell/Introgen "showed lower toxicity compared to most drugs, including Schering-Plough's high dose trial," he states. "Other than fever and chills, cancer patients showed no great toxicity." Antibodies are generally not an issue for intratumoral injections. But, "it's a different story to give the vector intravascularly," he acknowledges.
The researchers and FDA queried whether the vector should have been given directly into the liver--an issue that had been discussed at length at the
original RAC meeting in 1995. Ultimately it was decided that administering it via the hepatic artery would be the most direct and possibly least toxic route, and that it would only be given to one lobe of the liver, leaving the other free in case of irreversible liver damage.
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