Convinced it would be possible to influence the immuneresponse to tumors, scientists at the Whitehead Institute forBiomedical Research at the Massachusetts Institute ofTechnology conducted a comprehensive survey of immunemessengers in mice with a variety of malignancies and foundone cytokine stimulated long-lasting protection from cancer.
The study, published in last week's issue of the Proceedings ofthe National Academy of Sciences, identified granulocyte-macrophage colony stimulating factor (GM-CSF) as the mostpromising factor to help vaccines kill tumor cells. This cytokineimpelled mouse T cells to destroy cancer cells while allowingother white blood cells to retain a specific memory of thetumor so new cancer cells might be weeded out during arelapse.
The gene for GM-CSF was packaged with tumor cells so theimmune-boosting properties and antigens could be presentedtogether in an injection, explained Richard Mulligan, an authorof the paper and founder of Somatix Therapy Corp.(NASDAQ:SOMA) of Alameda, Calif., which will put the results topractice in upcoming Phase I clinical trials.
The company and its collaborators at the Whitehead Instituteand the Johns Hopkins Oncology Center in Baltimore receivedapproval March 1 from the Recombinant DNA AdvisoryCommittee (RAC) of the National Institutes of Health for genetherapy in patients with advanced kidney cancer.
Immunex Corp. of Seattle holds a patent for use of the humanGM-CSF protein and might be interested in exploring its use invaccines, including a gene-therapy vaccine, spokeswoman MaryMcConnon said. Sandoz Ltd. of Switzerland has licensed rightsto the gene from Genetics Institute Inc. of Cambridge, Mass.
However, Somatix determined the patent situation for the gene,which is subject to many process patents, is "very verymuddled," Chief Financial Officer Mark Bagnell told BioWorld,and the gene may eventually be declared in the public domain.
In any case, Somatix holds property rights to the gene transfervector and cell types used, and has a license from JohnsHopkins on using gene therapy to induce immunotherapy incancer. Holding these parts of the technology, Bagnell said,means "if someone ended up with rights to that gene, they'd behappy to collaborate with us."
In the published research, Whitehead Institute post-doctoralfellow and oncologist Glenn Dranoff and colleagues inserted thegene for GM-CSF and nine other cytokines into mousemelanoma cells using the engineered viral vector MFG, thenirradiated the cells and injected them into the mice.
Irradiation allowed the cells to produce GM-CSF and continuemetabolizing a few days before bursting open and dying,exposing their antigens to the immune cells in their vicinity.
Most mice that received this inoculation did not develop newtumors weeks after being injected with fresh tumor cells, thescientists learned. The mice also rejected small, pre-establishedtumors.
By contrast, simply irradiating mouse melanoma cells andinjecting these cells sans GM-CSF gene into mice only generateda weak immune response, Dranoff said.
Augmenting anti-cancer activity of the immune system with apatient's own cells has been attempted for nearly a centurywith only partial, transient effects. The method discovered byresearchers at the Whitehead Institute, by contrast, seems toallow the immune system to retain a specific "memory" of thetumor antigens, and discern and reject tumor cells somewhatthe way the immune system rejects foreign transplanted tissue.
Using irradiated cells that produce GM-CSF was also found themost effective in lung, kidney, colon tumors and fibrosarcoma,during additional studies by the reserchers are also associatedwith Massachusetts General Hospital and the Dana-FarberCancer Institute in Boston, and Johns Hopkins University Schoolof Medicine.
Jonathan Simons of Johns Hopkins will design the inital clinicaltrial in patients with end-stage kidney cancer, Somatix'sdirector of molecular biology, Larry Cohen, told BioWorld. Thesafety and toxicity study will also examine escalating doses oftumor cells removed during palliative surgery, propagated andtransfected in culture, tracking immune-response indicators.Future studies may involve breast, pancreas and lung cancers.
The therapeutic potential appears to lie in adjunct use to"debulk" minimal residual disease following conventionaltreatments of surgery, radiation and/or chemotherapy, Cohensaid.
The trial will involve using the human GM-CSF gene, althoughthe research reported this week in PNAS concerned the mouseversion.
-- Nancy Garcia Associate Editor
(c) 1997 American Health Consultants. All rights reserved.