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THE COUNCIL FOR TOBACCO RESEARCH-U.S.A.. INC. Memorandum To: Dr. H.McAllister and Staff From: D.H.Ford Re: Site visit with Dr. D.Weiner, Institute of Biotechnology and advanced molecular medicine, Philadelphia, July 9, 1992. Site Visitors: D.H. Ford and D.Stone Grant No.288R2 entitled "Structural basis for receptor activation in cellular transformation." Goals: 1.To deter.mine the relationship between tyrosine kinase activity o p185neu and the cellular transformation induced by this oncogene. 2. To construct immunological reagents using designed peptides to develop technologies to create bioactive immunogenic peptides. Such ~tw pl85neu peptides might then help in determining the relationship between pl85neu expression and tumor prognosis. 3. Evaluate the rela- tionship between the EGF receptor and p185neu in cellular transformatic Results: The progress which Dr. Weiner has made toward attaining these goals is adequately covered in his progress report included with his new proposal. One should note that as a result of his progress during the past 3 years that his new proposal indicates a change in direction with the new title "Retroviral vaccination against human tumor antigens. The receptor coded by p185neu is for a growth factor similar to that of the EGF receptor. In the oncogenic receptor form a valine has been changed to a glutamic acid which then provides for a hugher tyrosin kinase activity. Further, it has external membrane cygteines (2) which are comparable to the TAT cysteine-rich regions from the HIV virus. In evaluating pl85neu levels in various tumors Dr. Weiner noted it to be elevated in lung adenocarcinoma, breast cancer as well as in colon and pancreatic,cancer. The results described in his progress report have lead to the design of a retroviral system for an,tibody variable region expression to inhibit protein interactions, such as-growth factor receptor-ligand interactions. This leads to the idea of-•stimulating the immune system against specific antigens transfected into tumor cells by a retroviral vaccination procedure. In this line of study he appears to be making considerable progress. Briefly, retroviral immunization with human CD4 ( a human lymphocyte antigen common to T helper cell derived lymphomas) induced a humoral immune response. Conceivably this could be due to the ability of retroviral vectors to incorporate surface glycoproteins (including CD4) into budding particles which could serve as humoral immunogens. The immunization process was observed to provide protection against tumor formation from CD4 expressing SP2/0 cells in 2 of 4 mice. The life of the mice which died was also considerably prolonged. This particular experiment is of course very preliminary and did not consist of an adequate number of mice. Comment: This seemed to us to be an interesting application of imm'~ unological techni$ues which could provide for a successful approach to immunotherapy of cancer..and to be relevent to the interests of CTR with cancer studies. DHF