Human Gene Therapy Subcommittee - 11/21-22/91 
VI. PROPOSED AMENDMENT TO APPENDIX D OF THE NIH GUIDELINES 
REGARDING A HUMAN GENE THERAPY PROTOCOL ENTITLED A 
PHASE //// STUDY OF CELLULAR ADOPTIVE IMMUNOTHERAPY 
USING GENETICALLY MODIFIED CD8(+) HIV-SPECIFIC T CELLS 
FOR HIV-SEROPOSITIVE PATIENTS UNDERGOING ALLOGENEIC BONE 
MARROW TRANSPLANT /Dr. Greenberg: 
Review-Dr. Mclvor 
Dr. Walters called on Dr. Mclvor to present his review of the protocol submitted by Dr. 
Philip Greenberg of the University of Washington, Seattle, Washington. Dr. Mclvor 
explained that the protocol involves the molecular tagging of lymphocytes that will be 
administered as adoptive immunotherapy following bone marrow transplantation. The 
gene that will be introduced into the lymphocytes has the unique characteristic that it 
allows for the negative selection of these lymphocytes in the event that they cause 
untoward effects in the patient. The eligible patient population will be non-Hodgkin's 
lymphoma patients who are HIV positive. 
PBL will be obtained from patients 12 weeks prior to bone marrow transplantation. T 
cell clones will be established in vitro that are specific for the HIV gag protein, which will 
inhibit protein synthesis. These T cell clones will then be transduced with the HyTK 
retrovirus. The patient will receive an allogeneic bone marrow transplant. Following 
engraftment, the transduced T cell clones will be administered to the patient at 
increasing doses. The hypothesis is that the T cell clones will provide specific immunity 
against HIV and alleviate residual HIV infection in these patients. 
The persistence of the marked T cell clones will be monitored by PCR analysis. Patients 
will be monitored for HIV infection, relapse of the non-Hodgkin's lymphoma, and any 
toxic effects resulting from the infused T cell clones. If the infused transduced cells are 
creating toxic side effects (e.g., acute neurologic, pulmonary, hematopoietic, or organ 
toxicity), they can be eliminated by the administration of ganciclovir. Therefore, the 
introduction of the thymidine kinase (TK) gene will be an ablatable function that will 
add an element of safety over previous gene marking protocols. Dr. Mclvor said that 
this protocol is well designed and that Dr. Greenberg has extensive experience with the 
development of T cells. 
Dr. Mclvor stated that the HyTK gene is a bifunctional fusion protein between a 
bacterial hygromycin phosphotransferase (Hy) gene and the herpesvirus TK gene. The 
Hy portion of the gene is similar in function to the neo R gene in that it confers resistance 
to the antibiotic hygromycin B allowing for the positive selection of the inserted gene. 
The TK portion of the gene confers the ability to phosphorylate various drugs which are 
then able to kill the cell, e.g., ganciclovir. Therefore, any cell which contains the HyTK 
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