S3814 
Federal Register / Vol. 58, No. 199 / Monday, October 18. 1993 / Notices 
DEPARTMENT OF HEALTH AND 
HUMAN SERVICES 
National Institutes of Health 
Recombinant DNA Research: Actions 
Under the Guidelines 
AGENCY: National Institutes of Health, 
PHS, DHHS. 
ACTION: Notice of Actions Under the 
NIH Guidelines for Research Involving 
Recombinant DNA Molecules. 
SUMMARY: This notice sets forth eight 
actions to be taken by the Director, 
National Institutes of Health (NIH), 
under the May 7, 1986, NIH Guidelines 
for Research Involving Recombinant 
DNA Molecules (51 FR 16958). 
FOR FURTHER INFORMATION CONTACT: 
Additional information can be obtained 
from Dr. Nelson A. Wivel, Director, 
Office of Recombinant DNA Activities 
(ORDA), Office of Science Policy and 
Technology Transfer, National Institutes 
of Health, Building 31, room 4B11, 
Bethesda, Maryland 20892, (301) 496- 
9838. 
SUPPLEMENTARY INFORMATION: Today 
eight actions are being promulgated 
under the NIH Guidelines for Research 
Involving Recombinant DNA Molecules. 
These eight proposed actions were 
published for comment in the Federal 
Register of February 12, 1993 (58 FR 
8500) and August 18, 1993 (58 FR 
44098), and reviewed and 
recommended for approval by the NIH 
Recombinant DNA Advisory Committee 
(RAC) at its meetings on March 1-2, 
1993, and September 9-10, 1993. 
I. Background Information and 
Decisions on Actions Under the NIH 
Guidelines 
A. Major Amendment to Appendix D- 
XXVII to the NIH Guidelines 
On July 9, 1993, Drs. Philip Greenberg 
and Stanley R. Riddell of the Fred 
Hutchinson Cancer Research Center, 
Seattle, Washington, indicated their 
intention to submit a major amendment 
to their human gene transfer protocol to 
the Recombinant DNA Advisory 
Committee for formal review and 
approval. The request was to treat an 
additional 15 patients who do not have 
acquired immunodeficiency syndrome- 
related lymphoma and who are not 
undergoing autologous bone marrow 
transplantation. 
The current protocol is entitled: A 
Phase I Study of Cellular Adoptive 
Immunotherapy Using Genetically 
Modified CD8+ HIV-Specific T Cells for 
HIV-Seropositive Patients Undergoing 
Allogeneic Bone Marrow Transplant. 
The initial protocal was approved by the 
NIH Director on April 17, 1992, and 
published in the Federal Register on 
April 22, 1992 (57 FR 14775). 
Appendix D-XXVII currently reads: 
“Dr. Philip D. Greenberg of tne 
University of Washington, Seattle, 
Washington, can conduct gene transfer 
experiments on up to 15 HIV 
seropositive patients undergoing 
allogeneic bone marrow transplantation 
for non-Hodgkin's lymphoma to 
evaluate the safety and efficacy of HIV- 
specific cytotoxic T lymphocyte (CTL) 
therapy. CTL will be transduced wi(h a 
retroviral vector (HyTK) encoding s 
gene that is a fusion product of the 
hygromycin phosphotransferase gene 
(HPH) and the herpes simplex virus 
thymidine kinase (HSV-TX) gene. This 
vector will deliver both a marker gene 
and a suicide gene in these T cell clones 
in the event that patients develop side 
effects as a conseauence of CTL therapy. 
Data will be correlated over time, 
looking at multiple parameters of HTV 
disease activity. The objectives of these 
studies include evaluating the safety 
and toxicity of CTL therapy, 
determining the duration of in vivo 
survival of HIV-specific CTL clones, and 
determining if ganciclovir therapy can 
eradicate genetically modified, 
adoptively transferred CTL cells." 
The amended protocol is entitled: 
Phase I Study to Evaluate the Safety of 
Cellul&r Adoptive Immunotherapy using 
Genetically Modified CD8+ HTV- 
Specific T Cells in HIV Seropositive 
Individuals. This request was published 
for comment in the Federal Register of 
August 18. 1993 (58 FR 44098). 
The protocol was reviewed and 
recommended approval during the RAC 
meeting of September 9-10, 1993, by a 
vote of 16 in favor, 0 opposed, and 2 
abstentions. 
The following section may be 
amended as follows: 
"Appendix D-XXVII. 
“Drs. Philip Greenberg and Stanley R. 
Riddell of the Fred Hutchinson Cancer 
Research Center, Seattle, Washington, 
may conduct gene transfer experiments 
on 15 human immunodeficiency virus 
(HIV) seropositive patients (18—45 years 
old) undergoing allogeneic bone marrow 
transplantation for non-Hodgkin’s 
lymphoma and 15 HIV-seropositive 
patients (18-50 years old) who do not 
have acquired immunodeficiency 
syndrome (AlDS)-related lymphoma and 
who are not undergoing bone marrow 
transplantation to evaluate the safety 
and efficacy of HIV-specific cytotoxic T 
lymphocyte (CTL) therapy. CTL will be 
transduced with a retroviral vector 
(HyTK) encoding a gene that is a fusion 
product of the hygromycin 
phosphotransferase gene (HPH) and the 
herpes simplex virus thymidine kinase 
(HSV-TK) gene. This vector will deliver 
both a marker gene and an ablatabie 
gene in these T cell clones in the event 
that patients develop side effects as a 
consequence of CTL therapy. Data will 
be correlated over time, looking at 
multiple parameters of HIV disease 
activity. The objectives of these studies 
include evaluating the safety and 
toxicity of CTL therapy, determining the 
duration of in vivo survival of HIV- 
specific CTL clones, and determining if 
ganciclovir therapy can eradicate 
genetically modified, adoptively 
transferred CTL cells." 
I accept this recommendation, and 
Appendix D-XXVII of the NIH 
Guidelines will be amended 
accordingly. 
B. Addition of Appendix D-LVIl to the 
NIH Guidelines 
In a letter dated December 17. 1992, 
Drs. Richard G Boucher and Michael R. 
Knowles of the University of North 
Carolina, Chapel Hill, North Carolina, 
indicated their intention to submit a 
human gene therapy protocol to the 
Recombinant DNA Advisory Committee 
for formal review and approval. The 
title of this protocol is: Gene Therapy 
for Cystic Fibrosis Using El Deleted 
Adenovirus: A Phase I Trial in the Nasal 
Cavity. This request was published for 
comment in the Federal Register of 
February 12. 1993 (58 FR 8500). 
The protocol was reviewed and 
recommended for approval during the 
RAC meeting of March 1-2, 1993, by a 
vote of 16 in favor, 0 opposed, and 1 
abstention. Approval of this protocol 
was contingent on the following 
stipulation: the investigators must 
submit a letter of resolution regarding 
the correct sequence of the cystic 
fibrosis transmembrane conductance 
regulator (CFTR) gene. 
On June 25. 1993, Dr. James Wilson of 
the University of Pennsylvania Medical 
Center, Philadelphia. Pennsylvania, 
provided information to fulfill the 
stipulation requirement. On September 
10, 1993, Dr. Boucher provided 
additional materials as requested by the 
primary reviewers. These materials were 
reviewed by primary reviewers of the 
protocol, and it was determined that the 
stipulations of the RAC were met. The 
following section may be added to 
Appendix D: 
“Appendix D-LVII. 
“Drs. Richard C. Boucher and Michael 
R. Knowles of the University of North 
Carolina, Chapel Hill, North Carolina, 
may conduct experiments on 9 patients 
(18 years old or greater) with cystic 
fibrosis to test for the safety and efficacy 
of an El-deleted recombinant adenovirus 
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Recombinant DNA Research, Volume 18 
