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Federal Register / Vol. 57, No. 78 / Wednesday, April 22, 1992 / 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, 1988, 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 
Legislation, 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 July 2, 1991 (56 FR 30398). 
September 3. 1991 (56 FR 43686), 
November 4. 1991 (56 FR 56415), and 
January 3, 1992 (57 FR 316) reviewed and 
recommended for approval by the NIH 
Recombinant DNA Advisory Committee 
(RAC) at its meeting on February 10-11. 
1992. 
I. Background Information and 
Decisions on Actions Under the NIH 
Guidelines 
A. Addition of Appendix D-XXIV to the 
NIH Guidelines 
In a letter dated October 18, 1991, Dr. 
Gary J. Nabel of the University of 
Michigan Medical School, Ann Arbor, 
Michigan, indicated his intention to 
submit a human gene therapy protocol 
to the Human Gene Therapy 
Subcommittee (HGTS) and the RAC for 
formal review and approval. The title of 
this protocol is: “Immunotherapy of 
Malignancy by In Vivo Gene Transfer 
into Tumors." This request was 
published for comment in the Federal 
Register on November 4, 1991 (56 FR 
56415). 
The protocol was reviewed during the 
Human Gene Therapy Subcommittee 
(HGTS) meeting on November 21-22, 
1991. Provisional approval was given 
with the following conditions: (i) Amend 
consent form regarding possibility of 
sensitization to the human antigen: (ii) 
expand the clinical protocol regarding 
the number of biopsies; (iii) make 
available the nucleotide sequence 
analysis of the total construct of the 
vector; and (iv) provide clarification 
concerning the status of DNA 
integration in tumor cells. Dr. Nabel 
submitted the requested documentation 
to ORDA. The protocol was then 
forwarded to the RAC for consideration 
during the February 10-11, 1992, 
meeting. This request was published for 
comment in the Federal Renter on 
January 3. 1992 (57 FR 316). 
During the meeting on February 10, 
1992, the RAC met to review the 
protocol and recommendations from the 
HGTS. A modification was requested to 
the patient's informed consent document 
in the Description of Treatment or 
Procedures to be Undertaken section. 
The revised wording in the consent form 
is to read as follows: 
“By using techniques in the laboratory it is 
now possible to prepare large amounts of 
human DNA or genetic material and bacteria. 
This DNA will be mixed with fat bodies 
called liposomes, and we plan to transport 
the mixture into your tumor by a bacterial 
carrier or delivery system. 
Also included in this package is a separate 
bacterial gene which helps us trace the 
location of the DNA liposome mixture. Once 
introduced into the tumor the DNA produces 
a protein which stimulates tissue rejection. 
This protein, known as HLA-B7, causes the 
cells which will contain it to be recognized as 
a foreign enemy by your immune system. 
The purpose of our study is to determine 
whether this treatment will induce the cells of 
your immune system, known as lymphocytes, 
to attack and kill your tumor." 
The RAC, by a vote of 13 in favor, 0 
opposed, and 1 abstention, approved the 
protocol. The following section may be 
added to Appendix D: 
Appendix D-XXIV 
Dr. Gary J. Nabel of the University of 
Michigan Medical School, Ann Arbor, 
Michigan, can conduct gene therapy 
experiments on twelve patients with 
melanoma or adenocarcinoma. The patient 
population will be limited to adults over the 
age of 16 and female patients must be 
postmenopausal or have undergone tubal 
ligation or orchiectomy. The patient's immune 
response will be stimulated by the 
introduction of a gene encoding for a Class I 
MHC protein. HLA-87, in order to enhance 
tumor regression. DNA/liposome-mediated 
transfection techniques will be used to 
directly transfer the foreign gene into tumor 
cells. HLA-B7 expression will be confirmed 
in vivo and the immune response stimulated 
by the expression of this antigen will be 
characterized. 
These experiments will be analyzed for 
their efficacy in treating cancer. 
I accept this recommendation and 
appendix D-XXIV of the NIH Guidelines 
will be added accordingly. 
B. Addition of Appendix D-XXV to the 
NIH Guidelines 
In a letter dated October 10, 1991, Dr. 
Kenneth Cometta of Indiana University, 
Indianapolis, Indiana, indicated his 
intention to submit a human gene 
transfer protocol to the HGTS and the 
RAC for formal review and approval. 
The title of this protocol is: “Retroviral- 
Mediated Gene Transfer of Bone 
Marrow Cells During Autologous Bone 
Marrow Transplantation for Acute 
Leukemia." This request was published 
for comment in the Federal Register on 
November 4, 1991 (56 FR 56415). 
The protocol was reviewed during the 
HGTS meeting on November 21-22, 
1991. Provisional approval was given 
with the following conditions: (1) Amend 
the consent form regarding the possible 
benefit of the introduction of the gene; 
(ii) amend the consent form regarding 
compensation to the patient related to 
the research aspects of the protocol; (iii) 
demonstrate that the transduced 
leukemic cells will survive the freezing 
process; and (iv) add a statistical 
section that addresses the interpretation 
of recurrence of disease in labeled bone . 
marrow specimens; it is important to 
determine how many cells contribute to 
a relapse. Dr. Cometta submitted the 
requested documentation to ORDA. The 
protocol was then forwarded to the RAC 
for consideration during the February 
16-11, 1992, meeting. The request was 
published for comment in the Federal 
Register on January 3, 1992 (57 FR 316). 
During the meeting on February 11, 
1992, the RAC met to review the 
protocol and recommendations from the 
HGTS. It was decided that the issues 
raised by the HGTS had been 
adequately addressed. The RAG by a 
vote of 15 in favor, 1 opposed, and no 
abstentions, approved the protocol. The 
following section may be added to 
appendix D: 
Appendix D-XXV 
Dr. Kenneth Cometta of Indiana 
University, Indianapolis, Indiana, can 
conduct gene transfer experiments on up to 
10 patients with acute myelogenous leukemia 
(AML) and up to 10 patients with acute 
lymphocytic leukemia (ALL). The patient 
population will be limited to persons between 
18 and 65 years of age. Using the LNL-6 
vector, autologous bone marrow cells will be 
marked with the neomycin resistance gene. 
Gene marked and untreated bone marrow 
cells will be reinfused at the time of bone 
marrow transplantation. Patients will then be 
monitored for evidence of the neomycin 
resistance gene in peripheral blood and bone 
marrow cells in order to determine whether 
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Recombinant DNA Research, Volume 15 
