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Federal Register / Vol. 57, No. 18 / Tuesday, January 28, 1992 / Notices 
SUPPLEMENTARY INFORMATION: Today 
an action is being promulgated under 
the N1H Guidelines for Research 
Involving Recombinant DNA Molecules. 
This proposed action was published for 
comment in the Federal Register of April 
29, 1991 (56 .FR 19776), and reviewed and 
recommended for approval by the NIH 
Recombinant DNA Advisory Committee 
(RAC) on May 30, 1991. 
I. Background Information and Decision 
on Action Under the NIH Guidelines 
A. Addition of Appendix D-XXIII to the 
AT H Guidelines 
In a letter dated September 13, 1990. 
Dr. Michael T. Lotze of the University of 
Pittsburgh School of Medicine, 
Pittsburgh, Pennsylvania, indicated his 
intention to submit a human gene 
transfer protocol to the Human Gene 
Therapy Subcommittee and the 
Recombinant DNA Advisory Committee 
for formal review and approval. The title 
of this protocol is: 
‘The Administration of Interleukin-2, 
Interleukin-4, and Tumor Infiltrating 
Lymphocytes to Patients with 
Melanoma." 
The protocol was reviewed during the 
Human Gene Therapy Subcommittee 
meeting on November 30, 1990, and 
forwarded to the Recombinant DNA 
Advisory Committee on February 4, 
1991, for its approval. The Recombinant 
DNA Advisory Committee deferred 
approval and sent the protocol back to 
the Human Gene Therapy Subcommittee 
for further deliberations on April 5, 1991. 
On April 5, 1991, the Human Gene 
Therapy Subcommittee gave provisional 
approval with the stipulation that more 
information be provided about the 
quantitative assays of gene-marked 
tumor infiltrating lymphocytes. It was 
suggested that the consent form 
concerning the gene marking of tumor 
infiltrating lymphocytes be separated 
from the consent form regarding 
interleukin-2 and interleukin-4. 
Tthe Human Gene Therapy 
Subcommittee forwarded the protocol to 
the Recombinant DNA Advisory 
Committee for consideration during the 
May 30-31, 1991, meeting. 
The request was published for consent 
in the Federal Register on April 29, 1991 
(56 FR 19776). 
During the meeting on May 30-31, 
1991. the Recombinant DNA Advisory 
Committee met to review the protocol 
and recommendations from the Human 
Gene Therapy Subcommittee. 
Two additional modifications were 
made to the informed consent document. 
One involved the addition of a clarifying 
sentence concerning the minor risk of 
infection associated with the biopsy of 
subcutaneous tumor nodules. The 
second involved the addition of a 
sentence indicating that there was no 
requirement for patients undergoing 
interleukin therapy to take part in the 
gene marking study. Following a 
discussion of the data on the 
quantitative aspects of polymerase 
chain reaction (PCR), the Recombinant 
DNA Advisory Committee, by a vote of 
18 in favor, 0 opposed, and no 
abstentions, approved the protocol 
pending receipt of additional data 
showing the detection of Neo-R- 
transduced cells by PCR at a dilution of 
1 in 10 s non-transduced cells. The 
review of this additional data can be 
conducted by the Office of Recombinant 
DNA Activities (ORDA) staff and the 
primary reviewer of the protocol. 
On November 12. 1991, Dr. Lotze 
submitted to ORDA the PCR data from 
mixing experiments with Neo-R- 
transduced cells. To satisfy the 
Recombinant DNA Advisory 
Committee's request, ORDA requested 
additional experiments. On December 
17 and December 27, 1991, additional 
data were supplied. 
Following consultation between 
ORDA staff and the primary reviewer of 
the protocol, it was determined that the 
experimental results, submitted on 
December 27, 1991, showed the 
requested level of sensitivity, i.e., it was 
possible to detect Neo-R-transduced 
cells by PCR at a dilution of 1 in 10* non- 
transduced cells. Since this meets the 
request of the Recombinant DNA 
Advisory Committee, the following 
section may be added to Appendix D: 
"Appendix D-XXIII 
"Dr. Michael T. Lotze of the University of 
Pittsburgh School of Medicine. Pittsburgh, 
Pennsylvania, can conduct a series of 
experiments on 20 patients with metastatic 
melanoma who have failed conventional 
therapy. Tumor infiltrating lymphocytes 
(TILs) will be the targets for retroviral 
mediated gene transfer. This system will 
transfer a bacterial gene for 
neophotransferase activity (NEO-R) that 
confers resistance to the neomycin analogue 
G418. This marker gene is required to 
separately identify autologous TIL cells from 
the patient's endogenous cells. By using a 
tracer population of TIL cells, the following 
questions can be addressed: (1) How long can 
the TIL cells be detected in vivo in the 
peripheral blood of the patients? (2) How do 
combinations of interleukin-2 and interleukin- 
4 affect localization and survival of TIL in 
tumor sites?" 
I accept this recommendation and 
Appendix D-XXIII of the NIH 
Guidelines will be added accordingly. 
II. Summary of Action 
The following section is added to 
Appendix D: 
A. Addition of Appendix D-XXIII to the 
NIH Guidelines 
"Appendix D-XXIII. 
“Dr. Michael T. Lotze of the 
University of Pittsburgh School of 
Medicine, Pittsburgh, Pennsylvania, can 
conduct experiments on 20 patients with 
metastatic melanoma who have failed 
conventional therapy. A gene transfer 
experiment will be performed, 
transducing the patients' tumor 
infiltrating lymphocytes (TILs) with the 
gene for neomycin resistance. Through 
the use of this gene marking technique, 
it is proposed to determine how long TIL 
cells can be detected in vivo in the 
peripheral blood of the patients, and 
how the administration of interleukin-2 
and interleukin-4 affects localization 
and survival of TIL cells in tumor sites.” 
OMB's "Mandatory Information 
Requirements for Federal Assistance 
Program Announcements" (45 FR 39592) 
requires a statement concerning the 
official government programs contained 
in the Catalog of Federal Domestic 
Assistance. Normally NIH lists in its 
announcements the number and title of 
affected individual programs for the 
guidance of the public. Because the 
guidance in this notice covers not only 
virtually every NIH program but also 
essentially every Federal research 
program in which DNA recombinant 
molecule techniques could be used, it 
has been determined to be not cost 
effective or in the public interest to 
attempt to list these programs. Such a 
list would likely require several 
additional pages. In addition, NIH could 
not be certain that every Federal 
program would be included as many 
Federal agencies, as well as private 
organizations, both national and 
international, have elected to follow the 
NIH Guidelines. In lieu of the individual 
program listing, NIH invites readers to 
direct questions to the information 
address above about whether individual 
programs listed in the Catalog of Federal 
Domestic Assistance are affected. 
Effective Date: January 17. 1992. 
Bemadine Healy, 
Director. National Institutes of Health. 
(FR Dor. 92-2040 Filed 1-27-92; 8:45 am) 
BILLING CODE 4140-01-M 
[308] 
Recombinant DNA Research, Volume 15 
