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Federal Register / Vol. 56, No. 199 / Tuesday, October 15, 1991 / Notices 
DEPARTMENT OF HEALTH AND 
HUMAN SERVICES 
National Institutes of Health 
Recombinant DNA Research: Action 
Under the Guidelines 
agency: National Institutes of Health, 
PHS, DHHS. 
action: Notice of action Under the NIH 
Guidelines for Research Involving 
Recombinant DNA Molecules. 
summary: This notice sets forth an 
action 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). 
EFFEC T I VE DATE: October 15, 1991. 
FOR FURTHER INFORMATION CONTACT: 
Additional information can be obtained 
from Dr. Nelson A. Wivel. Director, 
Office of Recombinant DNA Activities, 
Office of Science Policy and Legislation, 
National Institutes of Health. Building 
31. room 4B11. Bethesda. Maryland 
20892. (301) 496-9838. 
SUPPLEMENTARY INFORMATION: Today 
an action is being promulgated under 
the NIH Guidelines for Research 
Involving Recombinant DNA Molecules. 
This proposed action was published for 
comment in the Federal Register of 
September 3. 1991 (56 FR 43686), and 
reviewed and recommended for 
approval by the NIH Recombinant DNA 
Advisory Committee (RAC) on October 
7. 1991. 
L Background Information and Decision 
on Action Under the NIH Guidelines 
A. Addition of Appendix D-XXI to the 
NIH Guidelines 
In a letter dated June 6. 1991. Dr. 
Steven A. Rosenberg of the National 
Institutes of Health indicated his 
intention to submit two human gene 
therapy protocols to the Human Gene 
Therapy Subcommittee and the 
Recombinant DNA Advisory Committee 
for formal review and approvaL The 
first protocol is entitled: “Immunization 
of Cancer Patients Using Autologous 
Cancer Cells Modified by Insertion of 
the Gene for Tumor Necrosis Factor." 
The second protocol is entitled: 
“Immunization of Cancer Patients Using 
Autologous Cancer Cells Modified by 
Insertion of the Gene for Interleukin-2." 
This request was published for 
comment in the Federal Register on July 
2. 1991. (56 FR 30398). 
The protocol was reviewed during the 
Human Gene Therapy Subcommittee 
meeting on July 29-30, 1991. Provisional 
approval was granted with the following 
stipulations. Although the NIH 
Institutional Biosafety Committee had 
requested a preliminary experiment • 
using tumor cells that were not gene- 
modified. the Human Gene Therapy 
Subcommittee requested that only tumor 
cells transduced with the cytokine genes 
be used in these protocols. Further, the 
Principal Investigator was requested to 
report his results after the first five 
patients have been studied: he was 
asked to measure the rate of cell growth 
8t the injection site, and to do a 
polymerase chain reaction assay for 
cytokine DNA in the inguinal lymph ■ 
nodes and in tumor biopsies at other 
sites in the body. 
The Human Gene Therapy 
Subcommittee forwarded the protocol to 
the Recombinant DNA Advisory . 
Committee for consideration during the 
October 7-8, 1991, meeting. 
This request was published for 
comment in the Federal Register on 
September 3, 1992 (56 FR 43686). 
During the meeting on October 7-8, 
1991. the Recombinant DNA Advisory 
Committee met to review the protocol 
and recommendations from the 
subcommittee. Following the discussion, 
the Recombinant DNA Advisory 
Committee by an identical vote of 17 in 
favor, 0 opposed, and 1 abstention, 
approved the two protocols with the 
following section to be added to 
Appendix D: 
"Appendix D-XXL 
"Dr. Steven A Rosenberg of the National 
Institutes of Health. Bethesda. Maryland, can- 
conduct two sets of experiments on patients 
with melanoma, renal cell cancer, and colon 
carcinoma. Tumor will be resected from the 
patients as a part of their treatment and 
tissue culture lines of the tumor will be 
established. The genes coding for tumor 
necrosis factor or interleukin-2 will be 
introduced into these tumor cells and the 
integration and expression of these genes will 
be tested. Tumor cells will be injected 
subcutaneously and intradermally into the 
thigh. The amount of tumor injected will be 
less than l/50th of the total of the tumor 
burden of the patient. The site of injection - 
will be followed and resection of these cells 
will take place in 21 days or at a previous 
time if the tumor readies a size of 1 
centimeter. After the first five patients have 
been treated, a report will be filed with the 
Recombinant DNA Advisory Committee that 
Addresses the following points: (1) The rale of 
growth at the injection site: (2) an estimate of 
other tumor growth in the patient (3) data 
pertaining to the presence of cytolytic or 
cytokine producing cells in the draining 
inguinal lymph nodes: (4) polymerase chain 
reaction (PCR) assay to test for the prese nce 
ofyumor cells in the draining lymph nodes to 
determine if there has been metastasis of the 
injected tumor, and (S) only gene modified 
tumor cells will be used for the immunization. 
I accept this recommendation, and 
Appendix D-XXI of the NIH Guidelines 
will be added accordingly. 
II. Summary of Action 
A. Addition of Appendix D-XXI to the 
“ NIH Guidelines “ 
The following section is added to • 
Appendix D: 
"Appendix D-XXI. 
"Dr. Steven A Rosenberg of the National 
institutes of Health. Bethesda. Maryland, can 
conduct experiments on patients with 
advanced melanoma, renal ceil cancer, and 
colon carcinoma who have failed all effective 
therapy, in an attempt to increase these 
patients' immune responses to the tumor, the 
tumor necrosis factor gene or the interleukin- 
2 gene will be introduced into a tumor cell 
line established from the patient. These gene- 
modified autologous tumor cells will then be 
Injected into the thigh of the patient. To 
further utilize the immune system of the 
patient to fight the tumor, stimulated 
lymphocytes will be cultured from either the 
draining regional lymph nodes or the injected 
tumor itself. The patients will be evaluated 
for antitumor effects engendered by the 
injection of the gene modified tumor cells 
themselves as well as after the infusion of the 
cultured lymphocytes. 
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 tould 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 
additioral 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 
pngram 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 
iffected. 
Dated: October 15, 1991. 
Bemsdiae Healy. 
Director, National Institutes of Health. 
(FR Doc 91-24772 Filed 10-11-91: *45 am] 
atUJNG COOC 41*0-01-* 
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Recombinant DNA Research, Volume 15 
