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Federal Register / Vol. 57, No. -166 / Wednesday. August 26, 1992 / ' Notices - 
conduct gene therapy experiments on 
twelve patients over 18 years of age 
with renal cell carcinoma who are HLA- 
A2 positive and who have failed 
conventional therapy. This Phase I study 
w ill examine whether allogeneic HLA- 
A2 matched renal cell carcinoma cells 
expressing recombinant human 
lnterleukin-2 (IL-2) can be injected 
subcutaneously and used to create a 
potent tumor specific immune response 
without producing toxicity. By allowing 
the tumor cells to present the MHC 
Class I molecule as well as the secreted 
IL-2. a clonal expansion of tumor 
specific effector cells is expected. These 
effector populations may access residual 
tumor at distant sites via the systemic 
circulation.” 
I accept this recommendation and 
Appendix D-XXX'M of the NIH 
Guidelines will be added accordingly. 
11. Summary of Actions 
A. Addition of Appendix D-XXVIII to 
the NIH Guidelines 
The following section is added to 
Appendix D: 
"Dr. Malcolm Brenner of SL Jude 
Children’s Research Hospital. Memphis. 
Tennessee, can conduct gene therapy 
experiments on twelve patients with 
relapsed/refractory neuroblastoma who 
have relapsed after receiving autologous 
bone marrow transplant In an attempt 
to stimulate the patient’s immune 
response, the gene coding for 
Interleukin-2 (IL-2) will be used to 
transduce tumor cells, and these gene- 
modified cells will be injected 
subcutaneously in a Phase 1 dose 
escalation trial. Patients will be 
evaluated for an anti-tumor response.” 
B. Addition of Appendix D-XXIX to the 
NIH Guidelines 
The following section is added to 
Appendix D: 
"Drs. Edward Oldfield. Kenneth 
Culver, Zvi Ram, and R. Michael Blaese 
of the National Institutes of Health, 
Bethesda, Maryland, can conduct gene 
therapy experiments on ten patients 
with primary malignant brain tumors 
and ten patients with lung cancer, breast 
cancer, malignant melanoma, or renal 
cell carcinoma who have brain 
metastases. The patient population will 
be limited to adults over the age of 18. 
“Patients will be divided into two 
groups based on the surgical 
accessibility of their lesions. Both 
surgically accessible and surgically 
inaccessible lesions will receive intra- 
tumoral injections of the retroviral 
I lerpes simplex thymidine kinase (HS- 
tk) vector-producer cell line, GlTVSvNa, 
using a guided stereotaxic approach. 
Surgically accessible lesions will be 
excised seven days after sterotaxic 
injection, and the tumor bed will be 
infiltrated with the HS-tk producer cells. 
The removed tumor will be evaluated 
for the efficiency of transduction. 
Ganciclovir (GCV) will be administered 
beginning on the fifth postoperative day. 
In the case of surgically inaccessible 
lesions, the patients will receive 
intravenous therapy with GCV seven 
days after receiving the intra-tumoral 
injections of the retroviral HS-tk vector- 
producer cells." 
C. Addition of Appendix D-XXX to the 
NIH Guidelines 
The following section is added to 
Appendix D: 
“Dr. Albert D. Deisseroth of MD 
Anderson Cancer Center, Houston, 
Texas, can conduct gene transfer 
experiments on ten patients who have 
developed blast crisis or accelerated 
phase chronic myelogenous leukemia 
(CML). The retroviral vectors GIN and 
LNL8 which code for neomycin 
resistance will be used to transduce 
autologous peripheral blood and bone 
marrow cells that have been removed 
and stored at the time of cytogenetic 
remission or re-duction of chronic phase 
in Philadelphia chromosome positive 
CML patients. Following reinduction of 
the chronic phase of CML and 
preparative chemotherapy, patients will 
be infused with the transduced 
autologous cells. 
"This protocol is designed to 
determine the cause of relapse of CML. 
If polyclonal CML neomycin marked 
blastic cells appear at the time of 
relapse, their presence will indicate that 
relapse arises from the leukemic CML 
blast cells present in the autologous 
cells infused following chemotherapy. If 
residual systemic disease contributes to 
relapse, the neomycin resistance gene 
will not be detected in the CML 
leukemic blasts at the time of relapse. 
“This study will compare the relative 
contributions of the peripheral blood 
and bone marrow to generate 
hematopoietic recovery after bone 
marrow transplantation and evaluate 
purging and selection of peripheral 
blood or bone marrow as a source of 
Stem cells for transplant. The percentage 
of neomycin resistant CML cells which 
are leukemic will be determined by PCR 
analysis and detection of bcr-abl 
mRNA.” 
D. Addition of Appendix D-XXX1 to the 
NIH Guidelines 
The following section is added to 
Appendix D: 
“Dr. Cynthia Dunbar of the National 
Institutes of Health, Bethesda. 
Maryland, can conduct gene transfer 
experiments on up to 48 patients with 
multiple myeloma, breast cancer, or 
chronic myelogenous leukemia. The 
retroviral vectors GIN and LNL6 will be 
used to transfer the neomycin resistance 
marker gene into autologous bone 
marrow and peripheral blood stem cells 
in the presence of growth factors to 
examine hematopoietic reconstitution 
after bone marrow transplantation. The 
efficiency of transduction of both short 
and long term autologous bone marrow 
reconstituting cells will be examined. 
“Autologous bone marrow and 
CD34 + peripheral blood stem cells will 
be enriched prior to transduction. 
Myeloma and CML patients will receive 
both autologous bone marrow and 
peripheral blood stem cell 
transplantation. These separate 
populations will be marked with both 
the GIN and LNL6 retroviral vectors. If 
short and long term marking 
experiments are successful, important 
information may be obtained regarding 
the biology of autologous reconstitution, 
the feasibility of retroviral gene transfer 
into hematopoietic cells, and the 
contribution of viable tumor cells within 
the autograft to disease relapse." 
E. Addition of Appendix D-XXXIl to the 
NIH Guidelines 
The following section is added to 
Appendix D: 
“Dr. Bemd Gansbacher of the 
Memorial Sloan-Kettering Cancer 
Center, New York, New York, can 
conduct gene therapy experiments on 
twelve patients over 18 years of age 
with metastatic melanoma who are 
HLA-A2 positive and who have failed 
conventional therapy. This is a phase I 
study to examine whether allogeneic 
HLA-A2 matched melanoma cells 
expressing recombinant human 
Interleukin-2 (IL-2) can be injected 
subcutaneously and used to create a 
potent tumor specific immune response 
without producing toxidty. By allowing 
the tumor cells to present the MHC 
Class I molecule as well as the secreted 
IL-2, a clonal expansion of tumor 
specific effector cells is expected. These 
effector populations may access residual 
tumor at distant sites via the systemic 
circulation.” 
F. Addition of Appendix D-XXXIII to 
the NIH Guidelines 
The following section is added to 
Appendix D: 
Dr. Bemd Gansbacher of the 
Memorial Sloan-Kettering Cancer 
Center. New York, New York, can 
conduct gene therapy experiments on 
twelve patients over 18 yjars of age 
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Recombinant DNA Research, Volume 16 
