Federal Register / Vol. 57, No. 78 / Wednesday, April 22, 1992 / Notices 
14775 
relapse of their disease is a result of residual 
malignant cells remaining in the harvested 
marrow, or inadequate ablation of the tumor 
cells by chemotherapeutic agents. 
Determining the source of relapse may 
indicate whether or not purging of the bone 
marrow is a necessary procedure for these 
leukemia patients. Further studies will be 
performed in order to determine the 
percentage of leukemic cells that contain the 
LNL— 6 vector and the clonality of the marked 
cells. 
I accept this recommendation and 
Appendix D-XXV of the NIH Guidelines 
will be added accordingly. 
C. Addition of Appendix D-XXVI to the 
NIH Guidelines 
In a letter dated October 15, 1991, Dr. 
lames S. Economou of the University of 
California, Los Angeles, 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: "The 
Treatment of Patients With Metastatic 
Melanoma and Renal Cell Cancer Using 
In Vitro Expanded and Genetically* 
Engineered (Neomycin 
Phosphotransferase) Bulk, CD8{+) and/ 
or CD4{+ ) Tumor Infiltrating 
Lymphocytes and Bulk, CD8(+) and/or 
CD4(+) Peripheral Blood Leukocytes in 
Combination With Recombinant 
Interleukin-2 Alone, or with 
Recombinant Interleukin-2 and 
Recombinant Alpha Interferon.” 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 approved was given 
with the following conditions: (i) All 
data concerning vector safety and 
testing must be submitted; (ii) patient 
eligibility will be limited to those with at 
least one lesion that can be biopsied 
post therapy; (ii) the schedule for the 
post therapy assessment of cell 
trafficking is to be added; (iv) develop a 
statistical section for analysis of cell 
trafficking; (v) submit proportionality 
experiments demonstrating the limi t* of 
the ability to quantitate differences in 
ratio of the two vectors; (vi) submit data 
showing stable integration of the genetic 
markers in chronic cell cultures; (vii) 
modify the consent form so that the 
language concerning biopsies is moved 
from the biomodulator section to the 
viral marker section; and (viii) include a 
stopping rule in the protocol if the in 
vivo trafficking data is uninterpretable. 
Dr. Economou submitted the requested 
documentation to ORDA. The protocol 
was forwarded to the RAC for 
consideration during the February 10-11, 
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 RAC, by a 
vote of 15 in favor, 0 opposed and no 
abstentions, approved the protocoL The 
following section may be added to 
appendix D: 
Appendix D-XXVI 
Dr. James S. Economou of the University of 
California, Los Angeles, can conduct gene 
transfer experiments on 20 patients with 
metastatic melanoma and 20 patients with 
renal cell carcinoma. These patients will be 
treated with various combinations of tumor- 
infiltrating lymphocytes and peripheral blood 
leukocytes. Including CDS and CD4 subsets of 
both types of cells. These effector cell 
populations will be given In combination with 
interleukin-2 (IL-2) in the melanoma patients 
and IL-2 plus alpha interferon in the renal 
cell carcinoma patients. The effector cells 
will be transduced with the neomycin 
resistance gene using either the LNL8 or GIN 
retroviral vectors. This “genetic marking” of 
the tumor-infiltrating lymphocytes and 
peripheral blood lymphocytes is designed to 
answer questions about the trafficking of 
these cells, their localization to tumors, and 
their in viro lifespan. 
I accept this recommendation and 
Appendix D-XXVI of the NIH 
Guidelines will be added accordingly. 
D. Addition of Appendix D-XXVII to the 
NIH Guidelines 
In a letter dated October 8, 1991, Dr. 
Philip D. Greenberg of the University of 
Washington, Seattle, Washington, 
indicated his intention to submit a 
human gene therapy protocol to the 
HGTS and the RAC for formal review 
and approval. The title of this protocol 
is: “A Phase I/II Study of Cellular 
Adoptive Immunotherapy Using 
Genetically Modified CD8 + HIV- 
Specific T Cells for HTV-Seropositive 
Patients Undergoing Allogeneic Bone 
Marrow Transplant" This request was 
published for comment in the Federal 
Register on November 4, 1991 (56 FR 
56415). 
Hie protocol was reviewed during the 
HGTS meeting on November 21-22, 
1991. Approval was given with the 
following requested changes in the 
patient consent form: (i) Reword the 
language regarding unforeseen 
problems; (ii) reword the language 
concerning the costs associated with the 
research aspects of the protocol and 
billing to the patients; (iii) clearly 
distinguish between the therapy and the 
gene modification portions of the 
protocol; (iv) use less technical 
terminology throughout the document; 
and (v) provide hard copies of the 
helper-virus assay and vector testing 
slides presented during the HGTS 
meeting. Dr. Greenberg submitted the 
requested documentation to ORDA. The 
protocol was forwarded to the RAC for 
consideration during the February 19-11, 
1992, meeting. The request was 
published for comment in the Federal 
Register on January 3, 1992 (57 FR 318). 
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 RAC, by a 
vote of 16 in favor, 0 opposed, and no 
abstentions, approved the protocol. The 
following section may be added to 
appendix D. 
Appendix D-XXVII 
Dr. Philip D. Greenberg of the University of 
Washington, Seattle, Washington, can 
conduct gene transfer experiments on up to 
15 HTV 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 with a retroviral vector (HyTK) 
encoding a gene that is a fusion product of 
the hygromydn phosphotransferase gene 
(HPH) and the herpes virus thymidine kinase 
(HSV-TK) 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 consequence of CTL therapy. 
Data will be correlated over time, looking at 
multiple parameters of HIV disease activity. 
The objectives of these studies indude 
evaluating the safety and toxidty of CTL 
therapy, determining the duration of in vivo 
survival of HIV-specific CTL done*, and 
determining if ganddovir therapy can 
eradicate genetically modified, adoptively 
transferred CTL cells. 
I accept this recommendation and 
appendix D-XXVH of the NIH 
Guidelines will be added accordingly. 
K Amendment to Appendix D-XV of the 
NIH Guidelines 
In a letter dated December 20, 1991, 
Drs. R. Michael Blaese and W. French 
Anderson of the National Institutes of 
Health, Bethesda, Maryland, requested 
an action item concerning a major 
amendment to the protocol entitled, 
"Treatment of Severe Combined 
Immunodeficiency Disease (SOD) due 
to Adenosine Deaminase (ADA) 
Deficiency With Autologous 
Lymphocytes Transduced With a 
Human ADA Gene.” This protocol was 
originally approved by the RAC at its 
meeting on July 31, 1990, and approved 
by the Director, NIH, published in the 
Federal Register on September 12, 1990 
(55 FR 37565). 
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