Original Article
Gene Transfer into Humans — Immunotherapy of Patients with Advanced Melanoma, Using Tumor-Infiltrating Lymphocytes Modified by Retroviral Gene Transduction
N Engl J Med 1990; 323:570-578August 30, 1990
- Abstract
- Abstract
Background and Methods.
Treatment with tumor-infiltrating lymphocytes (TIL) plus interleukin-2 can mediate the regression of metastatic melanoma in approximately half of patients. To optimize this treatment approach and define the in vivo distribution and survival of TIL, we used retroviral-mediated gene transduction to introduce the gene coding for resistance to neomycin into human TIL before their infusion into patients — thus using the new gene as a marker for the infused cells.
Results.
Five patients received the gene-modified TIL. All the patients tolerated the treatment well, and no side effects due to the gene transduction were noted. The presence and expression of the neomycin-resistance gene were demonstrated in TIL from all the patients with Southern blot analysis and enzymatic assay for the neomycin phosphotransferase coded by the bacterial gene. Cells from four of the five patients grew successfully in high concentrations of G418, a neomycin analogue otherwise toxic to eukaryotic cells.
With polymerase-chain-reaction analysis, gene-modified cells were consistently found in the circulation of all five patients for three weeks and for as long as two months in two patients. Cells were recovered from tumor deposits as much as 64 days after cell administration. The procedure was safe according to all criteria, including the absence of infectious virus in TIL and in the patients.
Conclusions.
These studies demonstrate the feasibility and safety of using retroviral gene transduction for human gene therapy and have implications for the design of TIL with improved antitumor potency, as well as for the possible use of lymphocytes for the gene therapy of other diseases. (N Engl J Med 1990; 323:570–8.)
Article Activity
- Article
TUMOR-infiltrating lymphocytes (TIL) are lymphoid cells that infiltrate solid tumors and that can be grown by culturing single-cell suspensions from tumors in interleukin-2.1 , 2 We have previously reported that TIL obtained from some human melanomas have unique lytic specificity for autologous tumors3 , 4 and that the adoptive transfer of TIL plus interleukin-2 can mediate substantial tumor regression in some patients with advanced malignant melanoma.5
Because of the potential use of TIL in the therapy of human cancer, studies have been undertaken to optimize the efficacy of this treatment approach. Important questions about TIL concern their distribution and possible long-term survival in the circulation, in lymph nodes, or at tumor sites, as well as clinical correlations between the traffic of TIL subpopulations and their effectiveness against tumors.6 , 7 In an attempt to answer some of these questions, we have used retroviral-mediated gene transduction to insert a selectable marker gene into TIL before the infusion of the lymphocytes into patients with cancer8 (and unpublished data). With the inserted gene as a stable component of the TIL genome, these cells and their offspring can be identified in long-term studies of patients even if they represent a tiny fraction of the total number of cells present.
Because this study involved the first transfer of a foreign gene into humans that was approved by the National Institutes of Health, and used new procedures of retroviral-mediated gene transduction, a variety of practical, safety, and ethical issues were considered.9 , 10 The possible consequences of using a modified retrovirus derived from the Moloney murine leukemia retrovirus and randomly integrating a new gene into the human genome raised concerns that led to extensive review by clinicians, scientists, ethicists, and lay people before the start of this clinical study.
We present the results of the administration of gene-modified TIL into five patients with advanced cancer and show that these lymphocytes can survive at the tumor site and in the circulation for months. Numerous studies have demonstrated the feasibility and safety of this approach to human gene therapy. These studies have implications for the design of TIL with improved antitumor potency and for the possible use of lymphocytes in the gene therapy of other diseases as well.
Methods
Clinical Protocol
Five patients with metastatic melanoma in whom all available therapy had failed were included in this protocol. The clinical protocol was similar to that described previously but was modified to exclude cyclophosphamide as a component of the treatment.5 The tumor deposits were resected, and the TIL were grown in culture for 30 to 65 days by techniques similar to those described elsewhere.5 , 11 After 8 to 19 days of growth, an aliquot of cells was removed for retroviral transduction and grown in parallel with the parent culture. A maximum of 2×1011 cells per infusion was administered in one to three infusions of 200 to 250 ml each over a period of 30 to 60 minutes. After the completion of the infusions, the patients received recombinant interleukin-2 (kindly supplied by the Cetus Corporation) at a dose of 720,000 IU per kilogram of body weight intravenously every eight hours; some doses were omitted depending on the patient's tolerance for the drug. The side effects of the administration of interleukin-2 and the cell infusions were treated with acetaminophen, indomethacin, ranitidine, and meperidine, as described elsewhere.5 , 12
After an interval of 10 to 22 days for recovery, the patients returned to the hospital for a second cycle of therapy with TIL and interleukin-2. Only Patient 2 did not receive TIL in the second cycle, because no cells were available. Patients 2, 4, and 5 received transduced cells in the first cycle only, and Patients 1 and 3 received transduced cells in the second cycle only.
Samples of serum and peripheral-blood mononuclear cells were cryopreserved before treatment and at various intervals after treatment. Peripheral-blood mononuclear cells, tumor-biopsy specimens when available, and lymphocytes grown from the specimens were analyzed by the DNA polymerase-chain-reaction assay for the presence of the vector Neo resistance (NeoR) gene.13 , 14 Peripheral-blood mononuclear cells were also tested periodically for the presence of replication-competent retrovirus with use of the S+L— assay15 with 3T3 amplification.16 The patients' serum samples were tested by Western blot analysis16 for antibody to retroviral 4070A amphotropic p30 gag antigens at intervals after cell infusion.
Two months after the start of treatment, radiographs and scans were obtained to evaluate the status of metastatic disease. Patients with stable or regressing cancer were given a second course of treatment, if possible, although transduced cells were given only in the first course.
Before the start of this study, approval was obtained from the investigational review boards of the National Cancer Institute and the National Heart, Lung, and Blood Institute, the Biosafety Committee of the National Institutes of Health, the Recombinant DNA Advisory Committee, and the Food and Drug Administration. Final approval was obtained from the director of the National Institutes of Health on January 19, 1989. All patients signed a detailed informed-consent form before entry into the study.
Retroviral Gene Transduction of TIL
The PA317/LNL6-c8 cell line used to produce the transduction vector referred to here as LNL6 has been described in detail elsewhere.17 LNL6 was derived from the N2 vector,18 a derivative of Moloney murine leukemia virus in which the gag, pol, and env genes have been removed or truncated and the bacterial NeoR gene inserted. NeoR encodes neomycin phosphotransferase, an intracellular enzyme that inactivates G418, a neomycin analogue toxic to eukaryotic cells. LNL6 differs from N2 in including mutations in the residual gag open-reading frame present in N2 to prevent the production of any viral proteins.17 LNL6 was introduced into the retroviral "packaging" cell line PA317,19 and a clone producing LNL6 at high liters was isolated (PA317/LNL6-c8).
LNL6 virions were produced in the following manner. The cryopreserved PA317/LNL6-C8 cell line was thawed and grown in Dulbecco's modified Eagle's medium containing high levels of glucose and glutamine (12–604B, Whittaker Bioproducts) and 10 percent heat-inactivated fetal bovine serum (A-1111-L, Hyclone). Supernatants from the PA317/LNL6-c8 cell cultures approaching confluence were harvested, pooled, filtered through 0.45-μm filters, titered on NIH/3T3 cells, and frozen at — 70°C until immediately before use. Viral titers ranged from 2×105 to 2×106 G418-resistant colony-forming units per milliliter on NIH/3T3 cells. Numerous tests of the retroviral supernatant were performed, including sterility tests for aerobic and anaerobic bacteria and mycoplasma, MAP tests, tests for lymphocytic choriomeningitis virus, and an S+L— assay for ecotropic, xenotropic, and amphotropic viruses after 3T3 amplification16 for helper virus. General safety tests in mice and guinea pigs were also performed, in accordance with FDA requirements.
When the total cell count in the cultures of TIL reached 1.2 to 7.6×108 cells, one third to one half of the cells were exposed to the LNL6 supernatant at a multiplicity of infection (the ratio of virions to cells) of 1.3 to 2.3 in the presence of 5 μg of protamine20 per milliliter of solution in 800-ml tissue-culture flasks containing 200 ml per flask; the cells were incubated at 37°C for two hours. They were then washed and placed in culture at a density of 106 cells per milliliter. The following day, the transduction procedure was repeated. The recovery rate of TIL after the transductions varied from 74 to 100 percent.
Tests of Transduced and Nontransduced TIL
Before the infusion of TIL, the cultures were characterized according to their expression of cell-surface markers by flow cytometry and according to their lytic properties against autologous tumors, allogeneic tumors, and the K562 and Daudi target-cell lines by four-hour chromium-51—release assays, as described elsewhere.3 4 5 The transduced cells were tested for the presence of helper virus by the S+L— assay (including a one-to-three-week 3T3 amplification), for the presence of 4070A envelope genes by the polymerase-chain-reaction assay, and for the presence of reverse transcriptase.15 , 16 , 21 , 22 The standard limulus assay was used to test for endotoxin, and tests for the autonomous growth of TIL were performed by withdrawing interleukin-2 and following the cell culture for at least one month. Southern blot assays, as well as assays for neomycin phosphotransferase, the bacterial gene product, were performed to confirm the presence and expression of the NeoR gene.23
Assessment of DNA and Polymerase-Chain-Reaction Assay
Genomic DNA was isolated from the cultured TIL, peripheral-blood mononuclear cells, or tumor-biopsy specimens from the patients after the cells were incubated at 55°C for two hours with proteinase K (200 μg per milliliter of solution) in 10 mM TRIS–hydrochloric acid (pH 8.0) and 1 percent sodium dodecyl sulfate (SDS), followed by phenol extraction and ethanol precipitation.12 , 13
To perform the Southern blot assays, 15-μg samples of total cellular DNA were digested to completion with the SstI restriction enzyme and subjected to electrophoresis in 0.8 percent agarose gels, followed by denaturation, neutralization, and blot transfer to nylon membranes in 10× SSC (1× SSC = 0.15 M sodium chloride and 0.015 M trisodium citrate). Hybridization with 32P-labeled probes was carried out as described below for the polymerase-chain-reaction assay.
The polymerase-chain-reaction mixture contained 2 μg of genomic DNA in a total volume of 100 μl, containing 70 mM TRIS–hydrochloric acid (pH 8.8); 20 mM ammonium sulfate; 6 mM dithiothreitol; 100 μg of bovine serum albumin per milliliter; 2 mM magnesium chloride (for NeoR-gene amplification) or 4 mM magnesium chloride (for amplification of the human beta-globin gene used as an internal control for single-copy genomic sequences); 500 μM each of deoxyadenosine triphosphate, deoxycytidine triphosphate, deoxyguanosine triphosphate, and deoxythymidine triphosphate; 10 percent dimethyl sulfoxide; 100 pmol of each primer; and 4 units of thermostable Tag DNA polymerase (New England Bio-labs).13 , 14 The samples were overlaid with 50 μl of mineral oil to prevent evaporation. The DNA samples were amplified for 25 cycles of denaturation (92°C for one minute), annealing (55°C for one minute), and polymerization (70°C for three minutes) with use of a Zymark robot.
After amplification, one fifth of the reaction mixture was removed and analyzed by electrophoresis on a 2 percent NuSieve plus 0.5 percent Sea Kem agarose gel (FMC Bioproducts), stained with homidium bromide, and transferred to nylon membranes (Nytran, Schleicher and Schuell) with 10× SSC. The filters were either baked in a vacuum oven at 80°C for two hours or cross-linked with ultraviolet light. The filters were prehybridized in 5× SSC, 1× Denhardt's solution, 20 mM sodium phosphate (pH 6.8), 0.2 percent SDS, 0.5 mM EDTA, and 200 μg of denatured salmon-sperm DNA per milliliter for 6 to 16 hours at 65°C. Hybridization was initiated by the addition of 32P-labeled (>108 disintegrations per minute per milligram) DNA from the NeoR gene, after polymerase-chain-reaction amplification, and incubation of the mixture at 65°C for 16 to 24 hours. The filters were washed two or three times with 2× SSC plus 0.25 percent SDS at 55°C for 60 minutes, and once with 0.1× SSC plus 0.1 percent SDS at 55°C for 10 to 15 minutes. For autoradiography, filters were exposed to x-ray film (XAR-5) at 80°C with the use of intensifying screens. Alternatively, the Southern blots were analyzed on a Betascope 603 instrument (Betagen) to measure beta-particle radioactivity directly. To estimate the number of cells bearing the NeoR gene in the infused TIL and the patients' peripheral-blood mononuclear cells, control samples were studied by the polymerase chain reaction and analyzed simultaneously with known mixtures of gene-transduced (selected) TIL and nontransduced cells.
To minimize false positive results in the polymerase chain reaction, the DNA samples were kept isolated in an area free of NeoR-containing plasmids by persons not involved with the handling of the NeoR-gene retrovirus. The samples amplified by the polymerase chain reaction were analyzed in laboratories in a separate building from the one in which the earlier DNA extraction and mixing had taken place. All polymerase-chain-reaction Southern blots were run and analyzed in a blinded fashion, and the sample code was broken after all data were recorded.
Results
Patient Characteristics
The characteristics of the five patients with advanced metastatic melanoma who received genetransduced cells are presented in Table 1Table 1
Characteristics of the Patients and Their Tumors.. Previous therapy had failed in all the patients, and all had metastatic cancer in at least two sites. Tumors ranging in diameter from 2 to 6 cm were resected, and they yielded viable cells numbering from 33 to 205×107. After some cells were cryopreserved, the remainder were used to initiate cultures of TIL.Characteristics of the Infused Cells
The characteristics of the infused gene-transduced and nontransduced TIL are presented in Table 2Table 2
Characteristics of Infused Cells.. The lymphocytes grew to a maximum of 63,400 times the initial number over a period of 30 to 65 days. The number of cells infused varied with the growth rate of the cells and the total time in culture, and because some cells were lost due to contamination or use in experimental studies. From 3.3 to 14.5×1010 cells from gene-transduced cultures were administered to the five patients. On the basis of semiquantitative polymerase-chain-reaction determinations, the estimated percentage of transduced cells in these cultures ranged from 1 to 11 percent. These estimates were similar to those obtained with quantitative Southern blot analysis (4 to 18 percent).An example (using TIL from Patient 5) of the growth rate of the gene-transduced and nontransduced TIL is shown in Figure 1Figure 1
Growth and Selection of Human TIL.. On days 8 and 9, half the cells were transduced with the LNL6 vector. The transduced and nontransduced cell populations grew at approximately equal rates for 30 days and were then infused. The nontransduced and gene-transduced cells had doubling times of 2.0 and 2.3 days, respectively.Studies of the Gene-Transduced and Nontransduced TIL
Studies of the expression of 11 cell-surface determinants and of the cytotoxicity of the gene-transduced and nontransduced cultures measured within one week of the day of infusion are presented in Table 3Table 3
Phenotype and Cytotoxicity of Infused Cells.. The majority of all cells were CD3+CD8+ T cells, although some cultures had up to 20 percent CD3+CD4+ cells, and in general the gene-transduced and nontransduced populations had similar percentages of CD4+ and CD8+ cells. The most variation was seen in the cells from Patient 4; 55 percent of the population of nontransduced cells were CD8+, as compared with 94 percent of the population of transduced cells. There were differences in cytotoxicity against various targets between the transduced and nontransduced TIL, as well as against the natural killer (NK)—sensitive K562 and the NK-insensitive Daudi cell lines, as might be expected from cultures grown independently for many weeks.Evidence for the insertion of the NeoR gene in each of the transduced-cell cultures was demonstrated on Southern blot assays (Fig. 2Figure 2
Southern Blot Assay of the LNL6 Vector DNA in Transduced (T) and Nontransduced (N) TIL.). Expression of neomycin phosphotransferase, the NeoR gene product, was also detected in all the transduced-cell populations and none of the nontransduced cells (data not shown). Further evidence for the expression of the NeoR gene was obtained by successfully culturing the TIL from all patients except Patient 2 in 300 μg per milliliter of the neomycin analogue G418. The nontransduced cells from all the patients died in concentrations of G418 exceeding 300 μg per milliliter. An example (from Patient 5) of the growth rates of gene-transduced and nontransduced cells in various concentrations of G418 is shown in Figure 1.Thus, on the basis of the direct assay of gene insertion by Southern blot analysis, the assay for neomycin phosphotransferase, and resistance to G418 in culture, successful insertion and expression of the NeoR gene were demonstrated in the TIL of the five patients studied before reinfusion.
Detection of Gene-Transduced Cells in Blood and Tumor Samples
Before and at various times after the infusion of the gene-marked cells, blood and tumor samples were obtained and polymerase-chain-reaction analysis performed to assess the presence of the NeoR gene. The samples of peripheral-blood mononuclear cells from all patients studied before infusion were negative. Blood samples taken during the infusions of genetransduced cells and three minutes and one hour thereafter were strongly positive for the NeoR gene in Patients 1, 2, 3, and 5; no corresponding samples were available for Patient 4. An example of the polymerase-chain-reaction data obtained from peripheral-blood mononuclear cells and tumor samples from Patient 5 is shown in Figure 3Figure 3
Polymerase-Chain-Reaction Detection of the NeoR Gene in Peripheral-Blood Lymphocytes and Lymphocytes Grown from Tumor-Biopsy Specimens from a Patient Infused with Gene-Transduced TIL., and a summary of the polymerase-chain-reaction analyses of all the patients is shown in Figure 4Figure 4
Results of Polymerase-Chain-Reaction Assays of Peripheral-Blood Mononuclear Cells (PBMC, Circles) and Tumor-Biopsy Specimens (Squares) Obtained from Patients at Various Intervals after the Infusion of the Gene-Transduced TIL.. Because of the pattern of tumor spread, multiple tumor-biopsy specimens could be obtained only from Patients 3 and 5 after cell infusion. Circulating peripheral-blood mononuclear cells containing the NeoR gene were found consistently for the first 19 to 22 days in samples from all patients (Fig. 4), except in one sample from Patient 1 on day 9. No gene-modified cells were found in circulating blood after 22 days in Patients 1, 2, and 4, although they were detected in Patient 3 on day 51 and in Patient 5 on day 60. All samples were assayed in two separate blinded experiments to confirm positive and negative results.Because of initial tumor regression with subsequent regrowth of tumor in Patient 3, a second tumor resection for TIL was performed on an abdominal-wall lesion on day 64, and these TIL were infused on day 94. In the absence of selection, TIL grown from this harvest contained 1 to 2 percent gene-modified cells that had persisted from the original infusion of TIL. Gene-modified cells were detected in the circulation on days 121 and 189, probably representing circulating cells from the second infusion. A graph of the Betascope counts of the polymerase-chain-reaction Southern blot assay of sequential samples of peripheral-blood mononuclear cells from this patient is shown in Figure 5Figure 5
Semiquantitative Polymerase-Chain-Reaction Analysis of Peripheral-Blood Mononuclear Cells from Patient 3..The number of gene-transduced cells in the circulation of the patients was estimated by semiquantitative polymerase chain reaction described elsewhere. In Patient 1, the incidence of transduced TIL in peripheral-blood mononuclear cells was approximately 1 in 5000, 1 in 8000, and 1 in 16,000 on days 1, 2, and 4 after cell infusion, respectively. Patient 5 had 1 transduced cell in 300, 1 in 1500, 1 in 3000, and 1 in 10,000 on days 3, 6, 14, and 19, respectively. Similar variations were seen in the other patients. Gene-modified cells were also found in tumor-biopsy specimens from Patient 3 on days 2 and 64 after cell administration, from Patient 4 on day 6, and from Patient 5 on days 5, 14, and 19 (Fig. 4). Lymphocytes from the tumor-biopsy specimens were detected after the tumor was grown in culture in interleukin-2, making it difficult to estimate the number of transduced cells present in the original tumor-biopsy specimen. DNA isolated directly from the specimens was shown to contain gene-transduced cells on day 2 from Patient 3 and on day 6 from Patient 4. TIL grown from the tumor in Patient 5 could be selected in G418, indicating that the NeoR gene was being expressed in these cells. It thus appears that a fraction of gene-modified TIL can survive in the circulation and tumor of some patients with cancer for at least two months after cell administration.
Clinical and Pathological Assessment of the Patients after Treatment
Patients 1 and 4 had progressive disease after the administration of TIL and died at home 327 and 274 days after treatment, respectively. Patient 2 had a 97 percent shrinkage of axillary-lymph-node metastases but no change in a 3-cm intramuscular thigh mass. Patient 5, a 26-year-old woman with multiple subcutaneous melanoma deposits, an expanding lesion on the soft palate, and lung metastases, had a complete regression of melanoma that was ongoing 11 months after treatment. Patient 3 had a 90 percent reduction in subcutaneous masses after cell infusion. The resection of a growing tumor nodule on day 64 and retreatment with the TIL from this tumor led to a more than 90 percent regression of a paraesophageal mass, which lasted approximately two months before regrowth occurred.
Safety Studies
The side effects of treatment seen in these patients were similar to those seen in other patients receiving TIL and interleukin-2, as described elsewhere.5 , 11 No additional toxic effects were seen as a result of the retroviral transduction of the TIL. All patients were discharged from the hospital four to six days after the infusion of the gene-transduced cells.
All viral supernatants used for gene transduction and all infused TIL were sterile when tested for the presence of aerobic and anaerobic bacteria, fungi, and mycoplasma and negative on S+L— assays for ecotropic, xenotropic, and amphotropic infectious viruses, as well as on NIH/3T3 amplification tests. The viral supernatants passed MAP tests and general safety tests in mice and guinea pigs; tests for lymphocytic choriomeningitis virus and thymic agent were also negative. Polymerase-chain-reaction analysis for the presence of the amphotropic helper virus 4070A envelope genes and reverse transcriptase assays of all TIL were negative. All infused TIL stopped growing shortly after interleukin-2 was withdrawn from the culture medium. Western blot assays of the patients' serum for antibodies to 4070A viral p30 gag protein and S+L — assays for virus performed at various times up to 180 days after cell infusion were negative.
Discussion
In this study we have demonstrated that gene-modified TIL can survive for at least several months in the circulating blood and at tumor sites after intravenous injection into patients with cancer and that this method of retroviral-mediated gene insertion can be a safe and feasible form of gene therapy in humans. Previous studies showed that TIL could be grown in large numbers from a variety of human cancers and defined many of the characteristics of these cells.2 3 4 5 , 24 25 26 27 28 After the adoptive transfer of autologous TIL, along with the administration of interleukin-2, approximately half the patients with metastatic melanoma had objectively verifiable regression of cancer,5 and efforts are under way to determine the factors associated with clinical response. In previous studies using TIL labeled with indium-111, we demonstrated that the lymphocytes became concentrated in tumor tissue in 13 of 18 patients, although these traffic studies were limited by the short half-life (2.8 days) of indium-111, the damage to lymphocytes caused by autoirradiation, and the high rate of spontaneous release of indium-111 from cells.6 , 7
To answer questions about the optimization of therapy with TIL and interleukin-2, we inserted a selectable marker gene, coding for resistance to neomycin, into TIL by retroviral-mediated gene transfer8 (and unpublished data). This gene, which becomes a permanent and stable component of the TIL genome, has several advantages as a cell marker, marking the cells and all their progeny for as long as they survive. It cannot be reused by other cells and can be inserted with use of a modified retrovirus by a simple procedure that does not expose the cell to toxic chemicals or autoirradiation that might alter the antitumor properties of the TIL. The genes inserted can be detected readily by polymerase-chain-reaction techniques able to identify 1 modified cell among 100,000 unmodified cells. The property of resistance to neomycin can also be used to select the modified cells for functional studies by exposure in vitro to the drug G418, which kills nontransduced but not gene-transduced cells.
Since this study represents the first approved clinical protocol to introduce foreign genes into humans, comprehensive data were presented to the Recombinant DNA Advisory Committee of the National Institutes of Health demonstrating that the NeoR gene could be integrated with stability into the TIL genome, that high levels of neomycin phosphotransferase were produced, that transduced cells could be selected in G418, and that the growth patterns, cell-surface phenotype, and cytolytic functions of the TIL were not consistently altered by gene transduction. We also presented evidence that transduced lymphocytes could be detected after adoptive transfer into laboratory animals and that the administration of such cells represented a minimal risk to the patient and posed no risk to health care personnel or the public8 , 16 (and unpublished data). Using the N2 vector, we demonstrated that the patterns of T-cell–receptor gene rearrangement of the beta-chain and gamma-chain genes and levels of messenger RNA coding for the beta and gamma chains, as well as for cytokines such as tumor necrosis factor alpha and beta or the p55 interleukin-2 receptor, were not different in gene-transduced cells as compared with nontransduced cells.8
In this clinical study, careful consideration was given to the potential hazards of using a retrovirus to transfer the marker gene into TIL. The retrovirus we used was derived from the Moloney murine leukemia virus, which can cause T-cell lymphomas in mice; it was modified, however, so that it no longer contained any intact viral genes and thus could not produce the virion proteins needed to package its RNA into an intact infectious virus.17 18 19 To produce the retroviral vector a "packaging" cell line was used, containing a second defective retrovirus that expressed the viral structural proteins. This packaging cell line does not produce retrovirus competent to replicate, because of multiple modifications to the second retrovirus that prevent its replication, including the removal of the signals required for RNA encapsidation, reverse transcription, and integration.19 Thus, the patients' cells were never exposed to a retrovirus capable of replication.
To further ensure that no replicating viruses were present, 3T3-amplification S+L— assays capable of detecting a single viral particle capable of replication per milliliter were performed on all TIL before infusion, and all tests were negative. Previous studies of safety had shown that the exposure of primates to large infusions of infectious murine amphotropic virus produced no serious pathologic effects,16 and in a study of 21 primates receiving retroviral-mediated gene-modified autologous bone marrow, no animal showed evidence of toxicity related to the gene transfer for as much as 2 1/2 years after infusion.29
Because retroviral vectors insert themselves randomly in the host-cell genome, there was a theoretical possibility that the insertion of a vector near an oncogene might activate cellular genes leading to malignant transformation of the TIL. We thus tested all transduced TIL for continued dependence on interleukin-2 before infusion. All the transduced lymphocytes we administered stopped growing shortly after interleukin-2 was withdrawn. Another theoretical concern was the possibility that there could be recombination between the retroviral vector and human endogenous retroviral sequences, leading to the production of a human retrovirus capable of replication. This possibility was remote, since known human endogenous retroviral sequences have no homology with retroviral sequences within the LNL6 vector.
In the five patients treated with gene-modified TIL in this study, no safety hazards due to the gene transduction were recognized. All the patients tolerated the procedure well, and all were discharged from the hospital.
A major finding of this study was the ability to detect gene-modified TIL in the circulation of patients with cancer. With the polymerase-chain-reaction technique, gene-modified TIL were consistently found in the circulation at frequencies of 1 in 300 cells to 1 in 10,000 during the first 21 days after cell infusion, and later in some patients. Circulating gene-modified cells were found on days 51 and 60 in two patients and on day 189 in one patient who received a reinfusion of gene-modified TIL from a second tumor resection. In most patients the administration of interleukin-2 ceased on about day 21, and this may be related to the decreased numbers of TIL in the circulation beyond that time. Of particular interest was our ability to identify gene-modified TIL in the tumor deposits of selected patients as much as 64 days after cell administration. This homing of TIL to tumor deposits was suggested at shorter intervals after cell infusion by our studies with 111In-labeled cells.6 , 7 The TIL from the tumor from Patient 5 could be selected in G418, indicating that the gene was not only inserted but also expressing its gene product.
Antitumor effects after treatment with TIL and interleukin-2 were seen in three patients in this study, including complete regression of cutaneous, mucosal, and lung metastases that continued 11 months after treatment in Patient 5.
Although these studies with gene-marked cells were originally designed to examine the distribution and survival of adoptively transferred TIL in patients with cancer, these approaches may also be useful in improving therapeutic efficacy. The ability to isolate lymphocytes from tumor deposits selectively after they have been infused provides the possibility of using the NeoR gene to select from the heterogeneous population of infused TIL those cells capable of recognizing and homing to the tumor deposit. The subsequent reisolation of these cells and expansion of their numbers may provide the patient who receives them in a second infusion with a higher concentration of tumor-reactive cells than was present in the original heterogeneous population itself. Furthermore, extensive laboratory studies to insert other genes into TIL, such as those coding for tumor necrosis factor, interferon alfa, or interleukin-2, represent an area of active investigation in which the therapeutic efficacy of TIL may be improved.
The studies reported here demonstrate the feasibility and safety of using retroviral-mediated gene transduction into lymphocytes as a method of introducing new genes into humans. These studies appear to have important implications for the design of TIL with improved therapeutic effectiveness. In addition, our finding that lymphocytes persist for long periods both in the circulation and at tissue sites suggests that they may be suitable vehicles for the introduction of other genes to correct inherited genetic defects such as hemophilia or severe combined immunodeficiency disease.
We are indebted to Cornelia Hyatt, Susan Johnson, Kenneth Hines, and Kathryn Ottaway, the laboratory technicians of the Surgery Branch tissue-culture laboratory, for their help; to Mark Manek and David Peterson of Biotech Research Laboratories for help with the polymerase-chain-reaction analyses; to Lisa Monis and Kirsten Wadhams of Genetic Therapy for assistance with the production of supernatant; to Susan Calabro, Stephen Karp, Richard Sherry, Julie Lange, Barbara Pockaj, and William Spencer, the surgical fellows who helped care for these patients; to Claudia Seipp and Joanne Sterling, the research nurses at the Surgery Branch; and to the dedicated nurses of the 2E Surgical Ward and the 2J Surgical Intensive Care Unit of the Clinical Center, National Institutes of Health, for providing these patients with excellent care.
Source Information
From the Surgery Branch, Division of Cancer Treatment (S.A.R., P.A., A.K., M.T.L., J.C.Y., S.L.T.), the Laboratory of Pathology (M.J.M.), and the Division of Cancer Biology and Diagnosis (K.C., R.M.B.), National Cancer Institute; and the National Heart, Lung, and Blood Institute (R.A.M., E.M.K., K.C., W.F.A.), both in Bethesda, Md.; Genetic Therapy, Rockville, Md. (R.M.); and the Fred Hutchinson Cancer Center, Seattle (A.D.M.). Address reprint requests to Dr. Rosenberg at the National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892.
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