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Surgery Branch, Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The recent identification of the genes encoding human tumor Ags has opened new possibilities for the development of immunization approaches capable of stimulating T lymphocyte reactivity against tumors (1, 2). Tumor infiltrating lymphocytes, whose administration was associated with tumor regression in vivo, were used to identify the genes that encoded Ags present on autologous melanomas (3, 4). The two predominant Ags identified in melanomas from HLA-A*0201+ patients were MART-1 and gp100, both melanoma-melanocyte nonmutated differentiation proteins (5, 6). The immunodominant peptides from these proteins were also identified (7, 8). Many of these peptides were of low to intermediate binding affinity to HLA-A*0201, and several synthetic peptides were identified containing substituted amino acids at anchor residues that bound more strongly to the HLA-A*0201 molecule. Replacement of threonine with methionine at the second position of the immunodominant peptide, gp100:209–217 (hereafter referred to as g209), appeared to be more immunogenic in vitro than the native peptide (9). Thus, this modified peptide, gp100:209–217(210M) (hereafter referred to as g209–2M) was selected for in vivo immunization studies in patients with metastatic melanoma.
We recently reported that the immunization of patients with the g209–2M peptide could generate potent T cell responses in patients against the native peptide and melanoma cells (10). The administration of this peptide, along with IL-2, in a pilot clinical trial mediated cancer regression in 13 of 31 (42%) of patients with metastatic melanoma. We have now extended these studies to perform a detailed immunologic analysis of the cellular immune reaction of patients receiving immunization with the g209–2M peptide plus IL-2. In addition, many animal models have suggested that the administration of IL-12 and GM-CSF could substantially increase the antitumor impact of immunization using vaccinia virus, adenovirus, or DNA-encoding model tumor Ags, presumably by increasing T cell-mediated immune reactions (11, 12, 13, 14). IL-12 has been shown to enhance immunization with a p53 peptide in mice bearing the Meth A tumor expressing the p53 mutation (14). Similarly, in mouse models, tumors transduced to secrete GM-CSF are more immunogenic than nonsecreting tumors (15), and Jaeger et al. (16) have reported that GM-CSF administration in conjunction with peptide immunization can increase immune reactions in humans. We thus studied the clinical and immunologic consequences of immunization with the g209–2M peptide in conjunction with the systemic administration of IL-12 or GM-CSF in patients with metastatic melanoma.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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All patients immunized in this study had biopsy-proven metastatic melanoma. The majority of patients were between the ages of 30 and 60 years, and all underwent clinical evaluation of tumor sites by physical examination and radiologic studies. All patients were confirmed to be HLA-A*0201-positive by using high resolution nested sequence PCR subtyping, and all signed an informed consent before treatment began.
The modified peptide, gp100:209–217 (210M) with the sequence IMDQVPFSV, was prepared under good manufacturing practice conditions by Multiple Peptide Systems (San Diego, CA). The identity of the peptide was confirmed by mass spectral analysis, and the peptide was shown to be >98% pure as assessed by high pressure liquid chromatography analysis. A total of 1.5 mg peptide in 1.5 ml water was mixed with an equal volume of IFA (Montanide ISA-51, Seppic, France) and vortexed vigorously on a vortex mixer for 12 min to form an emulsion. Two aliquots of 1 ml each were injected in the s.c. tissue of the anterior thigh for a total peptide injection of 1 mg. Injections of peptide in IFA was given every 3 wk. Before the initial peptide injection and following two injections, all patients were leukopheresed, and PBMC were cryopreserved. At 6 wk and at regular intervals thereafter, the clinical status of patients was assessed by repeat physical and radiologic examination. In this analysis, 11 patients were treated with the g209–2M peptide alone (these patients were reported in 10). Sixteen consecutive patients were treated with i.v. IL-2, 14 consecutive patients were treated with peptide plus i.v. IL-12, and 13 consecutive patients were treated with peptide plus s.c. GM-CSF.
Patients received IL-2 (Cetus-Oncology Division, Chiron, Emeryville, CA) at a dose of 720,000 IU/kg (corresponding to 120,000 Cetus U/kg) administered in 50 ml of normal saline containing 5% human serum albumin as an i.v. bolus over 15 min, starting either 1 day (11 patients) or 5 days (5 patients) after the peptide injection. Patients received IL-2 every 8 h until grade 3 or 4 toxicity was reached that could not be easily reversed by standard supportive measures (generally, 6–10 doses). After two consecutive cycles of peptide plus IL-2, some subsequent cycles involved peptide alone if additional time for recovery from IL-2 side effects was required. All patients received concomitant medications, including acetaminophen (650 mg every 4 h), indomethacin (50 mg every 8 h), and ranitidine (150 mg every 12 h), to prevent some of the side effects associated with IL-2 administration.
Recombinant IL-12 was supplied by Genetics Institute (Cambridge, MA) and was given i.v. at a dose of 250 ng/kg over 10–20 s. For the first four patients, a test dose of IL-12 was given and was followed 2 wk later by the s.c. injection of 1 mg peptide in IFA followed by five daily i.v. doses of 250 ng/kg IL-12. These five IL-12 doses were then repeated after each subsequent peptide injection. The next 10 patients received 1 mg peptide in IFA along with the test dose of IL-12, and then, 2 wk later, began two cycles of 1 mg peptide in IFA followed by five daily doses of IL-12 at 250 ng/kg i.v. All patients received acetaminophen 650 mg orally every 4–6 h while on therapy, and indomethacin 50 mg orally every 6 h was used to treat any constitutional symptoms.
GM-CSF was supplied by Immunex (Seattle, WA) and was injected immediately distal to the site of the peptide injection at a dose of 100 mcg (seven patients) or 500 mcg (six patients) daily for 6 days, starting 3 days before the peptide injection and ending 2 days after the peptide injection.
In vitro assessment of immunologic reactivity to the g209–2M peptide and melanoma
Cryopreserved PBMCs obtained before and 3 wk after two
immunizations were thawed and simultaneously tested. A total of 3
x 106 cells were suspended in 2 ml complete
medium consisting of IMDM with 25 mM HEPES buffer, 10%
heat-inactivated human AB serum, 2 mM L-glutamine, 100 U/ml
penicillin, and 100 µg/ml streptomycin (Biofluids, Rockville, MD;
Sigma, St. Louis, MO; Pel-Freez, Brown Deer, WI), and 1 µM g209–2M
peptide was added to the culture. Two days later, IL-2 was added to the
medium, and every 3–4 thereafter, half of the medium was withdrawn and
replaced with fresh complete medium containing IL-2. To determine the
optimal conditions for this assay, two different concentrations of IL-2
were evaluated: 30 IU IL-2/ml and 300 IU IL-2/ml. Cultures were
harvested at varying times between days 4 and 18, and lymphocyte
reactivity was tested in a final volume of 0.2 ml by mixing
105 harvested lymphocytes with stimulator cells
consisting of either 105 T2 cells pulsed with
peptide or tumor cells. A total of 6 x 106
T2 cells were pulsed with 1 µM, 10-2 µM, or
10-4 µM peptide and incubated for 3 h
with intermediate mixing before being washed and diluted into the assay
culture. After incubation for 18–24 h, the supernatant was harvested
and tested for IFN-
using a standard ELISA assay. The results of a
representative assay are shown in Table I
. Maximum reactivity appeared 11–15
days after initiation of the culture, and improved cell expansion with
no loss of specificity was seen using 300 IU IL-2/ml compared with 30
IU IL-2/ml. Thus, all tests reported in this paper represent assays
conducted in 300 IU IL-2/ml and harvested 11–13 days after initiation
of the culture. Data is sometimes reported here as a stimulation index
(S.I.),2 calculated as
the ratio of reactivity to the native gp100:209–217 peptide compared
with reactivity to a control gp100:280–288 peptide. All assays were
performed on PBMC obtained immediately before peptide injection or 21
days after the two peptide injections given 3 wk apart.
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T2 cells are an HLA-A2+ TAP-deficient T-B cell hybrid. Melanoma cell lines, 501-mel (HLA-A2+), 624–38 mel (HLA-A2+), 888-mel (HLA-A2-), and 624–28 mel (HLA-A2-) were established in the Surgery Branch, National Cancer Institute (Bethesda, MD). The melanoma cell line SK23 mel (HLA-A2+) was supplied by T. Boon at the Lugwig Institute for Cancer Research (Brussels, Belgium).
Evaluation of clinical response
The patient response to treatment was evaluated after two and four peptide injections with cytokine. All known sites of disease were evaluated, and, if patients showed evidence of stable or regressing disease, additional treatments were administered. A response was considered complete if all measurable tumor disappeared. A partial response was defined as a 50% or greater decrease of the sum of the products of the longest perpendicular diameters of all lesions, lasting at least 1 mo and without increase of any tumor or the appearance of any new tumor. Any patient not meeting the criteria of a complete or partial response was considered a nonresponder.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We previously reported that 10 of 11 patients immunized with the
g209–2M peptide developed circulating lymphocytes capable of
recognizing the native g209 peptide (10). Table II provides a characteristic experiment
of three patients (1, 2, 3) who received the peptide alone and three
patients (4, 5, 6) who received the peptide plus high-dose IL-2. None of
the patients exhibited reactivity to the 209 peptide before
immunization. All three patients who received peptide alone developed
reactivity to the native g209 peptide following immunization, and none
of the three patients who received i.v. IL-2 following the peptide
developed this reactivity. A summary of the development of specific
immune reactivity against the native g209 peptide after immunization
for all patients in this trial is shown in Fig. 1. The S.I. (specific reactivity as
measured by IFN- secretion against T2 cells pulsed with the 209
peptide, compared with T2 cells pulsed with the 280 peptide) was 2 or
greater for 10 of 11 patients receiving the g209–2M peptide in IFA,
compared with an S.I. of 2 or greater in only 4 of 11 patients who
received the g209–2M peptide in conjunction with IL-2, starting 1 day
after peptide injection (p2 =
0.02). The highest S.I. of 84 in a patient receiving peptide plus IL-2
occurred in the only patient in the entire series who exhibited
specific reactivity to the native g209 peptide prior to any
immunization and thus is probably not representative of the other
patients in this study. Because of the possibility that the
administration of IL-2 shortly after peptide injection might result in
activation-induced apoptosis of lymphocytes, a second cohort of five
patients was treated with peptide immunization, followed 5 days later
by the administration of IL-2. Only one of five of these patients
developed significant reactivity (S.I. 
2) against the native g209
peptide. Thus, compared with 10 of 11 patients developing reactivity
following injection of the g209–2M peptide alone, only 5 of 16
patients developed significant reactivity when IL-2 was administered
(p2 = 0.005). PBMC that did
not react to the 209 peptide, however, did contain cellular immune
reactivity against an influenza peptide, demonstrating that these
patients were immunocompetent and had cells capable of responding to a
prior natural challenge with influenza (examples in Table III, patients 2, 4, and 5).
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patients 1 and 3). The reactivity of PBMC against peptide was closely
correlated with the ability of these cells to respond to
HLA-A2+ tumors in 41 independent cultures from
multiple patients (p < 0.001) (Fig. 2).
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, patients 1
and 2).
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, patients 3 and 4. The administration of IL-12 or s.c. GM-CSF also led to a decrease in immune precursors when administered in conjunction with the g209–2M peptide
Immune reactivity in PBMCs was also tested before and after
immunization with the g209–2M peptide administered with either i.v.
IL-12 or s.c. GM-CSF (Fig. 1). IL-12 was administered in conjunction
with g209–2M peptide in IFA in 14 patients, and 7 developed an S.I. of
2-fold or greater against native g209 peptide. This was a lower
percentage of patients successfully immunized, compared with patients
receiving 209–2M peptide alone (10 of 11;
p2 = 0.04). Patients receiving IL-12
had a median S.I. of 2, compared with a median S.I. of 26 for patients
receiving the 209–2M peptide alone. Similarly, of 13 patients
immunized with g209–2M peptide in GM-CSF, only 4 achieved an S.I. of 2
or greater (p2 = 0.005,
compared with g209–2M peptide alone) with a median S.I. of 1. It thus
appears that the administration of either i.v. IL-12 or s.c. GM-CSF
also decreased the number of circulating immune precursors following
immunization with the g209–2M peptide.
Clinical response to treatment
No objective clinical responses (partial or complete) were seen in the 11 patients treated with the g209–2M peptide alone. Of the 16 patients in this analysis that received peptide plus IL-2, 6 (38%) responded to peptide injection plus IL-2. There were no objective clinical responses in the 14 patients treated with peptide plus IL-12 or the 13 patients treated with peptide plus GM-CSF.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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While the administration of IL-2 in addition to peptide was capable of mediating clinical tumor regression in many patients, the addition of IL-2 beginning 1 or 5 days after peptide administration significantly reduced the ability to detect antipeptide precursors in the peripheral circulation, compared with patients who received peptide alone (and had no clinical responses). This discordance between the development of antitumor precursors and clinical response is not clearly understood. The antitumor immune precursors detected in the in vitro assay from patients who received peptide alone were apparently not in an activation state sufficient to recognize tumor, since these patients exhibited no tumor regression and PBMC freshly isolated and uncultured did not recognize tumor in this assay or in a sensitive enzyme-linked immunospot assay (data not shown). The in vivo exposure of sensitized cells to tumor or normal cells expressing the gp100 Ag in the absence of costimulatory signals may have induced an anergic state in these lymphocytes (18). Incubation with peptide for at least 4 days in vitro, presumably to allow for peptide presentation on APC that expressed appropriate costimulatory molecules, was required to activate the cells to manifest peptide and tumor recognition. The administration of IL-2 may have supplied the necessary signals to activate cells newly sensitized by peptide in IFA to recognize tumor. But why then were immune precursors not detected in PBMC of patients receiving peptide plus IL-2?
The administration of IL-2 did not lead to the general elimination of
the ability to detect memory T cells in the circulation, since the
peripheral cells of patients receiving peptide plus IL-2 that had no
activity against the g209 peptide were fully capable of generating
immune reactivities to influenza peptide, which presumably were present
from prior environmental exposure to influenza (Table III, patients 2,
4, and 5). The inability to develop peptide reactivity in patients
given peptide plus IL-2 was also not an accident of patient selection,
since the same patients who could not develop precursor reactivity when
given peptide plus IL-2 were capable of generating normal antipeptide
reactivity when subsequently administered peptide alone (Table IV).
Thus, these patients appeared capable of generating new, as well as
memory responses, though specific peptide reactivity was not detectable
when peptide was given in conjunction with IL-2.
It also did not appear that the failure to detect precursors was due to
the redistribution of antitumor memory cells from the circulation,
since precursors could easily be detected in patients who received
peptide plus IL-2 following the induction of detectable precursors due
to the administration of peptide alone (Table IV). In addition, it did
not appear likely that the administration of IL-2 inhibited the initial
generation of antitumor precursors, since the administration of IL-2
beginning at day 1 or day 5 after peptide injection equally abrogated
circulating precursors. Further, it appears likely that the
administration of peptide plus IL-2 led to a substantial increase in
objective clinical responses, compared with that expected from IL-2
alone, and the likelihood exists that this increase in responses was
due to the enhancement of T cell reactivity to the peptide due to IL-2
administration.
Thus, since the administration of peptide plus IL-2 appears capable of mediating the generation of T cell precursors as evidenced by their ability to mediate antitumor responses and yet eliminates these precursors from the peripheral circulation, it appears likely that the combination of peptide administration plus IL-2 leads either to the destruction of T cells with antitumor reactivity at the tumor site once their effector function has been realized or to a sequestration of newly generated but not memory effector cells at the tumor site or elsewhere.
The apoptotic death of highly activated or IL-2-exposed lymphocytes
upon engagement of their TCR has been described in several model
systems and may be an important regulatory mechanism of active immune
responses (19, 20). In mice with acute viral infection,
stimulation of lymphocytes by specific Ag at the height of activation
can result in the induction of apoptosis (20). In studies
using the 
-galactosidase model tumor Ag, restimulation with specific
-galactosidase peptide either in vivo or in vitro at the height of
immunization can result in apoptotic elimination of specifically
reactive cells (Bronte et al., submitted for publication). The timing
of lymphocyte stimulation and restimulation, as well as the timing of
exposure to IL-2, can have profound impact on the activation or
suppression of specific immune reactions. Thus, in our clinical trial,
lymphocytes that were sensitized to peptide in IFA and encountered Ag
at the tumor site in the presence of IL-2 may be capable of manifesting
their effector function (tumor recognition and destruction) but undergo
apoptosis in the process. This hypothesis would explain why antitumor
effects are seen in patients receiving peptide immunization plus IL-2
but that precursors cannot be detected in the circulation. It should be
emphasized, however, that the explanation for a decrease in circulating
precursors when IL-2 is administered after peptide vaccination remains
speculative.
In our studies, contrary to the predictions resulting from studies of murine tumors (11, 12, 13, 14), the administration of GM-CSF or IL-12 did not result in clinical antitumor responses, but also appeared to reduce the level of T cell precursors, although perhaps not as profoundly as seen with IL-2. In other clinical trials of the administration of IL-12 or GM-CSF alone to cancer patients, little, if any, antitumor effects have been seen. It is possible that the exact dose, schedule, and routes of administration of these cytokines may be critical, and it is possible that alterations in these parameters could lead to different results. The mechanism by which the administration of IL-12 and GM-CSF decreased lymphocyte precursors in the circulation is unclear.
It should be emphasized that the studies reported in this paper deal with immunization against nonmutated self-Ags. The presentation of these Ags on normal cells in the absence of costimulatory molecules might represent a profound difference in immune reactivity, compared with the immune reactivity generated against mutated Ags present only on tumors, as is the case in most animal models used to demonstrate the efficacy of IL-12 or GM-CSF administration. A critical need exists for the development of animal tumor models directed against normal nonmutated differentiation Ags to explore the mechanisms involved in immunization, as well as to optimize the immunizing vectors, their modes of administration and adjuvant cytokine administration to help design effective immunotherapy strategies for patients with cancer.
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Footnotes |
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2 Abbreviation used in this paper: S.I., stimulation index.
Received for publication September 14, 1998. Accepted for publication May 20, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B T lymphocytes for apoptosis. Nature 353:858.[Medline]
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