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Clinical Trials |
Departments of Surgery [Y. M., T. S., T. M., H. I., K. S., H. Y.] and Immunology [N. I., A. Y., K. K., A. M., S. O., K. I.], Kurume University School of Medicine, and Cancer Vaccine Development Division, Research Center for Innovative Cancer Therapy [A. Y., M. N., K. I.], Kurume University, 830-0011 Fukuoka, Japan
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Eligibility Criteria and Clinical Protocol.
Twelve patients with advanced colorectal cancer (all adenocarcinomas: inoperable stages IIIa, IIIb, and IV and relapse cases) received the SART3 vaccination, and their characteristics are shown in Table 1
. All patients, except a patient who did not receive any chemotherapy, had failed to respond to previous fluorouracil-based chemotherapy treatments. The sites of tumors were the ascending colon (patients 008 and 012 in Table 1
), sigmoid colon (patient 001), and rectum (the other 9 patients). All patients were confirmed to be HLA-A24+ both by a conventional serological method and by staining of PBMCs with the anti-A24 mAb, as reported previously (5
, 6)
. No patient had received any treatments, steroids, or any other immunosuppressive drugs for 4 weeks prior to the study. For the skin test, 10 µg of SART3109–118 and 10 µg of SART3315–323 were independently injected intradermally with a tuberculin syringe with a 26-gauge needle. Immediate- and delayed-type hypersensitivity reactions were determined at 20 min and 24 h after the skin test, respectively. If immediate-type hypersensitivity was negative, the peptide was injected at the following dose escalation schedule: group 1 patients (n = 4) received 0.3 mg of each of the two peptides; group 2 patients (n = 5) received 1 mg of each of the two peptides; and group 3 patients (n = 3) received 3 mg of each of the two peptides. For groups 1 and 2, 1.5 ml of the peptide solution at 1 mg/ml was mixed with an equal volume of the IFA (Montanide ISA-51; Seppic, Paris, France) and emulsified in 5-ml sterilized-glass syringes; 0.6 ml and 2 ml were injected into the s.c. tissue of the anterior thigh of patients in groups 1 and 2, respectively. For group 3, 2 ml of the peptide solution at 2 mg/ml were mixed with an equal volume of IFA and emulsified in the 5-ml glass syringes, and 3 ml were injected into the s.c. tissue. It was intended that all patients would receive at least three vaccinations at 2-week intervals; vaccinations after the first three continued based primarily on patient requests, on clinical status evaluated by attending physicians, and on the results from immunological analyses. To study the immune responses, 30 ml of peripheral blood were withdrawn prior to the first vaccination and 7 days after every third vaccination, and PBMCs were isolated and cryopreserved at -198°C before use. This protocol was approved by the Kurume University Review Board and the Independent Ethical Committee (Protocol No. 9904). Before entry into this trial, all patients gave informed consent and received a document of the protocol design.
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Detection of Serum IgE and IgG Levels.
An ELISA was used to detect the serum IgE or IgG levels specific for the SART3-derived peptides (Fig. 1)
. The SART3 peptide-immobilized plate (20 µg/well) was blocked with Block Ace (Yukijirushi, Tokyo, Japan), washed with 0.05% Tween 20-PBS (PBST), and 100 µl/well of serum or plasma samples diluted with 0.05% Tween 20-Block ace were added to the plate. After a 2-h incubation at 37°C, the plate was washed with PBST and further incubated for 2 h at 37°C with a 1:1000-diluted rabbit antihuman IgE (
-specific; DAKO, Glostrup, Denmark) or antihuman IgG (
-specific; DAKO). The plate was washed nine times, then 100 µl of 1:100-diluted goat antirabbit immunoglobulin-conjugated horseradish peroxidase-dextran polymer (EnVision; DAKO) were added to each well, and the plates were incubated at room temperature for 40 min. After washing, 100 µl/well of tetramethylbenzidine substrate solution (KPL, Guildford, United Kingdom) were added, and the reaction was stopped by an addition of 1 M phosphoric acid. To estimate peptide-specific IgE levels, the absorbance values of each sample were compared with those of serially diluted standard samples, and values were shown as absorbance. Peptide-specific IgG levels were similarly estimated.
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The same PBMCs at day 7 of in vitro culture were subjected to CTL precursor frequency analysis by methods described elsewhere (19)
. In brief, the PBMCs were plated at different numbers (1–400) of cells/well of a 96-well, U-bottomed microculture plate. These cells were cultured with the cloning medium (25% RPMI 1640, 55% AIM-V medium, 20% FCS, 100 units/ml interleukin 2, 10 µg/ml PHA, and 0.1 mM MEM nonessential amino acid solution) in the presence of irradiated HLA-A24+ but allogenic PBMCs of 3 healthy donors as feeder cells, and in the absence of any peptides. Cells from each well were tested between days 13 and 20 for IFN- production in response to the target cells in duplicate assays. For the detection of tumor-reactive CTL precursors, wells were considered positive under the following conditions: (a) if both of the wells contained effector cells producing much higher levels (>50 pg/ml) of IFN- in response to the HLA-A24+ SW620 tumor cells than levels shown in response to the HLA-A24- Colo201 tumor cells and levels shown in culture without tumor cells; and (b) if the mean of IFN- values in response to the SW620 tumor cells were significantly higher (P < 0.05 by a two-tailed Student’s t test) than that in response to the Colo201 tumor cells and that in culture without tumor cells. For the detection of peptide-reactive CTL precursors, wells were considered positive under the following conditions: (a) if both wells contained effector cells producing much higher levels (>50 pg/ml) of IFN- in response to the CIR-A2402 cells pulsed with one of the two or three peptides (SART3109–118 and SART3315–323 and, in certain cases, Lck488–49) than levels shown in response to those pulsed with any of the other two peptides or in levels shown in those pulsed with an HIV peptide as a negative control; and (b) if the mean of IFN- values in response to the CIR-A2402 cells pulsed with one of the three peptides were significant (P < 0.05) in comparison with those in response to the other two peptides or an HIV peptide.
Details of the evaluation of results of CTL precursor frequency analyses are as follows. For example, the postvaccination PBMCs (after the third vaccination) of patient 006 were tested for their ability to produce IFN- by recognition of tumor cells. Representative results of positive well 49 and negative well 88 are shown in Fig. 2
(left column), and the overall results from a total of 1344 wells (96 wells/plate x seven different numbers of cells/well x 2 = 1344 wells) were provided for statistical analysis and the evaluation of positive wells/plate. The positive wells of the postvaccination PBMCs (after the third vaccination) of patient 011 at 80, 40, 20, 10, 5, 2.5, and 1.25 cells/well of the plate were 24, 5, 3, 0, 0, 0, and 0, respectively, whereas there were no positive wells in the prevaccination PBMCs. These scores are plotted for the CTL precursor frequency analysis (Fig. 3A
, bottom line and left side column), and the CTL precursors were calculated as <1/5237 and 1/217 for the pre- and postvaccination PBMCs (the limit of sensitivity, 1/5237), respectively, by the method of Taswell (21)
. The example of peptide-specific CTL precursor frequency analyses is also shown in the right column of Fig. 2
, in which the postvaccination PBMCs (after the third vaccination) of patient 006 were tested for their ability to produce IFN- after the third vaccination, and wells 5 and 74 were evaluated as positive for SART3109–118 and SART3315–323 peptide-specific CTL precursors, respectively. Frequencies of CTL precursors are shown in Fig. 3, B and C
. For example, the postvaccination PBMCs (after the third vaccination) of patient 013 had 21, 7, 6, 4, 1, and 0 positive wells containing CTL precursors reactive to the SART3315–323 peptide in the plates containing 200, 100, 50, 25, 12.5, and 6.25 cells/well, respectively, whereas the prevaccination PBMCs had 0, 0, 14, 2, 0, and 0 in these plates, respectively. These scores were plotted for the CTL precursor frequency analysis (Fig. 3C
, bottom line and right side column), and the CTL precursors reactive to the SART3315–323 peptide were calculated as undetectable (<1/12,407) and 1/631 for the pre- and postvaccination PBMCs, respectively.
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in response to appropriate target cells using many samples. In brief, pre- and postvaccination PBMCs were incubated with 10 µM of a peptide in 200 µl of culture medium (the complete medium) containing different numbers of effector cells (100,000, 50,000, 25,000, 12,500, and 6,250) per well of a 96-well, U-bottomed microculture plate in a triplicate assay. Half of the medium was removed and replaced with new a medium containing a corresponding peptide (20 µM); this procedure was performed every 3 days for up 12 days. Twenty-four h after the final stimulation, these effector cells were tested for their ability to produce IFN- by recognition of SW620 or Colo201 tumor cells or to produce IFN- in the absence of tumor cells as a negative control by ELISA. The same effector cells were also tested for their ability to produce IFN- in response to C1R-A2402 cells pulsed with a corresponding peptide or those pulsed with an irrelevant HIV peptide, or in response to C1R-A2402 cells alone as a negative control. |
RESULTS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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; patients 001, 002, and 005); subsequently, only the SART3109–118 peptide at 0.3 mg/injection was used for vaccination of these patients, and the remaining patient (patient 004) was vaccinated with the two peptides. Immediate-type hypersensitivity was not observed in the remaining 8 patients; subsequently, both peptides were used for vaccination. The numbers of injections varied among patients from 2 to 24; these numbers were primarily dependent on the requests of the patients, on clinical status as evaluated by the attending physicians, and on cellular immune responses after vaccination. Delayed-type hypersensitivity was not observed in any patient, either pre- or postvaccination. All 12 patients were evaluated for all common toxicities using the Japan Clinical Oncology Group criteria (22)
; the overall toxicities are shown in Table 1
. The SART3 peptide vaccine was generally well tolerated, although six patients had grade 1 local reactions at the injection sites. No medication was necessary for these local immune reactions, and no other adverse events were observed in this clinical trial.
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. Low levels of anti-SART3109–118 and anti-SART3315–323 IgG were detectable in prevaccination serum from only 1 patient (patient 011), and these levels were not largely different in postvaccination sera (after the third vaccination). High levels of anti-SART3109–118 IgG became detectable in the postvaccination sera of the remaining patient (patient 006) after the 11th and 13th vaccinations with the two peptides (Fig. 1)
. Anti-peptide IgE was not detectable in either pre- or postvaccination sera from 7 of 12 patients. Low levels of anti-SART3109–118 and anti-SART3315–323 IgE were detectable in the prevaccination serum of 1 patient (patient 009). Low levels of anti-SART3109–118 and anti-SART3315–323 IgE became detectable in only the postvaccination sera of 4 patients (patients 001, 002, 006, and 008) and 2 patients (patients 001 and 008), respectively.
Cellular Immune Responses.
The frequencies of CTL precursors reactive to HLA-A24+ SW620 tumor cells in all 11 patients are shown in Fig. 3A
. A significant augmentation in the postvaccination PBMCs was observed in 7 (patients 002, 007, and 009–013) of 11 patients, whereas the inverse was seen in 2 patients (patients 001 and 005). There were no detectable levels of the frequencies either in the pre- or postvaccination PBMCs of the remaining two patients (patients 006 and 008). A summary is given in Table 3
. The augmentation in the postvaccination PBMCs was observed in 1 of 3, 3 of 5, and 3 of 3 patients who received 0.3, 1, and 3 mg/injection of SART3 peptides, respectively. Frequencies of CTL precursors reactive to the SART3109–118 and SART3315–323 peptides are shown in Fig. 3, B and C
, respectively, and a summary is given in Table 3
. A significant augmentation of the SART3109–118-specific CTL precursors in the postvaccination PBMCs (after the third vaccination) was observed in 5 (patients 001, 006, 007, 011, and 012) of 10 patients tested, whereas the augmentation of the SART3315–323-specific CTL precursors in the postvaccination PBMCs was observed in 3 (patients 006, 010, and 013) of 10 patients tested. There were no detectable levels of the frequencies in either the prevaccination PBMCs or the postvaccination PBMCs (after the third vaccination) of 2 patients (008 and 009). CTL precursors reactive to the Lck488–497 peptide, taken as a negative control, were undetectable in either the pre- or postvaccination PBMCs from the majority of the patients tested (Table 3)
. Collectively, an augmentation of CTL precursors to at least one of the two SART3 peptides in the postvaccination PBMCs was observed in 1 of 2, 3 of 5, and 3 of 3 patients who received 0.3, 1, and 3 mg/injection of SART3 peptides, respectively.
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. HLA-A24-restricted and tumor-specific CTL activity was observed in both pre- and postvaccination PBMCs of 2 patients (patients 001 and 002), but these levels of cytotoxicity were not significantly different. No cytotoxicity was observed in either pre- or postvaccination PBMCs of 1 patient (patient 005), and low levels of HLA-nonrestricted cytotoxicity were observed in both pre- and postvaccination PBMCs of two patients (patients 007 and 008). Significant levels of HLA-A24-restricted and tumor-specific CTL activity were observed in the postvaccination PBMCs of 6 patients (patients 006 and 009–013) who received either 1 mg (patients 006, 009, and 010; 3 of 5 cases) or 3 mg (patients 011–013; 3 of 3 cases) of the two peptides, whereas their prevaccination PBMCs showed either HLA-nonrestricted cytotoxicity in 4 patients (patients 009, 010, 012, and 013), very low levels of HLA-A24-restricted and tumor-specific CTL activity in 1 patient (patient 006), and no cytotoxicity in the remaining patient (patient 011). The specificity of the CTL activity was confirmed with the two patients (patients 006 and 011). These effector cells from the postvaccination PBMCs showed significant levels of cytotoxicity to HLA-A24+ KE4 esophageal tumor cells but failed to lyse HLA-A24-QG56 lung tumor cells. Furthermore, these cytotoxicities were abrogated by anti-CD8 and anti-HLA-class I mAbs but not by anti-CD4 and anti-HLA class II mAbs (data not shown).
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production. In patient 001, >6 vaccinations with SART3109–118 peptide at 0.3 mg/injection induced significant levels of IFN- production in the PBMCs in response to HLA-A24+ tumor cells, and 18 such vaccinations induced significant levels of IFN- production in response to the SART3 peptide. In patient 006, vaccination of the two peptides at 1 mg/injection induced significant levels of IFN- production in the PBMCs in response to HLA-A24+ tumor cells after >9 vaccinations and in response to the corresponding peptides after 11 vaccinations. Prevaccination PBMCs from the remaining patient (patient 002; dose, 0.3 mg of SART3109–118) showed significant levels of IFN- production in response to HLA-A24+ tumor cells at concentrations of >25,000 cells (Fig. 4)
. These levels decreased in the PBMCs at 6 and 9 vaccinations and conversely increased in further vaccinations (i.e., 12 vaccinations). Vaccination of patient 002 with SART3109–118 after >6 vaccinations induced significant levels of IFN- production in response to the corresponding peptide.
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. SART3 vaccinations were continued thereafter, primarily dependent on patient requests at 2–4-week intervals, with or without the combination of the fluorouracil-based chemotherapy treatments, when the patient showed PD by treatment with the peptide vaccine alone. The median frequency of vaccinations in these 11 patients was 8 times (range, 3–24 times), and the median vaccination period was 5 months (range, 1–14 months). The overall observation time varied from 3 months (patient 005) to 20 months (patient 001), with a median time of 5 months. Five patients died of colorectal cancer; the other six patients were still alive at the time of this report (Table 1)
. Seven patients (patients 002, 006, 008–011, and 013) underwent the fluorouracil-based chemotherapy treatments again, and one patient (patient 010) had chemoradiotherapy after PD was observed during this vaccination period. Two patients (patients 001 and 002) were vaccinated with the other peptides. The other three patients (patients 005, 007, and 012) received the best supportive care available. Under these circumstances, 10 patients had PD and 1 patient (patient 006) had stable disease, based on the evaluation at the median time point of observation (5 months), and the median time to progression was 12 weeks. The clinical course of patient 006, who had been evaluated as having stable disease for 9 months, is shown in Fig. 5
. The patient was vaccinated with the SART3 peptides alone for the first six vaccinations, then received both the SART3 peptides (from the 7th to 17th vaccinations) and chemotherapy (oral administration of 450 mg/day of UFT-E (Taiho Pharmaceutical Co., Tokyo, Japan) and 40 mg/day of leucovorin, Takeda Chemical Industry, Osaka, Japan), and then received chemotherapy alone (hepatic arterial infusion of 2250 mg of 5-fluorouracil for 7 days and oral administration of 40 mg/day of leucovorin). Duration of stable disease continued for 9 months, after which time a discovery of regrowth of metastatic tumors in the liver was made. A tentative decrease of serum CEA levels was observed during the 9th to 15th vaccinations, and the perpendicular diameter of the indicator tumor lesion (metastatic liver tumor) was also decreased from 12.5 cm (after the third vaccination) to 10 cm (after the 12th vaccination). It is noteworthy that the kinetics of cellular immune responses inversely correlated with that of the serum CEA levels (Fig. 5)
; i.e., these cellular responses that were undetectable in either the pre- or postvaccination PBMCs from the first to sixth vaccinations became detectable from the 11th to 15th vaccinations and then gradually diminished thereafter. Decreases in CEA also corresponded in time with the initiation of chemotherapy. The CEA levels increased at approximately the 6th vaccination, decreased for up to the 15th vaccination, and then increased rapidly.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Kinetic studies indicated that the increased cellular immune responses to tumor cells required at least six vaccination times in two patients whose prevaccination PBMCs had no such activity. The studies also indicated that the pre-existing ability to produce IFN- of the remaining patient (002) decreased from the 6th to the 9th vaccination, followed by an increase in the 12th vaccination. The increase in cellular immune responses to the vaccinated peptides also required at least 9 vaccinations in all 3 cases tested. These results suggest that the priming of these peptides under the protocols used required approximately 6–9 vaccinations, although the increased cellular immune responses in PBMCs after the third vaccination was detectable by means of a highly sensitive monitoring assay such as CTL precursor frequency analysis and by the 51Cr release assay using effector cells cultured for a long time (28–30 days) in vitro. Preventative vaccine protocol to pathogenic microbes genetically consists of three steps: priming, boosting, and challenging (23)
. It usually takes 2–3 months for priming, which is consistent with the present results of SART3 vaccinations for cancer patients. In contrast to preventative vaccination, however, the main goal of the peptide-based specific immunotherapy of cancer is treatment, i.e., developing a therapeutic vaccine protocol for obtaining tumor regression. Increased cellular immune responses have been obtained in the majority of cancer patients vaccinated with the peptides, but clinical responses rarely have been obtained in melanoma patients of previous studies (7, 8, 9, 10, 11)
and in this present study of colorectal cancer patients. One explanation for the failure to obtain clinical responses would be the time lag for priming, given that the expected survival of most advanced cancer patients under these regimens is 6–9 months. Therefore, developing a new protocol for obtaining tumor regression in these cancer patients is necessary. One protocol might be a prevaccination measurement of peptide-specific CTL precursors in the circulation of cancer patients, followed by administration of a CTL precursor-oriented peptide vaccine. Another regimen would involve a vaccine combined with chemotherapy (24)
. Indeed, 1 patient (patient 006) in this study showed a clinical response by only the combined immunochemotherapy; either the preceding fluorouracil-based chemotherapy alone or the peptide vaccine alone failed to obtain tumor regression.
Immediate-type hypersensitivity to the SART3315–325 peptide, but not to SART3109–118, was observed in 3 of 12 patients in skin tests prior to the first vaccination, although significant levels of anti-SART3315–325 IgE were undetectable in the prevaccination sera of these patients. The IgE-type antipeptide antibodies became detectable in the postvaccination sera of a few patients, although neither immediate- nor delayed-type hypersensitivity was observed in these patients. Therefore, there was no obvious correlation between the skin reaction and serum levels of the IgE antibody. It was not surprising to observe that these SART3 peptides failed to elicit delayed-type hypersensitivity in any patients tested, because similar results were reported in the other clinical studies (7, 8, 9, 10, 11) . We observed recently that the repeated vaccination of 3 mg/injection of SART3315–325 induced delayed-type hypersensitivity in a few patients (data not shown). Further studies are needed to clarify the mechanisms involved in the SART3315–325-induced skin reactions.
This study investigated the safety of the SART3 vaccine and its ability to induce cellular and humoral immune responses in HLA-A24+ advanced colorectal cancer patients. An important clinical end point of clinical study will be determining the correlation between immune response and the overall survival rate to clarify whether augmented peptide-induced immunity can provide a clinical benefit, based on appropriate clinical trials.
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FOOTNOTES |
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1 Supported in part by Grants-in-Aid from the Ministry of Education, Science, Sport, Culture and Technology and Grant H10-genome-003 from the Ministry of Health and Welfare, Japan. 
2 These authors contributed equally to this work.
3 To whom requests for reprints should be addressed, at Department of Immunology, Kurume University School of Medicine, 67 Asahi Machi, Kurume 830-0011, Japan. Phone: 81-942-31-7551; Fax: 81-942-31-7699; E-mail: kyogo{at}med.kurume-u.ac.jp
4 The abbreviations used are: PBMC, peripheral blood mononuclear cell; IFA, incomplete Freund’s adjuvant; mAb, monoclonal antibody; CEA, carcinoembryonic antigen; PHA, phytohemagglutinin; CT, computed tomography; PD, progressive disease.
5 Hida, N., Maeda, Y., Katagiri, K., Takasu, H., Harada, M., and Itoh, K. A simple culture protocol to detect peptide-specific cytotoxic T lymphocyte precursors in the circulation. Under submission for publication.
Received 6/19/01; revised 8/27/01; accepted 8/28/01.
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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) and PBMCs taken after the third vaccination of 11 patients with the SART3 peptides were subjected to CTL precursor frequency analyses for HLA-A24+ tumor cells (A), SART3109–118 (B), and SART3315–323 peptide (C). The limit of sensitivity depends on the largest number of input cells/well as follows: 1/26,063, 1/12,407, and 1/5,237, if the largest numbers of cells/well are 400, 200, and 80, respectively.
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