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Clinical and Immune Responses in Advanced Melanoma Patients Immunized With an Anti-Idiotype Antibody Mimicking Disialoganglioside GD2

From the Division of Hematology/Oncology, Department of Internal Medicine, The Barrett Cancer Center for Prevention, Treatment and Research, University of Cincinnati College of Medicine and Oncology-Hematology Care, Inc, Cincinnati, OH; Mount Sinai Cancer Center, Miami, FL; Division of Hematology/Oncology, Department of Internal Medicine, and Lucille Parker Markey Cancer Center, University of Kentucky Medical Center, Lexington, KY; Division of Hematology/Oncology, Department of Internal Medicine, University of Arkansas School of Medicine, Little Rock, AK; Titan Pharmaceuticals, Inc, South San Francisco, CA; Aquila Biopharmaceuticals, Inc, Framingham, MA; and The Scripps Research Institute, La Jolla, CA.

Address reprint requests to Kenneth A. Foon, MD, Barrett Cancer Center, 234 Goodman St, ML 0502, Suite 1091, Cincinnati, OH 45219-2316; email kenneth.foon{at}uc.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To determine immune responses and toxicity to the anti-idiotype vaccine, as well as clinical responses and survival, we initiated a clinical trial for patients with advanced melanoma treated with an anti-idiotype antibody (TriGem) that mimics the disialoganglioside GD2.

PATIENTS AND METHODS: Forty-seven patients with advanced melanoma received either 1-, 2-, 4-, or 8-mg doses of TriGem (Titan Pharmaceuticals Inc, South San Francisco, CA) mixed with QS-21 adjuvant (Aquila Biopharmaceuticals, Inc, Worcester, MA) 100 µg subcutaneously weekly for 4 weeks and then monthly until disease progression. Median age was 57 years, there were 32 men and 15 women, 43% of patients had undergone prior therapy for metastatic disease, 55% had disease confined to soft tissue, and 45% had visceral metastasis.

RESULTS: Hyperimmune sera from 40 of 47 patients showed an anti–anti-idiotype (Ab3) response. Patient Ab3 was truly Ab1' because it specifically bound purified disialoganglioside GD2. The isotypic specificity of the Ab3 antibody consisted of predominantly immunoglobulin (Ig)G, and all IgG subclasses were represented. One patient had a complete response that persisted at 24 months, and 12 patients were stable from 14+ to 37+ months (median, 18+ months). Disease progression occurred in 32 patients on study from 1 to 17 months (median, 5.5 months), and 21 have died at 1 to 16 months (median, 6 months). The Kaplan-Meier–derived overall median survival has not been reached. Median survival has not been reached for the 26 patients with soft tissue disease only and was 13 months for 21 patients with visceral metastasis. Toxicity consisted of local reaction at the site of injection and mild fever and chills.

CONCLUSION: TriGem has minimal toxicity and generates robust and specific IgG immune responses against GD2. Objective responses were minimal, but there may be a favorable impact on disease progression and survival that will require prospective randomized trials.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
GANGLIOSIDES ARE sialic acid–containing glycosphingolipids that have increased surface membrane expression on malignant melanoma. There have been a number of immunotherapy studies targeted to gangliosides.^1-3 One limitation of vaccination with gangliosides has been the requirement to covalently link the ganglioside to keyhole limpet hemocyanin mixed with a potent adjuvant to produce more potent immunoglobulin (Ig)M and IgG responses.^3-5 Another limitation of gangliosides is their expensive and difficult purification process. An alternate approach to the natural ganglioside is the generation of anti-idiotype antibodies that mimic the ganglioside. The idiotype network hypothesis of Lindenmann⁶ and Jerne⁷ offers an elegant approach to transforming epitope structures into idiotypic determinants expressed on the surface of antibodies. According to the network concept, immunization with a given tumor-associated antigen (TAA) will generate production of antibodies against this TAA that are termed Ab1. Ab1 are then used to generate a series of anti-idiotype antibodies against the Ab1, termed Ab2. Some of these Ab2 molecules can effectively mimic the three-dimensional structure of the TAA identified by the Ab1. These particular antibodies, called Ab2-beta (ß), fit into the paratopes of Ab1 and express the internal image of the TAA. The Ab2ß can induce specific immune responses similar to those induced by the original TAA and can therefore be used as surrogate TAAs. Immunization with Ab2 can lead to the generation of anti–anti-idiotypic antibodies (Ab3) that recognize the corresponding original TAA identified by the Ab1. Because of this Ab1-like reactivity, the Ab3 is also called Ab1' to indicate that it might differ in its other idiotopes from Ab1. One such anti-idiotype antibody, BEC-2, which mimics disialoganglioside GD3, is currently being investigated in clinical trials.^8,9 We have been interested in the anti-idiotype approach to a number of antigens^10-14 and have generated an anti-idiotype antibody, designated TriGem, that mimics disialoganglioside GD2,^15,16 which, similar to GM2, is highly expressed on melanoma and other neuroectodermal tumors with only minimal expression on normal tissues. We previously reported on the first 12 patients in this trial¹⁷ and now report the final results of 47 patients with advanced melanoma vaccinated with TriGem mixed with the QS-21 adjuvant.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients and Treatment Schedule
All 47 patients had American Joint Committee on Cancer stage IV melanoma with measurable metastatic disease (Table 1). Twenty patients had prior radiation therapy, chemotherapy, and/or biotherapy for metastatic disease. Patient requirements included a life expectancy of 5 months, discontinuation of all prior therapy for at least 4 weeks, hemoglobin concentration more than 10.5 g/dL, renal and liver function less than 1.5 times upper limits of normal, and no concurrent corticosteroid drug administration. All patients were treated subcutaneously with either 1, 2, 4, or 8 mg of TriGem mixed with 100 µg of QS-21 (Aquila Biopharmaceuticals, Inc, Framingham, MA). Patients treated with 8 mg were given two separate injections at each vaccination because of the larger volume. The vaccine was injected subcutaneously every other week for four injections followed by monthly injections. Patients were evaluated for disease progression at the end of the fourth injection and every 3 months thereafter. Vaccination was discontinued at the time of disease progression, and patients were removed from the study. All patients signed informed consent forms approved by the respective institutional review boards.

Generation of Anti-Idiotype Antibody for the Clinical Trial
The murine monoclonal IgG2a anti-ganglioside GD2 antibody 14.G2a (Ab1) was used to immunize syngeneic BALB/c mice.¹⁸ Hybridoma fusion, cloning, and selection of the monoclonal anti-idiotype TriGem (Ab2) as well as production of ascites in bulk quantities in mice were performed as previously described.^11-13 TriGem was purified from ascites by affinity chromatography on a protein A-CL Sepharose (Pharmacia, Uppsala, Sweden) 4B column followed by diethylaminoethyl ion-exchange chromatography. The purity of the isolated Ig (> 99%) was determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis, high-pressure liquid chromatography, and isoelectric focusing.

Adjuvant
QS-21 is a saponin extract from the bark of the South American soap bark tree Quillaja saponaria monila and represents an adjuvant approved by the United States Food and Drug Administration for use in humans in experimental vaccine therapy.

Assay for Humoral Immunity
Sera from immunized patients were tested for the presence of anti–anti-idiotypic antibodies. Sera were preincubated with normal mouse Ig to block human antibodies against isotypic and allotypic determinants and then checked for the presence of anti–anti-idiotype antibodies (Ab3) by reaction with the immunizing anti-idiotype (TriGem) coated onto microtiter plates. Unrelated Ab2 served as control. After washing, the antigen–antibody reaction was tagged using an iodine-125–labeled anti-idiotype reagent in a homogeneous sandwich radioimmunoassay. Pretreatment sera were also used as controls in these assays.

Inhibition of Ab2 Binding to Ab1
Preimmune and hyperimmune patients’ sera samples were treated with normal mouse Ig to remove anti-isotypic and anti-allotypic reactivities. Serial dilutions of sera were then tested for inhibition in the Ab1–Ab2 binding assay. All assays were performed in triplicate. For direct binding inhibition between Ab1 and Ab2, purified Ab1 14.G2a was used to coat the plates (500 ng/well), and the binding of radiolabeled TriGem (Ab2) to Ab1 was tested for inhibition in the presence of hyperimmune Ab3 sera from other patients. Results from this assay indicated whether the Ab3 in patients’ sera shared idiotopes with 14.G2a (Ab1). In addition, this inhibition assay demonstrated whether the Ab3 was a true anti–anti-idiotype.

Immune Flow Cytometric Analysis With Ab1 and Patient’s Ab3 Serum
GD2-positive M21/P6 human melanoma cells and GD2-negative LS174T human colon cancer cells (5 x 10⁵ per tube) were reacted with Ab1 (14.G2a) or patients’ Ab3 sera (1/10 dilution) at 4°C for 2 hours. After washing, the cells were incubated with either goat antimouse or goat antihuman IgG/fluorescein isothiocyanate–labeled antibody (BioSource, Camarillo, CA) for 30 minutes at 4°C. The cells were washed with cold phosphate-buffered saline (PBS), fixed in 3% paraformaldehyde, and analyzed by flow cytometry (FACStar; Becton Dickinson, San Jose, CA).

Purification of Anti–Anti-Idiotypic Antibodies (Ab3) From Hyperimmunized Patients’ Sera
Ab3 was purified from the sera of immunized patients by an immunoadsorbent column consisting of immunizing anti-idiotypic Ig (TriGem) coupled to Sepharose 4B. Protein bound to this column was eluted with glycine-HCl, pH 2.7, neutralized to pH 7.0 with 3 mol/L Tris and dialyzed against PBS. This material was then passed over a mouse Ig immunoadsorbent column of Sepharose 4B to remove anti-isotypic and antiallotypic reactivities. Antibody that passed through this column was concentrated and used as purified Ab3.

Determination of Ig Isotypes and Subclasses
Microtiter plates were coated with 50 µL of purified GD2 (2 µg/mL) per well and treated with 1 µg of purified Ab3 from each patient. The reaction was developed by enzyme-linked immunosorbent assay using anti-isotype–specific reagents. Numbers represent the mean optical density of 450 nm of triplicate wells.

GD2-Binding Inhibition Assay
Purified GD2 antigen (500 ng/well) was coated onto a 96-well plate. After blocking with 1% bovine serum albumin in PBS, different dilutions of purified Ab3 or Ab1 along with radiolabeled 14.G2a antibody (~90,000 cpm) were added to the plates, and the mixtures were incubated 4 hours at room temperature. After washing, bound radioactivity was measured.

Binding of Ab3 to Purified GD2 and GD3
Anti-GD2 reactivity was determined in the purified Ab3 with GD2 and GD3 that were each adsorbed onto 96-well microtiter plates (250 ng/well). After blocking with 1% bovine serum albumin in PBS, test samples and Ab1 were added to plates at different dilutions and incubated for 4 hours at room temperature with shaking. After washing, the bound antibodies were detected, with alkaline phosphatase–conjugated goat antihuman IgG and goat antimouse IgG serving as second antibodies. The isotype of the antibodies was determined with anti-isotype–specific reagents (Southern Biotech, Birmingham, AL) such as goat antihuman IgG (-chain specific) and goat antihuman IgM (-chain specific).

	RESULTS

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Clinical Results
Forty-seven patients were entered onto the trial. There were 32 men and 15 women; 26 patients had disease confined to soft tissue and 21 had visceral metastasis. Six of these patients had visceral disease confined to the lungs. Among the 47, there were 20 who had received prior treatment with chemotherapy, hormone therapy, biologic therapy, or radiation therapy for metastatic disease. One patient with multiple sites of soft tissue metastases achieved a complete response after the ninth treatment with TriGem and remained in complete remission at 24 months, and 12 patients have continued on trial with stable disease from 14+ to 37+ months (median, 18+ months). Among the patients who continue with stable disease, seven have soft tissue disease only, one has disease localized to the sinus cavity, and four have multiple visceral metastasis, including bone, brain, lung, and gastrointestinal tract. Thirty-two patients have experienced disease progression on study from 1 to 17 months (median, 5.5 months), and 21 have died on study from 1 to 16 months (median, 6 months). The Kaplan-Meier–derived overall median survival for all 47 patients was not reached but is at least 16 months (Fig 1). For 26 patients with soft tissue metastasis, the median survival was not reached (Fig 2, upper curve). For 21 patients with visceral metastasis, the median survival duration was 13 months (Fig 2, lower curve).

View larger version (12K): [in this window] [in a new window]   Fig 1. Kaplan-Meier overall survival curve for all 47 patients entered onto the trial. Median survival duration was not reached but is at least 16 months. Dotted line shows 95% confidence intervals.

View larger version (11K): [in this window] [in a new window]   Fig 2. Kaplan-Meier median survival curves for patients with soft tissue metastasis (upper curve; median survival duration not reached) and visceral metastasis (lower curve; median survival duration, 13 months).

Humoral Immune Responses
Patients were treated with either 1-, 2-, 4-, or 8-mg doses of TriGem mixed with 100 µg of QS-21 adjuvant. There was no demonstrable qualitative or quantitative difference in responses at any of these doses (Fig 3). Hyperimmune sera from 40 of 47 patients demonstrated an anti–anti-idiotypic Ab3 response as indicated by the ability of patients’ immune sera to inhibit Ab2 binding to Ab1 or Ab1 binding to GD2. In Fig 4, 12 patients with stable disease plus an additional five who experienced disease progression after 8 months are compared with 27 patients who experienced disease progression before 8 months. Sera from all but 2 of the patients with stable disease demonstrated inhibition of Ab2 binding to Ab1 at a dilution of 1/5,200 or greater. Representative data of inhibition of Ab1 binding to GD2 are shown in Fig 5. Representative data from one patient showing binding to the GD2-positive human melanoma cell line M21/P6 by immune flow cytometry is shown in Fig 6. Sera from 10 patients in the stable-disease group and 10 in the disease-progression group were purified on two columns (see Materials and Methods), and the Ab3 concentration ranged from 34 to 240 µg/mL with no apparent difference between clinically stable patients and those who experienced disease progression (Table 2). Purified Ab3 sera were tested against GD2 and GD3 and reacted specifically with GD2 but not with control GD3 (Fig 7). No major differences were found between patients with stable disease and those whose disease progressed. The predominant Ig was IgG. The only difference between patients with stable disease and those whose disease progressed was a higher concentration of IgM in five of the patients whose disease progressed (Table 3). There did not appear to be any unusual features characteristic of these five patients; three were treated at the 1-mg dose, one at the 2-mg dose, and one at the 8-mg dose. IgG subclasses were shown to be predominately IgG1 and IgG4, with lesser quantities of IgG2 and IgG3 (Table 4) and no differences between patients with stable disease and those whose disease progressed.

View larger version (21K): [in this window] [in a new window]   Fig 3. Inhibition of Ab1 binding to Ab2 by patients’ immune sera at four different doses of TriGem. Purified TriGem was used to coat the plate, and binding of radiolabeled Ab1 to TriGem was tested for inhibition in the presence of patients’ immune sera (1/10 dilution). Data from seven representative patients in each dose group are presented.

View larger version (42K): [in this window] [in a new window]   Fig 4. Inhibition of Ab2 binding of Ab1 by patients’ immune sera. Purified Ab1 was used to coat the plate, and binding of radiolabeled Ab2 to Ab1 was tested for inhibition in the presence of patients’ immune sera (1/10 dilution). Data are presented for patients no. 1 to 10 and A to G, who had clinically stable disease (A), and patients no. 11 to 38, who experienced disease progression on study (B).

View larger version (18K): [in this window] [in a new window]   Fig 5. Inhibition of Ab1 binding to ganglioside GD2 by patients’ immune sera. GD2 was used to coat the plate, and binding of radiolabeled Ab1 to GD2 was tested for inhibition in the presence of patients’ hyperimmune sera (1/10 dilution). Data from 12 representative patients are presented.

View larger version (18K): [in this window] [in a new window]   Fig 6. Immune flow cytometry of GD2-positive human melanoma M21/P6 cells with patients serum. (A) GD2-positive M21/P6 cells were reacted with preimmune and immune patients’ sera at 1/10 dilution. (B) GD2-negative LS174-T cells were reacted with the same preimmune and immune sera. (C) M21/P6 cells were reacted with PBS control and Ab1 14.G2a. Representative data from one patient are presented.

View larger version (20K): [in this window] [in a new window]   Fig 7. Binding of patients’ purified Ab3 to ganglioside GD2 and GD3. Anti-GD2 and anti-GD3 antibody reactivity was measured by enzyme-linked immunosorbent assay (see Patients and Methods). Columns represent mean optical density (OD) at 405 nm. Purified Ab3 was added per well, and OD was taken 1 hour after the substrate addition. (A) Patients with stable disease; (B) patients with progressive disease.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

In previous studies that used infusional therapy of murine or humanized antibodies that bind to the disialoganglioside GD2, severe gastrointestinal toxicity as well as extremity pain and neurologic toxicity was reported.^24,25 One explanation for gastrointestinal toxicity was the expression of the GD2 ganglioside on neural tissue. Fortunately, we did not observe gastrointestinal or neural toxicity in any patients treated on this trial. Patients were immunized monthly and continued to generate high-titer anti-disialoganglioside GD2 polyclonal antibody responses as long as they continued on study.

Twenty of the 47 patients entered onto the trial had received prior therapy with either chemotherapy drugs, biotherapy, hormonal therapy, or radiation therapy for metastatic disease. One patient achieved a complete response after the ninth injection of TriGem, and 12 patients remained stable on study from 14 to 37+ months (median, 18+ months). The complete responder had multiple soft tissue sites of metastases and has remained in complete remission for 24 months. The Kaplan-Meier–derived overall median survival duration for the 47 patients was not reached but is at least 16 months. This median survival duration is superior to those reported from other phase II trials in which the expected survival durations are typically in the range of 5 to 10 months. Combination therapies of interferon and interleukin-2 with or without cisplatin have reported survival durations in the range of 9 months.²⁶ Similarly, combination chemotherapy with dacarbazine and cisplatin with or without tamoxifen has demonstrated overall median survival durations in the range of 9 months.²⁷ In another trial, median survival duration was 16 months with cisplatin, dacarbazine, and tamoxifen, and survival duration was 11 months with the addition of interleukin-2 and interferon-.²⁸ In a meta-analysis of 631 patients with metastatic melanoma treated with various combinations of interleukin-2 and interferon- with or without cisplatin, or dacarbazine chemotherapy, overall median survival duration was 10.5 months with only a trend in survival advantage for biochemotherapy.²⁹ In another trial of 271 patients treated with dacarbazine and tamoxifen with or without interferon-, a 9-month median survival duration was reported.³⁰ Intensive biochemotherapy studies have reported 12-month median survival durations.^31,32 Median survival duration of our total patient population was superior to that reported in all of the aforementioned studies. However, we had a high percentage of patients (55%) with metastatic disease initially confined to soft tissue. Median survival duration of patients with soft tissue metastasis was not reached and was 13 months for patients with visceral metastasis. Six of the 21 patients with visceral metastasis had visceral disease in the lung only or lung and soft tissue. This may represent a more favorable subgroup. Although patients treated with combination chemotherapy or biochemotherapy have higher complete and partial clinical responses than that reported with TriGem, they also have major toxicity. The disialoganglioside GD2 is a molecule that may have a role in metastasis and tumor invasion.^33-35 Immunity against GD2 should theoretically slow the rate of tumor growth and metastasis. These mechanisms may have a role in disease stabilization and prolonged survival in this group of patients. However, the apparent prolonged survival in these 47 patients must be viewed with caution because further evaluation and prospectively randomized trials are critical to evaluate survival benefit. We are also planning to evaluate TriGem in combination with biochemotherapy.

	ACKNOWLEDGMENTS

 
Supported by grant no. R01CA-72018-02 from the National Institutes of Health, Bethesda, MD.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted March 31, 1999; accepted August 3, 1999.

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