Clinical Cancer Research CR Helping Patients Frontiers in Basic Cancer Research
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Krug, L. M.
Right arrow Articles by Livingston, P. O.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Krug, L. M.
Right arrow Articles by Livingston, P. O.
Clinical Cancer Research Vol. 10, 916-923, February 2004
© 2004 American Association for Cancer Research

Clinical Trials

Vaccination of Small Cell Lung Cancer Patients with Polysialic Acid or N-Propionylated Polysialic Acid Conjugated to Keyhole Limpet Hemocyanin

Lee M. Krug1, Govind Ragupathi2, Kenneth K. Ng1, Chandra Hood2, Harold J. Jennings3, Zhongwu Guo3, Mark G. Kris1, Vincent Miller1, Barbara Pizzo1, Leslie Tyson1, Valerie Baez1 and Philip O. Livingston2

1 Thoracic Oncology Service and 2 Laboratory of Tumor Vaccinology, Department of Medicine, Memorial Sloan-Kettering Cancer Center and Weill Medical College of Cornell University, New York, New York, and 3 Institute of Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: Long chain polysialic acid (polySA) is a side chain on embryonal neural cell adhesion molecules that, in the adult, is largely restricted to small cell lung cancer (SCLC). Long chains of polySA are also expressed on group B meningococcus. In this clinical trial, we aimed to elicit an immune response against polysialic acid to target clinically inapparent residual disease in patients with SCLC who had successfully completed initial therapy.

Experimental Design: Patients were vaccinated with either 30 µg unmodified polySA or N-propionylated-polySA (NP-polySA), conjugated to keyhole limpet hemocyanin (KLH) and mixed with 100 µg of immunological adjuvant QS-21 at weeks 1, 2, 3, 4, 8, and 16.

Results: Of the 5 evaluable patients vaccinated with unmodified polySA, only 1 mounted an IgM antibody response to polySA. On the other hand, all 6 of the patients vaccinated with NP-polySA produced IgM antibodies to NP-polySA and these cross-reacted with unmodified polySA in all but 1 case. IgG antibodies to NP-polySA were observed in 5 of the patients, but these did not cross-react with polySA. The presence of IgM antibodies reactive with SCLC cell lines was confirmed in this group by flow cytometry. Complement-dependent lysis of tumor cells could not be demonstrated. However, postimmunization sera induced significant bactericidal activity against group B meningococcus when combined with rabbit complement.

Conclusions: Vaccination with NP-polySA-KLH, but not polySA-KLH, resulted in a consistent high titer antibody response. We are now conducting a de-escalation dosing study with NP-polySA-KLH to better assess the immunogenicity, toxicities, and optimal dose of this vaccine. We plan to incorporate this vaccine as a component of a polyvalent vaccine with GM2, fucosylated GM1, and Globo H to target SCLC.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Polysialic acid (polySA) is a polymer of >20 negatively charged {alpha}2–8 linked sialic acid residues found primarily on the surface of Gram-negative bacteria (such as group B meningococcus). It is also a component of embryonic neural cell adhesion molecule in developing tissues of vertebrates and is present in certain malignancies of neural crest origin (1 , 2) . PolySA was initially identified in neural tissues where its roles in cell-cell interactions and cell migration were elucidated (3 , 4) . The large size and negative charge of this carbohydrate side chain physically inhibit the binding of neural cell adhesion molecule to the receptors of adjacent cells and thereby promote cell motility (1) . This action has particular importance in embryonic development when polySA levels vary corresponding with periods of neural development, or in adult brains in regions of neural plasticity (1 , 5) .

PolySA expression has been noted in malignancies of neuroectodermal origin, particularly small cell lung cancer (SCLC). Several investigators have found immunostaining for polySA in nearly every SCLC tumor tested (6, 7, 8) . In two of these reports, the level of polySA expression was greater in SCLC than in carcinoid tumors, generating the hypothesis that this moiety may contribute to the clinically aggressive nature of SCLC (6 , 7) . The propensity for early metastases may derive from the inhibitory effect of polySA on cell adhesion. Data from various animal tumor models support this idea. In a rat transplantable pituitary model, polySA-neural cell adhesion molecule expression correlated with tumor invasiveness, metastases, and growth rate (9) . In nude mice injected i.p. with human rhabdomyosarcoma TE671 cells, cleavage of polySA by endoneuraminidase-N delayed the formation of ascites and decreased the number of lung and liver metastases (10) .

Because polySA is not expressed in normal tissues (aside from limited amounts in the brain) but is abundant in SCLC, a strong rationale exists to develop antitumor therapies targeting polySA (8) . However, likely due to its presence in the embryo and to a limited extent in adult brain tissues, humans have immunological tolerance to polysialic acid. This may explain the lack of clearance of group B meningococcus and the subsequent development of meningitis in humans (11) .

In this trial, we used two approaches to induce an immune response after vaccination with polySA. Using methods validated in prior cancer vaccine trials, polySA was conjugated to keyhole limpet hemocyanin (KLH) and administered with an adjuvant, QS-21 (12, 13, 14, 15) . We also assessed the impact of chemical manipulation of polySA by N-propionylation, a technique shown to boost the IgG response to meningococcal group B polysaccharide in mice (16) . We enrolled patients with SCLC who had achieved complete or partial responses with initial therapy. This group of patients is at high risk of lethal recurrence from residual, subclinical, resistant disease. Potentially, the production of anti-polySA antibodies could facilitate eradication of residual disease after initial therapy.


   PATIENTS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Selection
We enrolled adults with SCLC, limited or extensive stage, who had completed their initial therapy with chemotherapy (and radiation if needed) at least 4, but not more than 12 weeks previously. Patients needed to have a Karnofsky performance status of >=70%. Required hematological and biochemical parameters included a total white blood count >=3.0 x 106 cells/µl, a total lymphocyte count >=0.5 x 106 cells/µl, aspartate aminotransferase level <=1.5 x upper limit of normal, serum bilirubin <=1.5 mg/dl, and serum alkaline phosphatase level <=1.5 x upper limit of normal. Patients with known immune deficiency or autoimmune disease, prior splenectomy or splenic radiation, or patients on oral corticosteroids were excluded. Pregnant or lactating women, patients with New York Heart Association class III or IV heart failure, or patients with another active malignancy in the last 5 years were also excluded. This protocol was reviewed by the Memorial Sloan-Kettering Institutional Review Board. Written informed consent was obtained.

Within 3 weeks of starting treatment, all of the patients underwent a history and physical examination including neurological examination, chest X-ray, complete blood count, biochemical profile, and amylase. A chest computed tomography scan was required after completion of initial therapy to document ongoing partial or complete response to initial therapy.

Vaccine Preparation
N-propionylated polysialic acid (NP-polySA) was synthesized by H. J. J., in the Institute for Biological Sciences, National Research Council of Canada. PolySA, KLH, and sodium cyanoborohydride were obtained from Sigma Chemical Co., (St. Louis, MO). PolySA was additionally purified over a size exclusion column to yield high molecular weight polySA of ~10,000 before coupling with KLH. Human SCLC lines H345 and H69 were purchased from American Type Culture Collection. Goat antihuman IgG and goat antihuman IgM conjugated with alkaline phosphatase were purchased from KPL (Gaithersburg, MD), goat antihuman IgM-FITC and goat antihuman IgM-FITC were obtained from Southern Biotechnology Associates Inc. (Birmingham, AL).

Propionylation of PolySA (Fig. 1)Citation .
For the preparation of propionylated polySA, polySA was first deacetylated by treatment with 2 M NaOH at 107°C for 6 h. It was then mixed with sodium bicarbonate solution and propionic anhydride, and incubated at room temperature for ~12 h, dialyzed, and lyophilized as described previously (16) . Replacement of CH3-CO-HN-acetyl groups with CH3-CH2-CO-NH-propionyl groups was confirmed by nuclear magnetic resonance (data not shown).



View larger version (21K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 1. Synthesis of N-propionylated polysialic acid-keyhole limpet hemocyanin (KLH) conjugate by reductive amination.

 
PolySA/NP-PolySA-KLH Conjugation (Fig. 1)Citation .
PolySA-KLH and NP-polySA-KLH conjugates were prepared as described by Jennings et al. (16) . The conjugation procedure cleaved the vicinyl hydroxyl group of the terminal sialic acid of the polySA by periodate. The periodate method involved reaction with metaperiodate of the vicinyl hydroxyl group in polySA resulting in formation of a dialdehyde at the end of each polySA chain. The dialdehyde was then made to react with the free NH2-terminal amino group and to {epsilon}-amino groups on lysine of KLH by reductive amination in the presence of sodium cyanoborohydride. The linkage was stabilized by treatment with sodium cyanoborohydride, and the conjugate was washed extensively with normal saline and an Amicon Centriprep 30 unit concentration. Protein and sialic content were determined. The ratio of polySA and NP-polySA molecules conjugated to each KLH molecule was 80:1 and 38:1, respectively.

Immunization
Patients were vaccinated with 30 µg of polySA or NP-polySA in the KLH conjugate plus 100 µg of immunological adjuvant QS-21 (17) at weeks 1, 2, 3, 4, 8, and 16. Serum samples for immunological studies were obtained at weeks 1, 2, 3, 4, 6, 8, 10, 16, and 18, and stored at -70°C until analysis.

Serological Assays
ELISA.
IgM and IgG antibody titers were measured by ELISA as described previously (18) . Ninety-six-well flat-bottomed plates (Nunc, Rochester, NY) were precoated with polySA-human serum albumin or NP-polySA-human serum albumin at 0.1 µg/well in carbonate buffer. Serially diluted sera in 1% human serum albumin were added along with sera from patients with known specific high-titer antibodies or no antibodies, which served as positive and negative controls, respectively. Goat antihuman IgM or IgG conjugated to alkaline phosphatase were used to complete the assay. Plates were read at 10–15 min for IgG and IgM on an ELISA plate reader (Bio-Rad model 550 Microplate Reader) at 405 nm. The titer was defined as the highest dilution yielding an absorbance of >=0.1.

Flow Cytometric Analysis
Fluorescent-activated cell-sorting was performed as described previously (19) to demonstrate antibody binding to the cell surface of the cell lines. The polySA-positive SCLC cell line H345 served as the target. The cells were incubated with 20 µl of 1:20 diluted sera for 30 min on ice. After washing, 20 µl of 1:25 goat antihuman IgM and IgG was added, mixed, and incubated for 30 min. After washing, the positive population and mean fluorescence intensity of the stained cells were analyzed by flow cytometry. (FACScan; Becton and Dickinson, San Jose, CA). Pre- and peak titer postimmunization sera were run together with the pretreatment percentage of positive cells set at ~10%.

Complement-Dependent Cytotoxicity
Complement-dependent cytotoxicity was assayed with sera at a dilution of 1:4, H345 cells and human complement by a chromium-release assay as described previously (19) . Cells incubated only with culture medium, complement, or presera alone served as negative controls and monoclonal antibody 5A5 as a positive control. Spontaneous release was calculated based on the chromium released by target cells incubated with complement alone. Maximum release was determined by incubating target cells with complement and 1% Triton X-100. Percentage f cytolysis was calculated according to the formula:

Bacteriocidal Assays
The determination of the bacteriocidal activity of serum samples against group B meningococcus has been described previously (20) .

Statistical Considerations
This was a pilot study with a primary end point of immune response. We planned to vaccinate 6 patients with the polySA -KLH vaccine and 6 with the NP-polySA -KLH vaccine. An immune response was defined as: (a) an antibody titer of >=1:80 by ELISA against polySA and a titer of 1:20 against tumor cells expressing polySA for patients with no detectable baseline titer; and (b) an antibody titer >=8-fold increase over baseline for patients with a detectable baseline titer. An immune response in >=5 patients suggests >50% immunogenicity and would warrant additional study (21) .


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Thirteen patients were enrolled. Their clinical characteristics are specified in Table 1Citation . Seven patients were enrolled in the unmodified polySA group because 1 patient received only one vaccination due to disease progression. One patient was removed from study after two vaccinations due to increased shortness of breath that was unlikely related to the treatment. Of the remaining 6 patients, 4 completed all 6 of the planned vaccinations, and 1 patient suffered disease progression after the fifth vaccination. Six patients received NP-polySA. One patient completed all six of the injections, 4 patients received five vaccinations due to disease progression, and 1 patient was withdrawn after five vaccinations due to progressive neuropathy (see below).


View this table:
[in this window]
[in a new window]

  		Table 1 Patient characteristics (n = 13)

 
Immunological Response.
Five of the patients vaccinated with unmodified polySA were evaluable for immune response. Only 1 of those patients mounted an IgM response with a titer of 1:160 (Fig. 2)Citation , but this was not confirmed by flow cytometry. On the other hand, all 6 of the patients vaccinated with NP-polySA produced IgM antibodies to NP-polySA with titers ranging from 1:160 to 1:2560 (Fig. 2Citation ; Table 2Citation ). These antibodies cross-reacted with unmodified polySA in all but 1 case. IgG antibodies to NP-polySA were observed in 5 of the patients, but these did not cross-react with polySA. The presence of IgM antibodies reactive with SCLC cell lines was confirmed in this group by flow cytometry with the median percentage of cells increasing from 10% to 51% (Fig. 3)Citation . Complement-dependent lysis of polySA-positive H345 tumor cells with human complement could not be demonstrated using the serum of any patient.



View larger version (22K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 2. IgM antibody responses in evaluable small cell lung cancer patients vaccinated with polysialic acid-keyhole limpet hemocyanin (KLH) + QS-21 (5 patients) or N-propionylated-polysialic acid (NP-PolySA)-KLH + QS-21 (6 patients). Arrows indicate the time of vaccinations.

 

View this table:
[in this window]
[in a new window]

  		Table 2 Peak reciprocal IgM and IgG ELISA titers for antibodies binding to either polySAa or NP-polySA

 


View larger version (40K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 3. Fluorescence cell sorting results after immunization N-propionylated-polysialic acid (NP-PolySA) -keyhole limpet hemocyanin (KLH) +100 µg QS-21 for 6 patients. The peak percent positive H345 cells and mean fluorescent intensity are indicated for pre- and postimmunization sera.

 
Bacteriocidal Activity.
Sera from patients vaccinated with NP-polySA were analyzed. Table 3Citation shows that in all but 1 case, the sera significantly augmented the bacteriocidal activity over baseline.


View this table:
[in this window]
[in a new window]

  		Table 3 Bacteriocidal activity of sera from patients vaccinated with NP-polySA-KLHa plus QS-21 against group B meningococcus

 
Toxicity.
Toxicities are shown in Table 4Citation . The most common side effects were injection site pain, swelling, and erythema. Fatigue and flu-like symptoms were reported. Local and systemic side effects generally lasted only 2–4 days.


View this table:
[in this window]
[in a new window]

  		Table 4 Number of patients with select toxicities

Only toxicities occurring in >1 patient are included.

 
Four patients reported grade 1 or 2 peripheral sensory neuropathy during the course of vaccinations. Two of these patients also reported ataxia. All of these patients had received cisplatin. One patient who had been treated with carboplatin had no neurological complaints during the study, but on long-term follow-up developed grade II peripheral neuropathy. One patient was taken off study after five vaccinations when she developed numbness and weakness of her lower extremities that eventually left her wheelchair-bound. It was ultimately determined that she had developed radiation myelitis resulting from her thoracic radiation for limited stage SCLC at the same site of thymic radiation she received as a child. In all of these cases, it was impossible to determine whether the symptoms were caused by the vaccine or by the prior therapy of the patient. Neurological complaints did not correlate with the degree of antibody response.

Survival.
Survival data after the start of polySA immunization and sites of recurrence are presented in Table 5Citation .


View this table:
[in this window]
[in a new window]

  		Table 5 Time to progression and survival

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this trial, we attempted to induce an immune response against polySA, a surface moiety attached to embryonic neural cell adhesion molecule, which has highly restricted expression in humans aside from SCLC. Although patients with SCLC often have dramatic responses to initial therapy, they usually recur and ultimately die of chemoresistant, often micrometastatic, disease remaining after initial therapy. These micrometastases can be attacked by an immunological approach that induces circulating antibodies targeting unique antigenic targets on tumor cells (12) . Antibodies can eliminate tumor cells by several complement-mediated mechanisms including inflammation, opsonification and removal by the reticuloendothelial system and complement-dependent cytotoxicity, and by antibody-dependent cell-mediated cytotoxicity.

To stimulate an immune response against polySA, which is not usually immunogenic, we used the approach that has been successful against a variety of other antigens, conjugation with KLH and administration with the adjuvant QS-21. The patients vaccinated with unmodified polySA-KLH did not mount a significant immune response despite these manipulations. However, N-propionylation of polySA, an approach shown by Jennings et al. (16) to enhance immunogenicity against group B meningococcal polysaccharide (or polySA) in mice, yielded greater immunogenicity. All 6 of the patients vaccinated with NP-polySA produced IgM antibodies to NP-polySA, and these cross-reacted with unmodified polySA in all but 1 case. IgG antibodies to NP-polySA were observed in 5 of the patients, but these did not cross-react with polySA. However, these antibodies did not induce complement-dependent cytotoxicity of tumor cells.

Whether complement-induced inflammation or lysis is critical for the elimination of cancer cells remains to be proven. In bacterial infections, complement-induced inflammatory mechanisms may be more important than lytic mechanisms, because consequences of hereditary deficiency states involving either the classical or alternate complement pathways are severe, whereas deficiencies of the membrane attack complex are comparatively less important (22) .

Binding of IgM antibodies to their target antigens results in complement activation. Activation of the complement cascade results in inflammation (including opsonization, activation of leukocytes and macrophages, and increased vascular permeability) and formation of a membrane attack complex, which generally leads to complement-dependent cytotoxicity. We have noted previously that antibodies against a range of glycolipids result in complement-dependent cytotoxicity of antigen-positive tumor cells, whereas antibodies of comparable or greater titer against carbohydrate or peptide antigens on mucins are unable to mediate complement-dependent cytotoxicity. This is hypothesized to be a consequence of the structural nature of the antigens. Glycolipids are intimately associated with the cell membrane lipid bilayer, whereas mucins such as MUC1 have collars of carbohydrates, which assume a rigid rod-like formation extending thousands of angstroms from the cell surface. The complement membrane attack complex has a reach of <100 angstroms, which is more than enough for cell lysis when the antigens are glycolipids or globular proteins. The great majority of mucin epitopes, however, would be >100 angstroms from the cell membrane. In addition, the rigidity of the mucin molecule keeps it from contacting the cell membrane. It may be that polySA, with its highly negative charge, would assume a similar configuration. If complement activation occurs >100 angstroms from the lipid bilayer, inflammation would still result but the membrane attack complex would be quickly inactivated by serum proteins. There are also complement-inactivating factors that have been identified on tumor cells. However, these cannot explain the lack of complement-dependent cytotoxicity seen because immune sera and monoclonal antibodies against glycolipid antigens on the same MUC1 or polySA positive tumor cells readily induced complement-dependent cytotoxicity.

The toxicity of the polySA and NP-polySA vaccines was mild. Several patients had sensory neuropathy and ataxia that could not be distinguished from effects of prior treatment, paraneoplastic neurological syndromes, or nervous system involvement by SCLC. We are now initiating a follow-up dose de-escalation study with NP-polySA to better assess the immunogenicity, toxicities, and optimal dose of this vaccine. The eventual plan is to combine this vaccine with three others to broaden the immune response against SCLC tumors, which demonstrate significant heterogeneity. The proposed components of this polyvalent vaccine, NP-polySA, GM2, fucosyl GM1, and Globo H, were chosen based on their presence in a majority of SCLC cell lines and biopsy specimens (8) . Both a bovine-derived (19) and synthetic (23) fucosyl GM1 vaccine have been tested in SCLC patients, and induce antibody responses in >90% of patients. GM2 (24) and Globo H (25 , 26) have demonstrated immunogenicity in trials in patients with other types of cancers. Antibodies to these vaccines react with antigen-positive tumor cells and in most cases mediate complement lysis and, where investigated, antibody-dependent cell-mediated cytotoxicity. The antibody response generated in persons with SCLC with NP-polySA in this trial supports the addition of this component to a polyvalent vaccine.


   FOOTNOTES
 
Grant support: NIH (PO1CA33049), and the Lawrence and Selma Ruben Foundations.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Requests for reprints: Lee M. Krug, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Phone: (212) 639-8420; Fax: (212) 794-4357.

Received 8/26/03; revised 10/ 3/03; accepted 12/ 4/03.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Rutishauser U. Polysialic acid at the cell surface: biophysics in service of cell interactions and tissue plasticity. J. Cell Biochem., 70: 304-312, 1998.[CrossRef][Medline]
  2. Finne J., Finne U., Deagostini-Bazin H., Goridis C. Occurrence of {alpha} 2, 8 linked polysialosyl units in a neural cell adhesion molecule. Biochem. Biophys. Res. Commun., 112: 482-488, 1983.[CrossRef][Medline]
  3. Rutishauser U., Acheson A., Hall A. K., Mann D. M., Sunshine J. The neural cell adhesion molecule (NCAM) as a regulator of cell-cell interactions. Science (Wash. DC), 240: 53-57, 1988.[Abstract/Free Full Text]
  4. Acheson A., Sunshine J. L., Rutishauser U. NCAM polysialic acid can regulate both cell-cell and cell-substrate interactions. J. Cell Biol., 114: 143-153, 1991.[Abstract/Free Full Text]
  5. Rutishauser U., Landmesser L. Polysialic acid in the vertebrate nervous system: a promoter of plasticity in cell-cell interactions. Trends Neurosci., 19: 422-427, 1996.[Medline]
  6. Komminoth P., Roth J., Lackie P. M., Bitter-Suermann D., Heintz P. U. Polysialic acid of the neural cell adhesion molecule distinguishes small cell lung carcinoma from carcinoids. Am. J. Pathol., 139: 297-304, 1991.[Abstract]
  7. Lantuejoul S., Moro D., Michalides R. J., Brambilla C., Brambilla E. Neural cell adhesion molecules (NCAM) and NCAM-PSA expression in neuroendocrine lung tumors. Am. J. Surg. Pathol., 22: 1267-1276, 1998.[CrossRef][Medline]
  8. Zhang S., Cordon-Cardo C., Zhang H., Reuter V., Adluri S., Hamilton W., Lloyd K., Livingston P. Selection of tumor antigens as targets for immune attack using immunuhistochemistry: I. Focus on gangliosides. Int. J. Cancer, 73: 42-49, 1997.[CrossRef][Medline]
  9. Daniel L., Trouillas J., Renaud W., Chevallier P., Gouvernet J., Rougon G., Figarella-Branger D. Polysialylated-neural cell adhesion molecule expression in rat pituitary transplantable tumors (spontaneous mammotropic transplantable tumor in Wistar-Furth rats) is related to growth rate and malignancy. Cancer Res., 60: 80-85, 2000.[Abstract/Free Full Text]
  10. Daniel L., Durbec P., Gautherot E., Rouvier E., Rougon G., Figarella-Branger D. A nude mice model of human rhabdomyosarcoma lung metastases for evaluating the role of polysialic acids in the metastatic process. Oncogene, 20: 997-1004, 2001.[CrossRef][Medline]
  11. Finne J., Leinonen M., Makela P. H. Antigenic similarities between brain components and bacteria causing meningitis. Implications for vaccine development and pathogenesis. Lancet, 2: 355-357, 1983.[Medline]
  12. Livingston P. O. Approaches to augmenting the immunogenicity of melanoma gangliosides: from whole melanoma cells to ganglioside-KLH conjugate vaccines. Immunol. Rev., 145: 147-166, 1995.[CrossRef][Medline]
  13. Livingston P. O., Adluri S., Helling F., Yao T.-J., Kensil C. R., Newman M. J., Marciani D. Phase I trial of immunological adjuvant QS-21 with a GM2 ganglioside-keyhole limpet haemocyanin conjugate vaccine in patients with malignant melanoma. Vaccine, 12: 1275-1280, 1994.[CrossRef][Medline]
  14. Helling F., Shang A., Calves M., Zhang S., Ren S., Yu R. K., Oettgen H. F., Livingston P. O. GD3 vaccines for melanoma: Superior immunogenicity of keyhole limpet hemocyanin conjugate vaccines. Cancer Res., 54: 197-203, 1994.[Abstract/Free Full Text]
  15. Helling F., Zhang S., Shang A., Adluri S., Calves M., Koganty R., Longenecker B. M., Yao T-J., Oettgen H. F., Livingston P. O. GM2-KLH conjugate vaccine: Increased immunogenicity in melanoma patients after administration with immunological adjuvant QS-21. Cancer Res., 55: 2783-2788, 1995.[Abstract/Free Full Text]
  16. Jennings H. J., Roy R., Gamian A. Induction of meningococcal group B polysaccharide-specific IgG antibodies in mice by using an N-propionylated B polysaccharide-tetanus toxoid conjugate vaccine. J. Immunol., 137: 1708-1713, 1986.[Abstract]
  17. Kensil C. R., Patel U., Lennick M., Marciani D. Separation and characterization of saponins with adjuvant activity from Quillaja saponaria Molina cortex. J. Immunol., 146: 431-437, 1991.[Abstract]
  18. Ragupathi G., Meyers M., Adluri S., Howard L., Musselli C., Livingston P. O. Induction of antibodies against GD3 ganglioside in melanoma patients by vaccination with GD3-lactone-KLH conjugate plus immunological adjuvant QS-21. Int. J. Cancer, 85: 659-666, 2000.[CrossRef][Medline]
  19. Dickler M. N., Ragupathi G., Liu N. X., Musselli C., Martino D. J., Miller V. A., Kris M. G., Brezicka F., Livingston P. O., Grant S. C. Immunogenicity of a fucosyl-GM1-keyhole limpet hemocyanin conjugate vaccine in patients with small cell lung cancer. Clin. Cancer Res., 5: 2773-2779, 1999.[Abstract/Free Full Text]
  20. Pon R. A., Lussier M., Yang Q. L., Jennings H. J. N-Propionylated group B meningococcal polysaccharide mimics a unique bactericidal capsular epitope in group B Neisseria meningitidis. J. Exp. Med., 185: 1929-1938, 1997.[Abstract/Free Full Text]
  21. Yao T. J., Begg C. B., Livingston P. O. Optimal sample size for a series of pilot trials of new agents. Biometrics, 52: 992-1001, 1996.[CrossRef][Medline]
  22. Colten H. R., Rosen F. S. Complement deficiencies. Annu. Rev. Immunol., 10: 809-834, 1992.[CrossRef][Medline]
  23. Krug L. M., Ragupathi G., Livingston P. O., Tyson L., Hood C., Baez V, Danishefsky S. J., Miller V. A., Ng K., Gomez J., Kris M. G. Pilot trial of a synthetic fucosyl-GM1 ganglioside vaccine in patients with small cell lung cancer (SCLC). Proc. Am. Soc. Clin. Oncol., 21: 46(Abstr 1824) 2002.
  24. Chapman P. B., Morrissey D. M., Panageas K. S., Hamilton W. B., Zhan C., Destro A. N., Williams L., Israel R. J., Livingston P. O. Induction of antibodies against GM2 ganglioside by immunizing melanoma patients using GM2-keyhole limpet hemocyanin + QS21 vaccine: a dose-response study. Clin. Cancer Res., 6: 874-879, 2000.[Abstract/Free Full Text]
  25. Gilewski T., Ragupathi G., Bhuta S., Williams L. J., Musselli C., Zhang X., Bencsath K. P., Panageas K. S., Chin J., Hudis C. A., Norton L., Houghton A., Livingston P. O., Danishefsky S. J. Immunization of metastatic breast cancer patients with a fully synthetic globo H conjugate: a phase I trial. Proc. Natl. Acad. Sci. USA, 98: 3270-3275, 2001.[Abstract/Free Full Text]
  26. Slovin S. F., G R., Adluri S., Ungers G., Terry K., Kim S., Spassova M., Bornmann W. G., Fazzari M., Dantis L., Olkiewicz K., Lloyd K. O., Livingston P. O., Danishefsky S. J., Scher H. I. Carbohydrate vaccines in cancer: immunogenicity of a fully synthetic globo H hexasaccharide conjugate in man. Proc. Natl. Acad. Sci. USA, 96: 5710-5715, 1999.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 J. Biol. Chem.Home page
H. Geyer, M. Wuhrer, A. Resemann, and R. Geyer
Identification and Characterization of Keyhole Limpet Hemocyanin N-Glycans Mediating Cross-reactivity with Schistosoma mansoni
J. Biol. Chem., December 9, 2005; 280(49): 40731 - 40748.
[Abstract] [Full Text] [PDF]

Home page
 Clin Med ResHome page
L. E. Raez, S. Fein, and E. R. Podack
Lung Cancer Immunotherapy
Clin. Med. Res., November 1, 2005; 3(4): 221 - 228.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
G. Ragupathi, N. X. Liu, C. Musselli, S. Powell, K. Lloyd, and P. O. Livingston
Antibodies against Tumor Cell Glycolipids and Proteins, but Not Mucins, Mediate Complement-Dependent Cytotoxicity
J. Immunol., May 1, 2005; 174(9): 5706 - 5712.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
L. M. Krug, G. Ragupathi, C. Hood, M. G. Kris, V. A. Miller, J. R. Allen, S. J. Keding, S. J. Danishefsky, J. Gomez, L. Tyson, et al.
Vaccination of Patients with Small-Cell Lung Cancer with Synthetic Fucosyl GM-1 Conjugated to Keyhole Limpet Hemocyanin
Clin. Cancer Res., September 15, 2004; 10(18): 6094 - 6100.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Krug, L. M.
Right arrow Articles by Livingston, P. O.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Krug, L. M.
Right arrow Articles by Livingston, P. O.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online