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1.
J Med Life ; 16(2): 186-188, 2023 Feb.
Article in English | MEDLINE | ID: mdl-36937484

ABSTRACT

Serological analysis of tumor markers has emerged as a non-invasive method for monitoring cancer patients, including tumor recurrence and response to treatment. Tumor markers have the potential to aid in both the diagnosis and prognosis of cancer, but their most important role currently lies in the monitoring of tumor progression. Tumor markers can also provide valuable information on treatment effectiveness, with changes in plasma values indicating tumor regression or progression. This research aimed to investigate the correlation between the serum detection values of three tumor markers - CEA, CA 19-9, and CA 72-4 - and their utility in the diagnosis and prognosis of patients with gastric cancer. The study seeks to uncover the relationship between these tumor markers and the evolution of gastric cancer, providing insights into their potential use in clinical practice.


Subject(s)
Antigens, Tumor-Associated, Carbohydrate , Stomach Neoplasms , Humans , Antigens, Tumor-Associated, Carbohydrate/therapeutic use , Stomach Neoplasms/drug therapy , Stomach Neoplasms/pathology , Carcinoembryonic Antigen , Neoplasm Recurrence, Local , CA-19-9 Antigen/therapeutic use , Biomarkers, Tumor , Prognosis
2.
Monoclon Antib Immunodiagn Immunother ; 40(3): 89-100, 2021 Jun.
Article in English | MEDLINE | ID: mdl-34161162

ABSTRACT

Tumor cells are characterized by the expression of tumor-specific carbohydrate structures that differ from their normal counterparts. Carbohydrates on tumor cells have phenotypical as well as functional implications, impacting the tumor progression process, from malignant transformation to metastasis formation. Importantly, carbohydrates are structures that play a role in receptor-ligand interaction and elicit the activity of growth factor receptors, integrins, lectins, and other type 1 transmembrane proteins. They have been recognized as biomarkers for cancer diagnosis, and evidence demonstrating their relevance as targets for anticancer therapeutic strategies, including immunotherapy, continues to accumulate. Different approaches targeting carbohydrates include monoclonal antibodies (mAbs), antibody (Ab)-drug conjugates, vaccines, and adhesion antagonists. Development of bispecific antibodies and chimeric antigen receptor (CAR)-modified T cells against tumor-associated carbohydrate antigens (TACAs) as promising cancer immunotherapeutic agents is rapidly evolving. As reviewed here, there are several cancer-associated glycan features that can be leveraged to design rational drug or immune system targets, applying multiple TACA structural and functional features to be targeted as the standard treatment paradigm. Many of the underlying targets were defined by researchers at the Wistar Institute in Philadelphia, Pennsylvania, which provide basis for different immunotherapy approaches.


Subject(s)
Antigens, Tumor-Associated, Carbohydrate/immunology , Immunotherapy/trends , Neoplasms/therapy , Polysaccharides/immunology , Antibodies, Bispecific/therapeutic use , Antibodies, Monoclonal/therapeutic use , Antigens, Tumor-Associated, Carbohydrate/therapeutic use , Cancer Vaccines/therapeutic use , Humans , Immunoconjugates/therapeutic use , Molecular Targeted Therapy/trends , Neoplasms/genetics , Neoplasms/immunology , Polysaccharides/antagonists & inhibitors , Polysaccharides/genetics , Receptors, Chimeric Antigen/therapeutic use
3.
Methods Enzymol ; 597: 359-376, 2017.
Article in English | MEDLINE | ID: mdl-28935111

ABSTRACT

Tumor-associated carbohydrate antigens (TACAs) are attractive targets for anticancer vaccine development. Due to the low immunogenicity of TACAs, a powerful carrier system is needed to boost immune responses. Virus-like particles (VLPs) are an exciting platform for delivering TACAs to the immune system. The high symmetry of VLPs enables the display of TACAs in an organized manner, which in turn can potently activate antibody secreting B cells, eliciting high titers of antiglycan IgG antibodies. In this chapter, the protocol for conjugating a prototypical TACA, the Tn antigen to a VLP, bacteriophage Qß, is presented. On an average around 370 copies of Tn can be attached to each Qß capsid. Immunization of mice with Qß-Tn conjugate leads to over two orders of magnitude higher IgG antibodies compared to control mice receiving Qß only without the Tn antigen. Antibodies induced by Qß-Tn recognize Tn-expressing tumor cells strongly and protect mice from tumor-induced death. The techniques for evaluating antibody titers by enzyme-linked immunosorbent assay, antibody binding to tumor cells by flow cytometry, and the protection efficacy of the vaccine in a therapeutic model of tumor are discussed in this chapter.


Subject(s)
Antigens, Tumor-Associated, Carbohydrate/immunology , Neoplasms/therapy , Vaccines, Conjugate/immunology , Vaccines, Virus-Like Particle/immunology , Allolevivirus/immunology , Animals , Antigens, Tumor-Associated, Carbohydrate/therapeutic use , B-Lymphocytes/immunology , Biomarkers, Tumor/immunology , Disease Models, Animal , Flow Cytometry , Humans , Immunization/methods , Mice , Neoplasms/immunology , Vaccines, Conjugate/therapeutic use , Vaccines, Virus-Like Particle/therapeutic use
4.
ChemMedChem ; 12(17): 1424-1428, 2017 09 07.
Article in English | MEDLINE | ID: mdl-28675699

ABSTRACT

Breaking tolerance is crucial for effective tumor immunotherapy. We showed that vaccines containing tumor-associated human MUC1 glycopeptides induce strong humoral antitumor responses in mice. The question remained whether such vaccines work in humans, in systems where huMUC1 is a self-antigen. To clarify the question, mice transgenic in expressing huMUC1, mimicking the self-tolerant environment, and wild-type mice were vaccinated with a synthetic vaccine. This vaccine comprised STn and Tn antigens bound to a MUC1 tandem repeat peptide coupled to tetanus toxoid. The vaccine induced strong immune responses in wild-type and huMUC1-transgenic mice without auto-aggressive side effects. All antisera exhibited almost equivalent binding to human breast tumor cells. Similar increases of activated B-, CD4+ T-, and dendritic cells was found in the lymph nodes. The results demonstrate that tumor-associated huMUC1 glycopeptides coupled to tetanus toxoid are promising antitumor vaccines.


Subject(s)
Antigens, Tumor-Associated, Carbohydrate/therapeutic use , Breast Neoplasms/prevention & control , Cancer Vaccines/therapeutic use , Mucin-1/therapeutic use , Peptide Fragments/therapeutic use , Tetanus Toxoid/therapeutic use , Vaccines, Synthetic/therapeutic use , Animals , Antigens, Tumor-Associated, Carbohydrate/chemistry , Antigens, Tumor-Associated, Carbohydrate/immunology , Breast Neoplasms/immunology , Cancer Vaccines/chemistry , Cancer Vaccines/immunology , Female , Humans , Immunization , MCF-7 Cells , Mice, Inbred C57BL , Mice, Transgenic , Mucin-1/chemistry , Peptide Fragments/chemistry , Tetanus Toxoid/chemistry , Tetanus Toxoid/immunology , Vaccines, Synthetic/chemistry , Vaccines, Synthetic/immunology
5.
Future Oncol ; 11(1): 27-37, 2015.
Article in English | MEDLINE | ID: mdl-25572782

ABSTRACT

Ipilimumab (Yervoy(®); Bristol-Myers Squibb, NY, USA) is a fully human monoclonal antibody targeting CTLA-4 and is approved for the treatment of metastatic melanoma. Preclinical and clinical studies have shown its activity in a number of different cancer types, including prostate cancer. Recently, the results from a Phase III study of ipilimumab in prostate cancer patients with prior docetaxel therapy were reported. Although the study did not meet the primary end point of improved overall survival, prespecified subset analyses suggested that ipilimumab may be more active in men with lower disease burden, which suggests that immunotherapy should be tested early in men with castration-refractory prostate cancer. Immune-related adverse events are common and most can be well managed with standard immunosuppressive algorithms.


Subject(s)
Antibodies, Monoclonal/administration & dosage , Immunotherapy , Prostatic Neoplasms/therapy , Tissue Extracts/administration & dosage , Antigens, Surface/immunology , Antigens, Surface/therapeutic use , Antigens, Tumor-Associated, Carbohydrate/immunology , Antigens, Tumor-Associated, Carbohydrate/therapeutic use , CTLA-4 Antigen/immunology , CTLA-4 Antigen/therapeutic use , Docetaxel , Glutamate Carboxypeptidase II/immunology , Glutamate Carboxypeptidase II/therapeutic use , Humans , Ipilimumab , Male , Prostatic Neoplasms/immunology , Taxoids/administration & dosage
6.
Cancer Immunol Immunother ; 61(11): 2045-54, 2012 Nov.
Article in English | MEDLINE | ID: mdl-22539085

ABSTRACT

Tumor-associated carbohydrate antigens (TACAs) are useful targets for the development of cancer vaccines or immunotherapies. However, a major obstacle in this application of TACAs is their poor immunogenicity. To overcome the problem, a new immunotherapeutic strategy combining synthetic vaccines made of artificial TACA derivatives and metabolic glycoengineering of cancer cells to express the artificial TACA derivatives was explored. Using a murine leukemia model FBL3 with GM3 antigen as the target, it was shown that artificial GM3 N-phenylacetyl derivative (GM3NPhAc) elicited robust antigen-specific T cell-dependent immunity and that N-phenylacetyl-D-mannosamine (ManNPhAc) as the biosynthetic precursor of GM3NPhAc selectively glycoengineered cancer cells to express GM3NPhAc both in vitro and in vivo. It was also demonstrated that GM3NPhAc-specific antisera and antibodies mediated strong cytotoxicity to ManNPhAc-treated FBL3 cell. Furthermore, vaccination with a conjugate vaccine made of GM3NPhAc followed by ManNPhAc treatment could significantly suppress tumor growth and prolong the survival of tumor-bearing mouse. These results have proved the feasibility of the new cancer immunotherapeutic strategy, as well as its efficacy to cure cancer, which is of general significance.


Subject(s)
Antigens, Tumor-Associated, Carbohydrate/therapeutic use , Cancer Vaccines/therapeutic use , G(M3) Ganglioside/analogs & derivatives , Leukemia/therapy , Animals , Antigens, Tumor-Associated, Carbohydrate/immunology , Antineoplastic Agents/therapeutic use , Cancer Vaccines/chemical synthesis , Cancer Vaccines/immunology , Cell Engineering , Cell Line, Tumor , Female , G(M3) Ganglioside/chemical synthesis , G(M3) Ganglioside/immunology , Hexosamines/therapeutic use , Immunotherapy , Leukemia/immunology , Leukemia/mortality , Mice , Mice, Inbred C57BL , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , Treatment Outcome , Vaccines, Synthetic/immunology , Vaccines, Synthetic/therapeutic use
7.
Expert Opin Biol Ther ; 10(2): 281-7, 2010 Feb.
Article in English | MEDLINE | ID: mdl-20088718

ABSTRACT

IMPORTANCE OF THE FIELD: The expression and biology of the tumor-associated antigen (TAA) 5T4 suggest it is an effective target for cancer immunotherapy. AREAS COVERED IN THIS REVIEW: Development of a vaccine comprising highly attenuated modified vaccinia Ankara virus encoding 5T4 (MVA-5T4, a.k.a. TroVax). WHAT THE READER WILL GAIN: Preclinical studies demonstrated that MVA-5T4 is safe and effective in prophylactic and active treatment of syngeneic murine tumor models. Over 700 doses of MVA-5T4 have been administered to over 200 patients to date. Results from clinical trials on metastatic colorectal, metastatic renal and hormone-refractory prostate cancer patients demonstrate that MVA-5T4 is safe and immunogenic as a monotherapy and in combination with standard-of-care therapies. MVA-5T4 induced potent and sustained immune responses in approximately 95% of tested patients. Post hoc analyses have noted a correlation between anti-5T4 immune responses and indicators of clinical benefit. A Phase III randomized, placebo controlled study, which investigated MVA-5T4 added to first line standard of care to evaluate whether vaccination prolonged survival of patients with metastatic clear cell renal cell cancer did not meet the primary endpoint (overall survival). TAKE HOME MESSAGE: With its minimal side effects and ability to produce immune responses MVA-5T4 is a promising addition to the cancer therapy arsenal.


Subject(s)
Antigens, Tumor-Associated, Carbohydrate/therapeutic use , Cancer Vaccines/therapeutic use , Immunotherapy , Membrane Glycoproteins/immunology , Neoplasms/therapy , Vaccinia/immunology , Animals , Cancer Vaccines/immunology , Clinical Trials, Phase II as Topic , Colorectal Neoplasms/drug therapy , Genetic Vectors , Humans , Kidney Neoplasms/drug therapy , Kidney Neoplasms/secondary , Male , Prostatic Neoplasms/drug therapy , Vaccinia virus/genetics
9.
Expert Rev Vaccines ; 3(6): 655-63, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15606349

ABSTRACT

Cancer vaccines have demonstrated that they can stimulate antibody and cell-mediated immune responses against tumor-associated antigens in the laboratory. However, few clinical studies with cancer vaccines have demonstrated convincing clinical responses. Sialyl-Tn is a carbohydrate associated with MUC1. It is a unique tumor-associated antigen, present on many adenocarcinomas including breast, ovarian, colorectal, gastric and pancreatic. Consequently, Sialyl-TN is an ideal candidate for boosting the patient's immune system specifically against a unique tumor-associated antigen. The cancer vaccine Theratope was developed by Biomira, Inc. using a synthetic Sialyl-Tn antigen that emulates the unique carbohydrate on human cancer. Clinical trials have predominantly been carried out in breast cancer patients and these trials are outlined in this profile.


Subject(s)
Antigens, Tumor-Associated, Carbohydrate/therapeutic use , Breast Neoplasms/therapy , Cancer Vaccines/therapeutic use , Hemocyanins/therapeutic use , Immunotherapy , Animals , Antigens, Tumor-Associated, Carbohydrate/immunology , Antineoplastic Agents/therapeutic use , Breast Neoplasms/immunology , Combined Modality Therapy , Drug Evaluation, Preclinical , Female , Hemocyanins/immunology , Humans , Randomized Controlled Trials as Topic , Stem Cell Transplantation
10.
Cancer Res ; 64(6): 2162-6, 2004 Mar 15.
Article in English | MEDLINE | ID: mdl-15026358

ABSTRACT

Tumor-associated carbohydrate antigens are typically perceived as inadequate targets for generating tumor-specific cellular responses. Lectin profile reactivity and crystallographic studies demonstrate that MHC class I molecules can present to the immune system posttranslationally modified cytosolic peptides carrying O-beta-linked N-acetylglucosamine (GlcNAc). Here we report that a peptide surrogate of GlcNAc can facilitate an in vivo tumor-specific cellular response to established Meth A tumors that display native O-GlcNAc glycoproteins on the tumor cell surface. Peptide immunization of tumor-bearing mice had a moderate effect on tumor regression. Inclusion of interleukin 12 in the immunization regimen stimulated complete elimination of tumor cells in all of the mice tested, whereas interleukin 12 administration alone afforded no tumor growth inhibition. Adoptive transfer of immune T cells into tumor-bearing nude mice indicates a role for CD8+ T cells in tumor regression. This work postulates that peptide mimetics of glycosylated tumor rejection antigens might be further developed for immune therapy of cancer.


Subject(s)
Acetylglucosamine/immunology , Antigens, Tumor-Associated, Carbohydrate/therapeutic use , Histocompatibility Antigens Class I/metabolism , Molecular Mimicry , Peptide Fragments/therapeutic use , Sarcoma, Experimental/prevention & control , Animals , Antigen Presentation , Antigens, Tumor-Associated, Carbohydrate/immunology , Antigens, Tumor-Associated, Carbohydrate/metabolism , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Cytosol/metabolism , Female , Histocompatibility Antigens Class I/immunology , Humans , Immunization , Immunotherapy , Interferon-gamma/metabolism , Interleukin-12/therapeutic use , Mice , Mice, Inbred BALB C , Mice, Nude , Peptide Fragments/immunology , Peptide Fragments/metabolism , Sarcoma, Experimental/immunology , Sarcoma, Experimental/pathology , Spleen/immunology , T-Lymphocytes, Cytotoxic/drug effects , T-Lymphocytes, Cytotoxic/immunology
11.
Curr Cancer Drug Targets ; 3(6): 433-43, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14683501

ABSTRACT

Mucin-type O-glycans are upregulated and aberrantly glycosylated in many carcinomas. O-glycan Core 1 (Galbeta1-3GalNAcalpha-O-), also called Thomsen-Friedenreich disaccharide, is a cryptic structure overexpressed in cancer cells through modification of its glycosyltransferase profile. This molecule is a useful model for study of carbohydrate immunogenicity as well as a candidate for active specific immunotherapy of cancer patients. Several strategies are discussed for enhancing immune response to a particular region of carbohydrate: carbohydrate-protein conjugation, linkers, synthetic clustered sugars, chemical modifications, peptide/protein mimetics, and molecular rotation.


Subject(s)
Antigens, Neoplasm/immunology , Antigens, Tumor-Associated, Carbohydrate/immunology , Neoplasms/immunology , Animals , Antigens, Neoplasm/therapeutic use , Antigens, Tumor-Associated, Carbohydrate/therapeutic use , Humans , Immunotherapy , Neoplasms/therapy
12.
J Clin Oncol ; 21(23): 4292-8, 2003 Dec 01.
Article in English | MEDLINE | ID: mdl-14645418

ABSTRACT

PURPOSE: We report the synthesis of a mucin-related O-linked glycopeptide, alpha-N-acetylgalactosamine-O-serine/threonine (Tn), which is highly simplistic in its structure and can induce a relevant humoral response when given in a trimer or clustered (c) formation. We tested for an antitumor effect, in the form of a change in the posttreatment versus pretreatment prostate-specific antigen (PSA) slopes, that might serve as a surrogate for effectiveness of vaccines in delaying the time to radiographic progression. METHODS: We compared the antibody response to immunization with two conjugates, Tn(c)-keyhole limpet hemocyanin (KLH) and Tn(c)-palmitic acid (PAM) with the saponin immunologic adjuvant QS21, in a phase I clinical trial in patients with biochemically relapsed prostate cancer. Patients received Tn(c)-KLH vaccine containing either 3, 7, or 15 microg of Tn(c) per vaccination. Ten patients received 100 microg of Tn(c)-PAM. QS21 was included in all vaccines. Five vaccinations were administered subcutaneously during 26 weeks with an additional booster vaccine at week 50. RESULTS: Tn(c), when given with the carrier molecule KLH and QS21, stimulated the production of high-titer immunoglobulin M (IgM) and IgG antibodies. Inferior antibody responses were seen with T(c)-PAM. There was no evidence of enhanced immunogenicity with increasing doses of vaccine. An antitumor effect in the form of a decline in posttreatment versus pretreatment PSA slopes was also observed. CONCLUSION: A safe synthetic conjugate vaccine in a trimer formation was developed that can break immunologic tolerance by inducing specific humoral responses. It seemed to affect the biochemical progression of the disease as determined by a change in PSA log slope.


Subject(s)
Antigens, Tumor-Associated, Carbohydrate/therapeutic use , Cancer Vaccines/therapeutic use , Neoplasm Recurrence, Local/therapy , Prostatic Neoplasms/therapy , Vaccines, Conjugate/therapeutic use , Aged , Aged, 80 and over , Antigens, Tumor-Associated, Carbohydrate/chemistry , Antigens, Tumor-Associated, Carbohydrate/immunology , Biomarkers, Tumor/blood , Cancer Vaccines/chemical synthesis , Cancer Vaccines/chemistry , Cancer Vaccines/immunology , Carbohydrate Sequence , Complement System Proteins/immunology , Cytotoxicity Tests, Immunologic , Hemocyanins/chemistry , Hemocyanins/metabolism , Humans , Immunoglobulin G/blood , Immunoglobulin M/blood , Male , Middle Aged , Molecular Sequence Data , Mucins/immunology , Neoplasm Recurrence, Local/immunology , Neoplasm Recurrence, Local/prevention & control , Palmitic Acid/chemistry , Palmitic Acid/metabolism , Prostate-Specific Antigen/blood , Prostatic Neoplasms/immunology , Vaccination , Vaccines, Conjugate/chemistry , Vaccines, Conjugate/immunology
13.
Semin Oncol ; 30(5): 659-66, 2003 Oct.
Article in English | MEDLINE | ID: mdl-14571413

ABSTRACT

Immunotherapy is currently being investigated as a treatment for patients with asymptomatic, recurrent prostate cancer manifested only by a rising prostate-specific antigen (PSA) level. Several different approaches to active immunization against antigens found on cancer cells have been explored. Immunization with DNA overcomes many of the obstacles noted in previous studies. Injection of plasmid DNA encoding a xenogeneic differentiation antigen (prostate-specific membrane antigen [PSMA]) is a potent means to induce antibody and T-cell responses to these otherwise poorly immunogenic self proteins. Use of the xenogeneic DNA (ie, human PSMA DNA injected into mouse) has been shown to be an absolute requirement to overcome immunologic tolerance. We are currently conducting a phase I trial of human and mouse PSMA DNA vaccines in patients with recurrent prostate cancer, based on preclinical experiments described below.


Subject(s)
Neoplasm Recurrence, Local/therapy , Prostatic Neoplasms/therapy , Vaccination/methods , Vaccines, DNA/therapeutic use , Animals , Antigens, Heterophile/immunology , Antigens, Heterophile/therapeutic use , Antigens, Surface/immunology , Antigens, Surface/therapeutic use , Antigens, Tumor-Associated, Carbohydrate/immunology , Antigens, Tumor-Associated, Carbohydrate/therapeutic use , Autoantigens/immunology , Biomarkers, Tumor/blood , Clinical Trials, Phase I as Topic , Dendritic Cells/immunology , Disease Models, Animal , Drug Evaluation, Preclinical , Glutamate Carboxypeptidase II/immunology , Glutamate Carboxypeptidase II/therapeutic use , Heat-Shock Proteins/immunology , Humans , Immune Tolerance/immunology , Male , Mice , Neoplasm Recurrence, Local/blood , Neoplasm Recurrence, Local/immunology , Prostate-Specific Antigen/blood , Prostatic Neoplasms/blood , Prostatic Neoplasms/immunology , T-Lymphocytes/immunology , Vaccines, DNA/classification , Vaccines, DNA/immunology , Viral Vaccines/immunology , Viral Vaccines/therapeutic use
14.
Drugs R D ; 4(4): 236-40, 2003.
Article in English | MEDLINE | ID: mdl-12848588

ABSTRACT

Biomira is developing a therapeutic cancer vaccine [THERATOPE] for treatment of breast and other cancers. This profile has been selected from R&D Insight, a pharmaceutical intelligence database produced by Adis International Ltd. THERATOPE consists of the mucin antigen, sialyl-Tn (STn), a carbohydrate located on the surface of breast, colorectal and ovarian cancer cells, conjugated to keyhole limpet haemocyanin (KLH). Merck KGaA has acquired a worldwide licence to THERATOPE for treatment of breast cancer. Under the terms of the licence, Biomira and Merck KGaA, via its US affiliate, EMD Pharmaceuticals, will jointly market the vaccine in the US. Merck KGaA holds exclusive marketing rights for the rest of the world, except in Canada (where Biomira retains rights), Israel and the Palestine Autonomy Area. Merck KGaA is now collaborating on phase III development for breast cancer. Biomira stands to receive $US150 million in licence, milestone payments and equity investments. The development costs will be shared between the two companies in North America but Merck KGaA will be solely responsible for these costs in countries outside the US. Previously, Chiron Corporation had purchased a licence to THERATOPE in 1997; however, Chiron terminated this agreement in June 2000. Under the terms of the termination, Biomira paid Chiron $US2.25 million to compensate the company for its investment in the development of THERATOPE. In addition, Biomira will make another payment of $US3.25 million to Chiron upon FDA approval of the vaccine. No further payments or royalties will be made. In the third quarter of 2002, an independent review of interim data from the trial was conducted. This was the fifth scheduled review of the data by the Independent Data Safety Monitoring Board (DSMB), all of which produced a positive response. Following the completion of the review, the DSMB stated that the trial should continue and that it had no safety concerns regarding this trial. Although the data, to which Biomira and Merck KgaA are blinded, did not meet the predetermined statistical significance for either endpoint at the time of the review, both companies have chosen to continue with the trial. Biomira has since announced that the p-value for the interim survival analysis was set at 0.01, while it is set at 0.03 for final survival analysis. The tighter criteria was set for the interim analysis to potentially give the companies the opportunity of applying for marketing approval earlier than expected. Final analysis of the trial will take place in mid-2003. If these analyses indicate therapeutic efficacy, Biomira will meet the FDA and Canadian regulatory officials to obtain marketing approval for the vaccine for breast cancer under the accelerated review guidelines. Assuming a best-case scenario, the vaccine could be filed for approval in 2004. The phase III trial was initiated following positive preliminary results achieved in a bridging study in patients with metastatic breast cancer in the US and UK. Biomira announced final results of the bridging study in May 1999. The results confirmed that antibody titres against the STn antigen were significantly higher in patients treated with the improved formulation of THERATOPE, compared with the corresponding titres of patients in the phase II trials of the old formulation of THERATOPE. In September 2002, the first patient was enrolled in a phase II THERATOPE trial, which is enrolling patients with metastatic breast cancer who are taking either an aromatase inhibitor or fulvestrant. Approximately 95 patients will be enrolled in the trial at up to 12 US sites. The study is primarily designed to evaluate THERATOPE's ability to induce an immune response in these patients. However, the safety and tolerability of the aromatase inhibitor plus THERATOPE, and the fulvestrant plus THERATOPE combinations will also be evaluated. The trial has not been designed to evaluate the efficacy of the two combinations. The US FDA has granted fast-track status tranted fast-track status to THERATOPE for development as an adjunct to first-line combination chemotherapy in responding patients with metastatic breast cancer. A phase II trial in patients with metastatic colorectal cancer has been completed in the US; positive preliminary results from this trial were released in May 2001. On 24 November 1999, Biomira announced that it had licensed two patents covering methods of preventing growth of cancer cells expressing a mucin-type glycoprotein. The patents have been issued in the US and are pending in Japan and Canada. When issued in Japan, the patents will provide additional protection for THERATOPE in that country. The patents were licensed from Dr Sen-itiroh Hakomori of the Biomembrane Institute in Seattle, with whom Biomira has also entered into a research collaboration. Biomira announced in April 2003 that following examination of its re-issue application by the US Patent and Trademark Office, its patent 5798090 was re-issued (RE 38046) with additional claims. These additional claims represent broader patent coverage. The additional coverage will last until 2015. Earlier, in February 2000, Biomira announced an expansion of equity line for up to $US100 million; a 3-fold rise that was done without any additional shares of Biomira stock being issued. In June 2002, Biomira stated that it believes the market size for THERATOPE in the US, Europe and Japan to be approximately 184000 patients for the indication of metastatic breast cancer, of which the US would be 100000, Europe 75000 and Japan 9000. For the indication of colorectal cancer, the total market population for THERATOPE is expected to be 183000 patients, of which the US has been estimated at 100000, Europe 75000 and Japan 9000.


Subject(s)
Adjuvants, Immunologic/therapeutic use , Antigens, Tumor-Associated, Carbohydrate/therapeutic use , Cancer Vaccines/therapeutic use , Hemocyanins/therapeutic use , Neoplasms/drug therapy , Adjuvants, Immunologic/adverse effects , Adjuvants, Immunologic/economics , Antigens, Tumor-Associated, Carbohydrate/adverse effects , Antigens, Tumor-Associated, Carbohydrate/economics , Breast Neoplasms/drug therapy , Breast Neoplasms/immunology , Cancer Vaccines/adverse effects , Cancer Vaccines/economics , Clinical Trials as Topic , Costs and Cost Analysis , Drug Industry/economics , Female , Hemocyanins/adverse effects , Hemocyanins/economics , Humans , Injections, Subcutaneous , Marketing of Health Services , Neoplasms/immunology , Treatment Outcome
15.
Clin Breast Cancer ; 3 Suppl 4: S139-43, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12620151

ABSTRACT

The development of active specific immunotherapy depends on the identification of altered cancer cell-specific molecules or epitopes that are immunogenic. Many cancer-specific peptide or glycoprotein target antigens have been identified. Tumors carrying aberrant epitopes as a result of underglycosylation of mucins are associated with poor prognosis in many epithelial cancers. The aberrant mucin sialyl-Tn (STn) epitope, in addition to being a predictor of poor prognosis when expressed in tumors, is associated with increased aggressiveness and metastatic potential, making it a promising target for immunotherapy. The STn-keyhole limpet hemocyanin (KLH) vaccine (Theratope) is an investigational active specific immunotherapy consisting of a synthetic STn epitope conjugated to a high molecular weight protein carrier, KLH. The immune response generated by the STn-KLH vaccine is both humoral and cellular. More than 1000 breast cancer patients with metastatic disease are currently enrolled in a phase III clinical trial to assess the safety and efficacy of the STn-KLH vaccine. Interim analysis from a current phase III trial has confirmed the safety of the STn-KLH vaccine, and the clinical outcome awaits the final analysis expected in 2003.


Subject(s)
Antigens, Tumor-Associated, Carbohydrate/immunology , Antigens, Tumor-Associated, Carbohydrate/therapeutic use , Breast Neoplasms/immunology , Breast Neoplasms/prevention & control , Cancer Vaccines , Hemocyanins/immunology , Hemocyanins/therapeutic use , Antigens, Tumor-Associated, Carbohydrate/pharmacology , Breast Neoplasms/pathology , Clinical Trials as Topic , Epitopes , Female , Hemocyanins/pharmacology , Humans , Immunotherapy/trends , Neoplasm Metastasis , Prognosis
16.
Clin Breast Cancer ; 3 Suppl 4: S134-8, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12620150

ABSTRACT

Mucin-1 (MUC-1) is a high-molecular-weight glycoprotein rich in serine and threonine residues that are O-glycosylated. Expression of MUC-1 is increased in breast, ovarian, and other adenocarcinomas, and altered glycosylation results in exposure of novel peptide epitopes and the expression of tumor-associated carbohydrate residues, such as Thomsen-Freidenreich and sialyl-Tn (STn) antigens. Preclinical studies suggested that induction of immune response to tumor-associated carbohydrate moieties results in inhibition of tumor growth. A synthetic STn-keyhole limpet hemocyanin (KLH) vaccine (Theratope) is currently being evaluated in clinical trials as active specific immunotherapy in the treatment of advanced breast cancer. Two phase II trials in 50 breast cancer patients compared the STn-KLH vaccine with and without a single low-dose infusion of cyclophosphamide used as an immunomodulator prior to initiation of treatment. Humoral immune responses were higher in patients who had received low-dose cyclophosphamide intravenously (I.V.) compared with patients who had received no cyclophosphamide or oral cyclophosphamide. There was a statistically significant survival difference between all patients treated with the STn-KLH vaccine (overall median survival, 19.1 months; n = 50) and the retrospective control patients (overall median survival, 9.2 months; n = 104). Furthermore, patients who received cyclophosphamide I.V. prior to the STn-KLH vaccine had median survival rates close to 3 times that of patients in a retrospective, frequency-matched, control group who received conventional therapies (cyclophosphamide-I.V. group, 26.5 months vs. 9.2 months, control group). The trials reported minimal toxicity profile with local reactions in the injection site and some flu-like symptoms. On the basis of the phase II trial results, a phase III clinical trial of the STn-KLH vaccine is underway. The trial was closed to enrollment in March 2001 with the accrual of 1030 women. The final analysis is event driven and is expected to commence mid 2003.


Subject(s)
Antigens, Tumor-Associated, Carbohydrate/therapeutic use , Breast Neoplasms/immunology , Breast Neoplasms/prevention & control , Cancer Vaccines , Hemocyanins/therapeutic use , Mucin-1/immunology , Administration, Oral , Animals , Antigens, Tumor-Associated, Carbohydrate/administration & dosage , Antigens, Tumor-Associated, Carbohydrate/immunology , Clinical Trials as Topic , Cyclophosphamide/administration & dosage , Female , Glycoconjugates , Hemocyanins/administration & dosage , Hemocyanins/immunology , Humans , Immunologic Factors/administration & dosage , Infusions, Intravenous , Survival Analysis , Treatment Outcome
17.
Clin Breast Cancer ; 3 Suppl 4: S144-51, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12620152

ABSTRACT

The success of high-dose chemotherapy followed by autologous stem-cell rescue as treatment for breast and ovarian cancer is limited by a high incidence of relapse. After autologous transplantation, patients are likely to have a low tumor burden and thus would be more likely to respond immunologically to a cancer vaccine. Sialyl-Tn (STn) is a carbohydrate associated with the MUC1 mucin on breast and ovarian cancer and is an ideal candidate for vaccine immunotherapy. Sialyl-Tn-keyhole limpet hemocyanin (STn-KLH) vaccine (Theratope) incorporates a synthetic STn antigen that mimics the unique tumor-associated STn carbohydrate and is designed to stimulate tumor antigen-specific immune responses in patients with mucin-expressing tumors. Between 1995 and 2000, 70 patients (16 with stage II/III breast cancer, 17 with stage III/IV ovarian cancer, and 37 with stage IV breast cancer) were treated with 2 different formulations of STn-KLH. Toxicity, outcome, and immune response data are reported. STn-KLH was well-tolerated with minimal toxicity. The most common side effects were indurations and erythema at the sites of injections. Humoral and cellular responses were elicited in the majority of patients. Overall, these data indicate that post-autologous transplant patients are able to mount an effective immune response to vaccine immunotherapy with minimal side effects, and that vaccine immunotherapy may be a useful addition to high-dose chemotherapy regimens.


Subject(s)
Antigens, Tumor-Associated, Carbohydrate/immunology , Antigens, Tumor-Associated, Carbohydrate/therapeutic use , Breast Neoplasms/immunology , Breast Neoplasms/therapy , Cancer Vaccines/therapeutic use , Hemocyanins/immunology , Hemocyanins/therapeutic use , Ovarian Neoplasms/immunology , Ovarian Neoplasms/therapy , Peripheral Blood Stem Cell Transplantation , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cancer Vaccines/administration & dosage , Cancer Vaccines/adverse effects , Cell Proliferation , Disease Progression , Female , Humans , Mucin-1/immunology , Survival Analysis , Transplantation, Autologous , Treatment Outcome
19.
Curr Opin Investig Drugs ; 3(1): 150-8, 2002 Jan.
Article in English | MEDLINE | ID: mdl-12054066

ABSTRACT

Cancer vaccines have been explored clinically against melanomas, adenocarcinomas and lymphomas. Breast cancer vaccines include Theratope, MUC1 mucin peptides and HER-2/neu peptide vaccines. Phase II trials suggest prolongation of survival of advanced breast cancer patients who generate high titers of antibody to Theratope. In contrast, melanoma ganglioside vaccines, which also elicit only antibodies, have not been effective in improving survival in controlled trials. Anti-idiotype vaccines for solid tumors, which depend upon mimicry of the tumor-associated antigens, have also had limited success. In lymphomas, where the idiotypes are the tumor-associated antigens, greater success has been achieved. A number of tumor-associated antigens have been identified in melanoma, such as the lineage related cancer-testis group (MAGE) and tyrosinase-related antigens. Non-lineage related antigens shared among a variety of very different tumors have recently been demonstrated too, which may permit immunization against more than one tumor group. Telomerase and MG50, one of several interleukin-1 receptor antagonist molecules, are both immunogenic and widespread in their representation. Carcinoembryonic antigen is the basis for vaccines against many adenocarcinomas. Both viral and non-viral vectors are being used to improve the reactivity to peptides in adenocarcinomas. Dendritic cell-carried vaccines, which package the antigens ex vivo rather than depending upon in vivo uptake, are being extensively explored in clinical models to improve the effectiveness of defined vaccines, such as peptides and RNA. 'Naked' DNA vaccines injected intramuscularly also have their advocates. Among the most recent attempts to improve the immunogenicity of vaccines is the use of antigens newly identified by genomic techniques and 'superagonist' peptide mimics, selected from combinatorial peptide libraries. These modern biochemical and molecular biological methods may greatly expand our ability to immunize against tumor antigens, which are essentially 'self' molecules. Finally, a greater understanding of ways in which tumors escape immunological detection or thwart immunological responses should lead to improved strategies against the tumor to augment the effect of vaccination.


Subject(s)
Cancer Vaccines/therapeutic use , Neoplasms/drug therapy , Animals , Antigens, Tumor-Associated, Carbohydrate/pharmacology , Antigens, Tumor-Associated, Carbohydrate/therapeutic use , Cancer Vaccines/pharmacology , Genetic Vectors/pharmacology , Genetic Vectors/therapeutic use , Hemocyanins/pharmacology , Hemocyanins/therapeutic use , Humans , Melanoma/drug therapy , Melanoma/immunology , Neoplasms/immunology
20.
Expert Opin Biol Ther ; 1(5): 881-91, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11728222

ABSTRACT

Active specific immunotherapy (ASI) is a promising approach to treating cancer. Numerous studies in the laboratory have demonstrated that various cancer vaccines can stimulate antibody and cell mediated immune responses against tumour-associated antigens [1-9]. Yet few studies have demonstrated convincing clinical responses. Sialyl-Tn (STn) is a carbohydrate associated with the MUC1 mucin on a number of human cancer cells and is associated with more aggressive disease. Consequently, STn is an ideal candidate for ASI therapy. Theratope vaccine is a cancer vaccine that was designed by Biomira, Inc. (Edmonton, Alberta, Canada) by incorporating a synthetic STn antigen that emulates the carbohydrate seen on human tumours. The clinical trials conducted to date with Theratope vaccine are outlined in this report. Overall, Theratope vaccine has been well-tolerated with minimal toxicity. The most common side effects have been in duration and erythema at the site of injections. Both in a non-transplant setting following low dose iv. cyclophosphamide and high dose autologous transplant setting, there has been a trend toward Theratope vaccine decreasing the risk for relapse, prolonging the time to relapse and thus impacting on overall survival. The definitive Phase III trial comparing the outcome of patients with metastatic breast cancer receiving vaccinations with Theratope vaccine versus vaccination with the nonspecific immune stimulants Keyhole Limpet Hemocyanin (KLH) and Detox -B stable emulsion (Detox-B) (now called Enhanzyn Immunostimulant) was closed to enrolment on March 30, 2001. Over 1000 women with distant metastatic breast cancer were enrolled into the program.


Subject(s)
Antigens, Tumor-Associated, Carbohydrate/therapeutic use , Cancer Vaccines/therapeutic use , Glycoconjugates/therapeutic use , Hemocyanins/therapeutic use , Animals , Antigens, Tumor-Associated, Carbohydrate/immunology , Clinical Trials as Topic , Hemocyanins/immunology , Humans , Mucin-1/immunology , Survival Rate
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