Overview - View Day Two - Advances in Cancer Vaccines Brochure
WEDNESDAY, AUGUST 13 - DAY ONE
7:30 am Registration and Morning Coffee
ILLUMINATING THE PROMISE OF CANCER VACCINES
8:25 Chairperson’s Remarks
Hossein A. Ghanbari, Ph.D., Chairman, Chief Executive Officer & Chief Scientific Officer, Panacea Pharmaceutials, Inc.
8:35 OPENING KEYNOTE PRESENTATION
Opportunities and Challenges for Cancer Vaccines
Tibor Keler, Ph.D., Senior Vice President and Chief Scientific Officer, Celldex Therapeutics Inc.
Disease prevention by vaccination is one of the most successful and cost effective health interventions, but exploiting immunization technologies for therapeutic intervention has been challenging. The importance and power of the immune system in controlling cancers has now been demonstrated in many settings, and recent developments continue to open new opportunities for developing more effective regimens. In particular, the development of combination therapies with conventional and novel immunotherapies may bring more success to cancer vaccines.
9:05 FEATURED PRESENTATION
Vaccine, Immunotherapy and the Immunological Constant or Rejection
Francesco M. Marincola, Ph.D., Chief, Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health
The expanded licensure of FluMist (Live, attenuated influenza vaccine) for children less than 5 years of age in 2007 gave MedImmune and the FDA the opportunity to negotation of the first Risk Management Action Plans (Risk-MAPs) for a pediatric vaccine. This presentation explores the rationale for applying Risk-MAPs to vaccines, the role of the product label in Risk-MAPs, the negotiations and types of commitments that were made for FluMist as a result of those negotiations, and the unique requirements in implementing a plan for a vaccine that is used on a seasonal basis and is reformulated each year.
9:35 Treating Prostate Cancer Using Androgen Receptor Epitope (ARE) DNA Vaccinination
David Zarling, Ph.D., CEO, Colby Pharmaceutical Co.
Prostate cancer is a significant health risk for men over the age of 50 and is a current pervasive health threat with as many as 200,000 new cases diagnosed each year in the US alone. At present, there is no accepted adjuvant treatment for patients undergoing radical prostatectomy or ablative radiation therapy that has been proven to prevent progression to metastatic disease. A new approach is to induce an immune response to an ARE which is critical in the progression of prostate cancer. A DNA vaccine has been developed directed against the androgen receptor (AR) will be discussed administration by a DNA plasmid containing all or select portions of the AR gene in order to elicit an immune response in a mammal, including in a human.
10:05 Networking Coffee Break (Sponsorship Available)
10:45 GVAX Immunotherapy for Prostate Cancer
Kristen M. Hege, M.D., Vice President, Clinical Research and Development, Cell Genesys
GVAX immunotherapy for prostate cancer is comprised of 2 established allogeneic prostate tumor cell lines (LNCap and PC3) that have been modified to secrete GM-CSF. Preclinical studies in multiple tumor model systems have demonstrated the immunologic and anti-tumor activity of GM-CSF secreting whole tumor cell immunotherapies. Results of phase 2 clinical trials in hormone-naïve and hormone-refractory prostate cancer have reported a favorable safety profile as well as evidence of activity, including treatment-associated changes in PSA kinetics, dose-dependent induction of anti-tumor immunity, and encouraging overall survival. Two phase 3 registration trials evaluating GVAX immunotherapy for prostate cancer alone and in combination with docetaxel in hormone-refractory prostate cancer (HRPC) are underway and the first is fully accrued. The primary endpoint in both trials is improvement in overall survival. In addition, a phase 1 trial in combination with ipilimumab, an antibody directed against CTLA-4, a major regulator of T cell immune responses, is underway. Evidence of PSA, measurable tumor, and pain responses have been reported. Responding patients developed immune breakthrough events concurrent with onset of PSA responses, including hypophysitis (5 cases) and alveolitis (1 case). All cases of hypophysitis were managed with standard hormone replacement therapy. GVAX immunotherapy for prostate cancer has reported promising clinical and immunological activity in preclinical models and in Phase 1 and 2 human trials both alone and in combination with other immunomodulatory agents.
11:15 Development of a Therapeutic Vaccine Against HPV-Induced Cancer
Joerg Schneider, Ph.D., Department Head, Molecular Immunology, Transgene SA
This talk describes the development of Transgene's therapeutic HPV CIN 2/3 vaccine from concept to Phase III. My talk will present an important case study addressing the development path of a cancer vaccine that is about to enter phase III testing.
11:45 Development of Optimized Cryptic Peptides for Tumor Immunotherapy
Kostas Kosmatopoulos, M.D., Ph.D., Dr.Sc., Founder, President and CSO, Vaxon Biotech
Tumor immunotherapy is mainly based on the activation of cytotoxic T lymphocytes (CTL). CTL recognize peptides derived from tumor antigens and presented at the cell surface in association with HLA molecules. Two types of peptides have been described i) Dominant peptides, which exhibit high HLA affinity, are abundant at the cell surface and are immunogenic, ii) Cryptic peptides, which exhibit low HLA affinity, are weakly presented at the cell surface and are non immunogenic. Dominant peptides appeared to be attractive candidates for tumor immunotherapy and had, therefore, been targeted in all clinical trials performed to date with results not as encouraging as expected. This relative ineffectiveness seems to be due to T cell tolerance to tumor antigens which are proteins expressed by tumor and also by normal cells. Tolerance results in the deletion or inactivation of CTLs specific for dominant peptides. We have shown that CTLs specific for cryptic peptides escape tolerance mechanisms, suggesting that cryptic peptides would be better than dominant peptides for cancer vaccination – provided they can be rendered immunogenic (Gross et al., 2004). Cryptic peptides, which have low HLA affinity, have to be “optimized” by altering their amino acid sequence, thereby transforming them into high-affinity peptides capable of stimulating a T cell response. We have developed a method for optimizing cryptic peptides presented in association with HLA-A2. It consists of substituting the amino acid in position 1 by a tyrosine (Y). This modification increases HLA affinity, and has been shown to render immunogenic 90% of cryptic peptides so far studied (Tourdot et al., 2000; Scardino et al., 2002). More importantly, immunization of HLA-A2 expressing HHD mice with optimized TERT-derived cryptic peptides protects them against tumor growth in vivo (Gross et al., 2004). Optimized cryptic peptides are, therefore, more promising than dominant peptides for tumor immunotherapy.
12:15 pm Lunch on Your Own (Lunch Workshop Sponsorship Available)
TARGETING T CELLS
1:40 Chairperson’s Remarks
Arya Biragyn, Ph.D., Investigator Head, Immunotherapeutics Unit, National Institute on Aging, NIH
1:45 Antigens Recognized by Cytolytic and Helper T Cells with Vaccine Potential for Cancer Patients
Dorothee Herlyn, D.V.M., D.Sc., Professor, The Wistar Institute
A melanoma and a colon cancer antigen recognized by cytolytic T lymphocytes (CTL) were cloned using the COS cell cDNA library expression approach and identified as tRNA isopentyltransferase 1 (TRIT-1)-related protein and nucleophosmin (NPM, B23, nutramin, or NO38), respectively. TRIT-1 has been described as a tumor suppressor in lung carcinoma. Nucleophosmin has oncogenic activity, is expressed by lymphomas and upregulated by colon carcinomas, hepatomas, bladder carcinomas, and melanomas. A melanoma antigen recognized by helper T (Th) cells was cloned using a novel phage display approach which offers several advantages over the previously used invariant chain fusion approach. The antigen was identified as ribosomal protein (RP) L8. RPL8 is expressed by melanomas, gliomas and breast carcinomas. Mutated BRAF (V600E mutation) is a tumor-specific epitope expressed by approximately 70% of melanomas derived from different patients. Peptides of mutated BRAF induced CTL in melanoma patients’ lymphocytes. This study shows for the first time that TRIT-1 related protein, nucleophosmin, RPL8 and BRAF-V600E are recognized by patients’ T cells. The antigens express numerous epitopes potentially associating with different class I and II human lymphocyte antigens (HLA) and therefore they may induce CTL and Th cells in patients expressing various HLA types. These antigens also have potential as vaccines for patients with tumors of various histological types.
2:15 Enhancing the Efficacy of Cancer Immunotherapeutics and Vaccines by Suppressing the Induction of Regulatory T Cells
Kingston Mills, Ph.D., Professor, Experimental Immunology and Head of Immunology, School of Biochemistry and Immunology, Trinity College Dublin
A major obstacle to the development of therapeutic vaccines against cancer is the immune suppressive environment of the growing tumor, including the induction of regulatory dendritic cells and T cells which suppress the development of protective effector T cell responses. This can be compounded by the use of TLR ligands as adjuvants or immunotherapeutics. A problem with TLR agonists that has not been fully appreciated is that they can generate suppressive as well as inflammatory responses in innate immune cells and can generate regulatory as well as effector T cells. This is part of a normal mechanism for limiting collateral damage during infection or sterile inflammation, but can constrain their ability to induce protective anti-tumor immunity in the immune suppressed environment of the tumor. However, manipulating the TLR-activated innate immune responses to selectively block the suppressive arm may hold the key to enhancing their efficacy as tumor immunotherapeutics and as adjuvants for cancer vaccines. (see 127.Conroy, Marshall and Mills, 2008, Oncogene, 27(2):168-80)
2:45 Poster Spotlights
Immunotherapy of Solid Tumors Utilizing PLGA/ Tumor Lysate Nanoparticles to Stimulate TIL and Circulating CD8+ Tumor‐specific T Cells
Douglas Hanlon, Ph.D., Associate Research Scientist, Dermatology, Yale University
3:00 Comparative Evaluation of Techniques for the Manufacturing of Dendritic Cell-based Cancer Vaccines
Thomas Felzmann, Ph.D., Tumor Immunology, Children’s Cancer Research Institute, St. Anna Children’s Hospital
3:15 Networking Refreshment Break (Sponsorship Available)
ANTIGEN INNOVATIONS
4:00 Immunotherapeutic Potency of Embryonic and Sperm-Expressed Antigens
Arya Biragyn, Ph.D., Investigator Head, Immunotherapeutics Unit, National Institute on Aging
Although tumor-associated antigens (TAAs) are considered to be the main target of cancer immunotherapy, they are often poorly immunogenic and their immune effector cells could be eliminated due to thymic selection. In contrast, TAAs that are usually expressed during normal embryonic stage or spermatogonia, such as OFA-iLRP and SPANX-B, are immunogenic in humans. Importantly, humans contain circulating T cell precursors that can be readily expanded, for example, to generate SPANX-B –specific helper CD4+ T cells and cytolytic CD8+ T cells that recognize unique immunodominant epitopes. The CD8+ T cells were fully functional and could recognize and lyse HLA-A2-expressing tumors, including primary human melanomas. Furthermore, these antigens can be efficiently utilized to eradicate established tumors in mice if combined with the strategies that target them to APCs to induce both arms of T cell immunity, CD8+ and CD4+ T cell responses. For example, DNA immunizations with chemokines fused with the embryonic antigen OFA-iLRP elicit CD8+ T cell-mediated therapeutic antitumor immunity against syngeneic murine tumors that express OFA-iLRP. Thus, these groups of TAAs may hold significant therapeutic value as a target antigen for the development of effective anticancer immunotherapeutics.
4:30 Cancer Mucosa Antigens as Novel Immunological Targets for Tumor Therapy
Adam E. Snook, Ph.D., Research Fellow, Department of Pharmacology and Experimental Therapeutics, Jefferson Medical College, Thomas Jefferson University
Cancer immunotherapy is hindered, in part, by a lack of suitable target antigens. This is particularly relevant in tumors derived from mucosal tissues, in which antigens that are sufficiently immunogenic, tumor-restricted and shared among patients are lacking. We have explored a novel class of tumor-associated antigens fulfilling these criteria by exploiting immune compartmentalization, which restricts cross-talk between systemic and mucosal immune compartments. This compartmentalization limits systemic tolerance to mucosa-restricted self-antigens and shields mucosa from systemic autoimmune responses. Therefore, a novel paradigm suggests that targeting self-antigens expressed by normal mucosal tissues and by derivative neoplasms, should permit effective immunotherapy against systemic metastases, without inducing autoimmunity in normal mucosa. We have recently explored targeting the first of these antigens, termed cancer mucosa antigens, in animal models of metastatic cancer (Snook et al, JNCI submitted). Viral vector vaccines were generated containing guanylyl cyclase C (GCC), expressed in normal intestinal epithelium and in all primary and metastatic human colorectal cancer (CRC) specimens. Immunization elicited CD8+ T cell responses in multiple strains of mice. Moreover, responses effectively prevented development of lung and liver CRC metastases and treated established lung CRC metastases. This occurred in the absence of autoimmunity against normal GCC-expressing intestinal tissue. These results suggest the utility of GCC-specific immunotherapy for gastrointestinal malignancies, as well as the potential for CMA-targeted immunotherapy for malignancies of other mucosae such as oral, respiratory, mammary, and urogenital tissues, to treat head and neck, lung, breast, and bladder cancers, respectively.
5:00 Specific Lytic Antibody Production Against Myeloma Cell Associated CD38 Antigen by the Modified Vaccination Technique
Arpad Z. Barabas, Ph.D., Research Scientist, Surgery, University of Calgary
I have developed a new vaccination methodology called Modified Vaccination Technique (MVT) [patent pending]. It is able to redirect the immune response outcome specifically without causing side effects. The method was utilized with 100% success to terminate an experimental autoimmune disease and with equal effectiveness to produce lytic antibodies against a CD38 bearing human myeloma cell line. The vaccine is composed of two components: a specific antigen against which a desired immune response is sought and a specific antibody against the target antigen. (In case of myeloma: CD38 antigen was combined with specific antibody directed against CD38 antigen at slight antigen excess). Injection of the immune complex into animals produced the same class of antibody with the same specificity against the target antigen as resided in the inoculum. The MVT promises to be the missing vaccination methodology for dealing with endogenous antigen induced disorders such as cancer.
5:30 Happy Hour in the Exhibit Hall
6:30 End of Day One
Overview - View Day Two