Cancer Vaccine Program

The LICR Cancer Vaccine Program was established to coordinate and focus the integration of immunological vaccine research being performed at a number of Branches and Affiliate Centers. One objective of the Program has been the identification and development of components of, and delivery technologies for, therapeutic cancer vaccines. The second focus of the Cancer Vaccine Program has been the development of standardized techniques to monitor the immune response following vaccination; a requirement vital for the success of the LICR Clinical Trials Model (see accompanying article). Early-phase clinical trials of cancer vaccines are conducted by the members of the Cancer Vaccine Collaborative (CVC), which was formed in 2002 by the LICR and the Cancer Research Institute (CRI) a New York-based charity (http://www.cancerresearch.org/). The clinical trials are coordinated, under the auspices of the CVC, by the LICR Office of Clinical Trials Management (Figure 1).

Figure 1. Schematic overview of the Cancer Vaccine Collaborative. The CVC was formed by LICR and CRI to conduct early-phase clinical trials (managed by the LICR Office of Clinical Trials Management, OCTM) of therapeutic cancer vaccines through an international network of Clinical Trial Centers. Study agents are being produced by LICR’s Biological Production Facilities (BPF) or are from our commercial partners.

Schematic overview of the Cancer Vaccine Collaborative

The cutting edge of cancer vaccine research, a good proportion of which is originating in laboratories involved in the Cancer Vaccine Program, was presented at the latest of the International Cancer Vaccine Symposia. The symposium, entitled "Cancer & HIV Vaccines: Shared Lessons", was held in New York from October 1- 3, and was a first in gathering together many scientists from both the cancer immunology and HIV fields. The acclaimed symposia are sponsored by CRI, and the planning committee includes LICR Director Dr. Lloyd J. Old (Chairman of the committee, and also Scientific Director of the CRI) and LICR Affiliate Dr. Alexander Knuth (Zürich, Switzerland). The following overviews of the presentations given by LICR investigators summarize the current preclinical and clinical research in the Institute’s Cancer Vaccine Program.

The symposium’s Opening Address, given by Dr Old, was an overview of the cancer vaccine field; from historical tenets through to the most recent theories (The entire text is available at http://www.cancerimmunity.org/v3suppl2p1/031017.htm). The LICR’s Antigen Discovery Program, which has thus far contributed a significant number of all known cancer antigens, was briefly outlined, as was the ‘Cancer Immunome Database’ created and maintained by the LICR Office of Information Technology led by Dr. Victor Jongeneel. From the discovery of cancer antigens, Dr. Old went on to further describe the principal antigens currently being trialed as vaccine targets within the Cancer Vaccine Program: MAGE (1), the first human cancer antigen to be cloned (through a collaboration between the Brussels Branch and Dr. Knuth); Melan-A (2), which was also discovered at the Brussels Branch; and NY-ESO-1 (3), which was discovered at the New York Branch. Finally Dr Old outlined the breadth and scope of the CVC’s clinical trials using the NY-ESO-1 vaccination program, which is carried out in ten international centers, as an example (Figure 2).

The first of the LICR speakers was Dr. Thierry Boon, the Brussels Branch Director, who reported on a series of clinical trials performed by the team at the Brussels Branch. In these trials, melanoma patients were vaccinated primarily with MAGE peptides. Immunological monitoring performed during the study detected MAGE-specific cytotoxic T lymphocytes (CTL) in approximately 20% of the patients following vaccination (4,5). Induction of these T cells demonstrates that the patients are capable of mounting an immune response against the MAGE antigen following vaccine delivery. Although the patient numbers in early-phase clinical trials are not sufficient to give statistically valid efficacy data (they are designed to evaluate safety only), it was encouraging that about half of the patients capable of mounting an immune response had observable tumor responses. The team is now developing even more sophisticated vaccine strategies to induce stronger, broader, and more sustained immune responses.

Figure 2. The Cancer Vaccine Collaborative’s NY-ESO-1 Vaccination Program. The four vaccine formulations being trialed, peptide (broken into three arms: major histocompatibility complex (MHC) Class I; MHC Class II; and overlapping peptides), protein, vector, and DNA, are indicated in orange. Vaccine composition variables being trialed are indicated in blue, and the corresponding Centers trialing the variables are shown in pink.

NY-ESO-1 Vaccination Program

Legend: ISCOM = immunostimulatory complex; DC = dendritic cells; GM-CSF = granulocyte macrophage – colony stimulating factor; CHP = cholesteryl hydrophobized polysaccharide; BCG = Bacillus Calmette-Guerin.

One of the numerous sessions of the conference focused on the development of Melan-A/MART1 vaccines, which is principally being conducted at the Lausanne Branch. Branch Director Dr. Jean-Charles Cerottini began the session with some background on Melan-A, reporting that the lack of expression of Melan-A in melanoma may be associated with a less favorable prognosis, suggesting a link between a naturally occurring immune response associated with Melan-A expression and a slower cancer progression. Research performed at the Branch has characterized the Melan-A gene and its splice variants, and has led to the development of a vaccination strategy that uses a protease-resistant analog of a Melan-A peptide against which CTLs have been detected (6). Dr. Pedro Romero described his research in which he compared the Melan-A-specific T cell repertoire in healthy individuals and in patients with melanoma, and found that there appeared to be a tumor-driven selection of CTLs with high avidity T cell receptors for the Melan-A antigen. Using specially designed multimeric HLA-peptide complexes, Dr. Romero was able to isolate the CTLs with high avidity Melan-A-specific T cell receptors (7). This method can be used to isolate and expand high avidity CTLs to develop vaccines with greater efficacy. Finally, Dr. Daniel Speiser outlined the results of an early-phase clinical trial in which patients with metastatic melanoma were vaccinated with a composition of peptide plus the adjuvant (a compound that enhances the immunological response to an antigen), Montanide. Significant activation of antigen-specific CTLs was detected in a majority of the patients, and this vaccine-induced activity was sustained in almost all of the responding patients. Further trials will now test different vaccine formulations and compositions, and delivery methods to increase the efficacy of the vaccine.

Another session of the conference was devoted to NY-ESO-1, one of the most immunogenic human cancer antigens discovered to date, and a promising vaccine candidate. Dr. Knuth reported on recent NY-ESO-1-based vaccine research and development, which includes the optimization of monitoring technologies, the comparison of adjuvants, and the optimization and development of molecular biology- and immunohistochemistry-based applications such as antigen characterization (e.g. typing NY-ESO-1 expression in tumors) and the identification and mapping of specific epitopes recognized by distinct MHC molecules. Dr. Sacha Gnjatic (New York Branch) reported on monitoring technologies, and his analysis of naturally occurring immunogenicity that results in an integrated (CD4+/CD8+ T cells plus antibody) immune response, in patients with tumors that express the NY-ESO-1 antigen (8). LICR Affiliate Dr Elke Jäger (Frankfurt, Germany) presented results from just two of the clinical trials being conducted at Krankenhaus Nordwest; one in which patients are vaccinated intensively with NY-ESO-1 peptides (9), and another in which recombinant viral constructs are being used to both deliver the NY-ESO-1 antigen (10) and enhance the response to the antigen through the concomitant immunological ‘recognition’ of the virus particles. Induction of vaccine-induced, antigen-specific immune responses was observed in both studies. Finally Dr. Jonathan Cebon presented results from a melanoma study that he and Dr. Ian Davis are conducting at the Melbourne Branch. In this study, patients with resected NY-ESO-1+ tumors, primarily metastatic melanoma, were vaccinated with NY-ESO-1 protein complexed with ISCOM®, an immunostimulatory compound developed by one of the LICR’s commercial partners, CSL Ltd (Melbourne, Australia). A broad T cell response to many different NY-ESO-1 epitopes was detected following vaccination, and the disease-free survival of patients that received the NY-ESO-1 protein/ISCOM® vaccine was substantially longer than those that received the NY-ESO-1 protein alone. Again, these are early-phase clinical trials with small numbers of patients, and the clinical results from such studies are encouraging but not significant until corroborated in randomized clinical trials that are designed for such a purpose.

Part of the data presented by Dr. Cebon clearly demonstrated that some tumors that were NY-ESO-1+ at the start of the clinical trial ‘lost’ NY-ESO-1 or MHC expression following vaccination. This concept of selective pressure against the antigen, resulting in ‘immunoediting’ (11) - the down-regulation of antigen expression - had earlier been introduced by the presentation from LICR Affiliate Dr. Robert Schreiber (St Louis, USA). In response to the growing body of evidence that immunoediting allows the tumor to evade immunological recognition, the Cancer Vaccine Program began developing multi-antigen vaccines that will be applicable to larger numbers of patients (instead of just those whose tumors express only one particular antigen) and that should, it is hoped, circumvent ‘tumor evasion’ through immunoediting. As part of this new strategy, LICR Affiliate Dr. Vincenzo Cerundolo (Oxford, UK) presented results of his preclinical and clinical research into the use of a ‘polyepitope’ melanoma vaccine, which incorporates eight antigens (MAGE, Melan-A, and NY-ESO-1 among them). Initial results suggest that some antigens, particularly Melan-A, are ‘immunodominant’ to others, hierarchically skewing the immune response induced by vaccination. It is apparent that further careful consideration is required in the design and delivery of next-generation multi-antigen vaccines.

The highly successful conference enabled scientists from both the cancer and HIV vaccine fields to freely share information and experiences obtained so far in the development of therapeutic vaccines, and to gain an understanding of the complexities of each disease. Viewed from the perspective of the cancer vaccine field, the presentations by participants in the Cancer Vaccine Program clearly demonstrated success in the induction of specific immunity following vaccination. The task is now to translate this immunity into effective clinical responses, and thus fulfill LICR’s goal of bringing laboratory discoveries to patient benefit.

References

  1. van der Bruggen P, Traversari C, Chomez P, Lurquin C, De Plaen E, Van den EB, Knuth A, and Boon T. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science (1991) 254(5038):1643-1647
  2. Coulie PG, Brichard V, Van Pel A, Wolfel T, Schneider J, Traversari C, Mattei S, De Plaen E, Lurquin C, Szikora JP, Renauld JC, and Boon T. A new gene coding for a differentiation antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas. The Journal of Experimental Medicine (1994) 180(1):35-42
  3. Chen YT, Scanlan MJ, Sahin U, Tureci O, Gure AO, Tsang S, Williamson B, Stockert E, Pfreundschuh M, and Old LJ. A testicular antigen aberrantly expressed in human cancers detected by autologous antibody screening. Proc.Natl.Acad.Sci.U.S.A (1997) 94(5):1914-1918
  4. Karanikas V, Lurquin C, Colau D, Van Baren N, De Smet C, Lethe B, Connerotte T, Corbiere V, Demoitie MA, Lienard D, Dreno B, Velu T, Boon T, and Coulie PG. Monoclonal anti-MAGE-3 CTL responses in melanoma patients displaying tumor regression after vaccination with a recombinant Canarypox virus. J Immunol. (2003) 171(9):4898-4904
  5. Coulie PG, Karanikas V, Colau D, Lurquin C, Landry C, Marchand M, Dorval T, Brichard V, and Boon T. A monoclonal cytolytic T-lymphocyte response observed in a melanoma patient vaccinated with a tumor-specific antigenic peptide encoded by gene MAGE-3. Proc.Natl.Acad.Sci.U.S.A (2001) 98(18):10290-10295
  6. Blanchet JS, Valmori D, Dufau I, Ayyoub M, Nguyen C, Guillaume P, Monsarrat B, Cerottini JC, Romero P, and Gairin JE. A new generation of Melan-A/MART-1 peptides that fulfill both increased immunogenicity and high resistance to biodegradation: implication for molecular anti-melanoma immunotherapy. J.Immunol. (2001) 167(10):5852-5861
  7. Pittet MJ, Rubio-Godoy V, Bioley G, Guillaume P, Batard P, Speiser D, Luescher I, Cerottini JC, Romero P, and Zippelius A. alpha3 domain mutants of peptide/MHC class I multimers allow the selective isolation of high avidity tumor-reactive CD8 T cells. J Immunol. (2003) 171(4):1844-1849
  8. Gnjatic S, Atanackovic D, Jager E, Matsuo M, Selvakumar A, Altorki NK, Maki RG, Dupont B, Ritter G, Chen YT, Knuth A, and Old LJ. Survey of naturally occurring CD4+ T cell responses against NY-ESO-1 in cancer patients: correlation with antibody responses. Proc.Natl.Acad.Sci.U.S.A (2003) 100(15):8862-8867
  9. Jaeger E, Karbach J, Neumann A, Jager D, Herrlinger K, Gnjatic S, Hoffman E, Old L, and Knuth A. LUD00-009: phase I study of intensive course immunization with NY-ESO-1 peptides in HLA-A2+ patients with NY-ESO-1+ cancer. ASCO American Society of Clinical Oncology (2002) Tumor Vaccines Category:1859
  10. Jaeger E, Karbach J, Neumann A, Gnjatic S, Hoffman E, Oettgen HF, Old LJ, and Knuth A. Phase I Study of Recombinant Vaccinia-NY-ESO-1 (rV-NY-ESO-1) and Recombinant Fowlpox-NY-ESO-1 (rF-NY-ESO-1) in Patients with NY-ESO-1 or LAGE Positive Cancers. Proceedings of the American Society of Clinical Oncology (2003) Tumor Vaccines Category(# 717)
  11. Dunn GP, Bruce AT, Ikeda H, Old LJ, and Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nat.Immunol. (2002) 3(11):991-998