Phase II Trial of NY-ESO-1/ISCOMATRIX Melanoma Vaccine

In 1995, LICR made the commitment to evaluate the therapeutic applications of its research discoveries for human benefit. Since then, the Institute has established the infrastructure, processes and procedures for taking laboratory discoveries into the clinic. Once identified, study agents for use in humans are produced, clinical protocols are developed, regulatory filings are prepared and submitted and ethics committee review is obtained; a complex set of procedures undertaken and/or coordinated by the LICR’s Office of Clinical Trials Management (OCTM). Often it is necessary to identify and negotiate industry interactions before clinical trials are performed. A current and fitting example of this process is the ‘story’ of the NY-ESO-1/ISCOMATRIX™ cancer vaccine.

The NY-ESO-1 cancer/testis (CT) antigen was discovered at the LICR New York Branch by Drs. Yao-Tseng Chen and Lloyd Old, and patented by LICR’s Office of Intellectual Property. NY-ESO-1, or ‘ESO’ as it is affectionately known, was soon shown to be a) expressed on a wide variety of cancers including melanoma, sarcoma, hepatocellular, lung, and head and neck(1), and b) induce an immunological response in humans. In fact, NY-ESO-1 is one of the most immunogenic cancer antigens discovered to date. The immunogenicity and wide-spread expression of NY-ESO-1 make the antigen a prime candidate for a therapeutic cancer vaccine. To evaluate the therapeutic potential of NY-ESO-1 based vaccines, LICR’s Cancer Vaccine Program devised clinical discovery strategies aimed at determining the best antigen constitution (protein, peptide, viral vector or DNA), method, frequency and intensity of antigen delivery, and adjuvants or immunostimulatory compounds (chemicals that enhance the immune response) required to induce a strong, sustained, integrated (antibody plus CD8+ and CD4+ T cells) immunological response against NY-ESO-1. Two other key antigens are being investigated by the Cancer Vaccine Program in much the same way: MAGE(2) led by the Brussels Branch; and Melan-A(3) led by the Lausanne Branch.

On the premise that strong NY-ESO-1 specific immunity is required before clinical benefit of a NY-ESO-1 cancer vaccine could be expected, different vaccine formulations of ESO have been utilized in early-phase clinical trials at several LICR Clinical Trials Centers (Table 1) with immune response endpoints to ascertain the formulation that provided the strong NY-ESO-1 immune response desired. To efficiently evaluate the many potential approaches to NY-ESO-1 vaccination, the trials have been largely conducted concurrently with coordination by the Office of Clinical Trials Management. From 2000, much of this work has been carried out under the auspices of the Cancer Vaccine Collaborative (CVC), established by LICR and the Cancer Research Institute (CRI) in New York, to develop therapeutic cancer vaccines.

One cancer vaccine formulation tested at the Clinical Trials Center of the Melbourne Branch, was the combination of the ESO antigen and an adjuvant called ISCOMATRIX™, produced by the Australian biotechnology company, CSL Ltd. The ‘ESO/ISCOM’ vaccine was produced jointly by CSL Ltd’s biological production facility (BPF) and LICR’s own BPF in Melbourne.

The Phase I trial of the ‘ESO/ISCOM’ vaccine was conducted by Drs. Ian Davis and Jonathan Cebon at ‘Austin Health’, one of Australia’s premier oncology hospitals, and the Melbourne Branch’s clinical trials site. The trial was designed to determine the safety and NY-ESO-1 specific induced immunity of the cancer vaccine. Dr. Weisan Chen at the Melbourne Branch monitored the patient samples to characterize the immunological responses to the vaccine.

Drs. Chen, Davis and Cebon

Drs. Chen, Davis and Cebon

The study treated 46 patients, most with melanoma, with three monthly doses of the NY-ESO-1/ISCOMATRIXTM vaccine following surgical removal of the tumor. In the trial, some patients received different doses of the NY-ESO-1/ISCOMATRIXTM vaccine, some received the NY-ESO-1 protein without ISCOMATRIXTM, and some received an inactive placebo. Dr. Chen’s detailed studies of the patients’ immune responses(4) revealed that the NY-ESO-1/ISCOMATRIXTM vaccine, in contrast to vaccination with the placebo, induced the production of antibodies, plus CD8 and CD4 T cells that target the NY-ESO-1 antigen. In other words, there was a full ‘integrated’ immunological response to the ESO/ISCOM vaccine. (Vaccination with the NY-ESO-1 protein alone produced antibodies in 25% of patients and CD4+ and CD8+ T cell responses in all patients. However, the T cell responses could not be proved to be due to vaccination, and spontaneous T cell responses to NY-ESO-1 had been previously reported in a collaboration between the LICR New York Branch and the Frankfurt Affiliate Center (5).)

“The immunological results are very exciting,” says Dr. Chen. “They show that it is possible to stimulate an integrated immune response that has the potential to attack cancer from a number of different angles. Being able to get antibodies, together with both types of T cells, gives us enormous confidence that we are heading in the right direction for developing a clinically effective therapy.”

According to Dr. Cebon, who is also the Head of the Joint Austin Health/Ludwig Institute Oncology Unit, the vaccine also appeared to delay the recurrence of melanoma in these resected melanoma patients. “Relapse within the next five years is quite likely in this patient group so we had a unique opportunity to gather preliminary data on the vaccine’s effect over a relatively long period of time.” In a review of the melanoma patients two years later, five out of seven patients who received the placebo and nine out of 16 who received just the NY-ESO-1 protein had relapsed whereas 14 out of 19 the patients who received the full NY-ESO-1/ISCOMATRIXTM vaccine, remained cancer-free.

Notwithstanding the encouraging clinical results, the Melbourne team is quick to point out that this type of retrospective analysis must be considered only suggestive since the data were not collected prospectively. “In interpreting these data, we need to be mindful that there may be unforeseen variables that we didn’t control for when we set up the trial,” warns Dr. Davis, who was the lead author of the clinical study (6). “And of course this is a small number of patients.”

The next step, according to Dr. Eric Hoffman, Director of the Office of Clinical Trials Management, is to confirm these results with prospectively obtained data in an appropriately designed study. “It is well known that a definitive answer in this patient population will require a randomized study with hundreds of patients. Prior to any undertaking of such an effort and in order to design such a trial, prospectively collected data are required.”

A Phase II trial, to prospectively collect the data required to justify a randomized study, will be conducted under the auspices of the CVC (with funding from both LICR and CRI) and is expected to commence in 2005. “Make no mistake,” says Dr. Hoffman. “This trial is going to be a big challenge for the OCTM and the trial sites involved, in terms of logistics, clinical monitoring, and immunological monitoring. But ultimately, this is what cancer research is about; understanding the disease and turning research discoveries into therapies.”

Newspaper clippings

Newspaper clippings reporting on the research

References

  1. Scanlan M.J., Simpson A.J., and Old L.J. The cancer/testis genes: review, standardization, and commentary. Cancer Immun. (2004) 4:1
  2. Coulie P.G., Karanikas V., Lurquin C., Colau D., Connerotte T., Hanagiri T., Van Pel A., Lucas S., Godelaine D., Lonchay C., Marchand M., Van Baren N., and Boon T. Cytolytic T-cell responses of cancer patients vaccinated with a MAGE antigen. Immunol.Rev. (2002) 188(1):33-42
  3. Romero P., Valmori D., Pittet M.J., Zippelius A., Rimoldi D., Levy F., Dutoit V., Ayyoub M., Rubio-Godoy V., Michielin O., Guillaume P., Batard P., Luescher I.F., Lejeune F., Lienard D., Rufer N., Dietrich P.Y., Speiser D.E., and Cerottini J.C. Antigenicity and immunogenicity of Melan-A/MART-1 derived peptides as targets for tumor reactive CTL in human melanoma. Immunol.Rev. (2002) 188:81-96
  4. Chen Q., Jackson H., Parente P., Luke T., Rizkalla M., Tai T.Y., Zhu H.C., Mifsud N.A., Dimopoulos N., Masterman K.A., Hopkins W., Goldie H., Maraskovsky E., Green S., Miloradovic L., McCluskey J., Old L.J., Davis I.D., Cebon J., and Chen W. Immunodominant CD4+ responses identified in a patient vaccinated with full-length NY-ESO-1 formulated with ISCOMATRIX adjuvant. Proc Natl.Acad.Sci.U.S.A (2004) 101(25):9363-9368
  5. Gnjatic S., Nagata Y., Jager E., Stockert E., Shankara S., Roberts B.L., Mazzara G.P., Lee S.Y., Dunbar P.R., Dupont B., Cerundolo V., Ritter G., Chen Y.T., Knuth A., and Old L.J. Strategy for monitoring T cell responses to NY-ESO-1 in patients with any HLA class I allele. Proc.Natl.Acad.Sci.U.S.A (2000) 97(20):10917-10922
  6. Davis I.D., Chen W., Jackson H., Parente P., Shackleton M., Hopkins W., Chen Q., Dimopoulos N., Luke T., Murphy R., Scott A.M., Maraskovsky E., McArthur G., MacGregor D., Sturrock S., Tai T.Y., Green S., Cuthbertson A., Maher D., Miloradovic L., Mitchell S.V., Ritter G., Jungbluth A.A., Chen Y.T., Gnjatic S., Hoffman E.W., Old L.J., and Cebon J.S. Recombinant NY-ESO-1 protein with ISCOMATRIX adjuvant induces broad integrated antibody and CD4+ and CD8+ T cell responses in humans. Proc Natl.Acad.Sci.U.S.A (2004) 101(29):1067-702.