March 01, 2004
New York (March 1st) — There are many therapeutic cancer vaccines designed to harness the immunological system to limit the growth or spread of cancer under investigation in early-phase clinical trials. However, the vast majority are being developed with little or no immunological monitoring to determine whether and how the human immune system is responding to the vaccine being studied. The Cancer Vaccine Collaborative (CVC), a partnership established by the Cancer Research Institute in New York and the international Ludwig Institute for Cancer Research (LICR), has today announced that it is the first to demonstrate that vaccination with a cancer-specific recombinant protein antigen has successfully induced a fully integrated immunological response in humans.
In a Phase I clinical trial conducted by the CVC in conjunction with GlaxoSmithKline (GSK), patients with non-small cell lung cancer received a vaccine of recombinant protein, MAGE-3, which was discovered at the LICR Branch in Brussels, and AS02B, one of GSK’s immunological adjuvants. MAGE-3 is a member of a family of highly cancer-specific antigens present on a wide variety of tumors, and AS02B stimulates the body’s immunological response to the protein. Most of the antigen-specific cancer vaccines that are currently in early-phase clinical trials use protein fragments called peptides. In contrast, the CVC cancer vaccine contains the full-length protein antigen. Infectious disease vaccines routinely used today also contain full-length proteins, and not peptides.
Induction of vaccine-specific antibodies and CD8 T cells, which destroy tumor cells carrying the antigen, have been previously observed in trials of cancer vaccines. However, antibodies and CD8 cells represent only two parts of the complex immunology equation. The results of the CVC study, published in the Journal of Immunology, showed that in the majority of patients the vaccine induced CD4 T cells, which function to enhance CD8 T cell activity and, most importantly, act to sustain the attack on the cancer antigen for longer periods of time. The team used a new method, developed in the CVC laboratories in New York, which allows researchers to monitor, for the first time, all three major components of the immunological response to cancer vaccines. The patients in the study are now being followed to measure their long-term clinical response to the vaccine, and to assess whether vaccine booster shots are necessary to maintain their immunization.
“We have a mantra for cancer vaccine development,” says Dr. Lloyd J. Old, Director of the Cancer Vaccine Collaborative, and a senior author on the paper. “’You won’t know how to vaccinate until you know how to immunize. And you won’t know how to immunize until you know how to monitor.’ Being able to monitor the full set of immunological responses allows us to specifically test different antigens and vaccine component combinations, like the addition of AS02B, and identify therapeutic responses that are associated with immune responses.”
The necessity of immunological monitoring to enable rational vaccine development was echoed by Dr. Herbert Oettgen of Memorial Sloan-Kettering Cancer Center’s Clinical Immunology Service. “We should keep in mind that every modern vaccine developed for infectious diseases has gone through a rigorous progression of testing components and monitoring the immune responses to establish strong and sustained immunization in humans. And yet cancer vaccines have often been given to patients without having demonstrated that they illicit a strong immune response.”
Dr. Jill O’Donnell-Tormey, the Executive Director of the Cancer Research Institute, says that the CVC has already begun to apply the new monitoring method to their clinical trials at CVC Centers in Australia, Belgium, Germany, Japan, Switzerland, the United Kingdom, and the USA. “The ability to monitor is really making a big difference to our work. We are now using a systematic, coordinated approach to vaccine development, by comparing the immunological responses produced by single vaccine variables being tested in parallel at each of our different sites. We believe that this approach will yield cancer vaccines with the greatest efficacy, and in a much shorter time than the conventional approach of trying variables sequentially with limited monitoring of responses.”
Atanackovic D, Altorki NK, Stockert E, Williamson B, Jungbluth AA, Ritter E, Santiago D, Ferrara CA, Matsuo M, Selvakumar A, Dupont B, Chen YT, Hoffman EW, Ritter G, Old LJ, Gnjatic S. Vaccine-induced CD4+ T cell responses to MAGE-3 protein in lung cancer patients. J Immunol. 2004 Mar 1;172(5):3289-96. [PMID:14978137]