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At Broadways Hudson Theater this week, more than 400 scientists from around the world assembled to present the multitude of findings -- and frustrations -- that have marked the last few years of cancer vaccine research. Symposium chairman Dr. Old, director of the Ludwig Institute for Cancer Research and the Cancer Research Institutes Scientific Advisory Council, opened the discussion by depicting the tremendous progress that has been achieved since Cancer Vaccines 1994, the inaugural conference of the Cancer Research Institutes annual Cancer Immunotherapy International Symposium series.

That meeting two years ago represented a landmark in the history of tumor immunology, celebrating the transition of the field from its initial phenomenological origins, to the refounding of the field on the solid base of structural information about tumor antigens, said Dr. Old.

In particular, Dr. Old emphasized what would prove to be a theme for the talks -- identification of tumor antigens and the profound impact this has had on the field of cancer immunology. Antigens -- molecules produced and presented by cancer cells -- serve as targets for immune destruction, and so have long been viewed as the potential basis for therapeutic vaccines that could jumpstart the immune system. But scientists needed to structurally identify these antigens before they could test this theory.

Identification of Tumor Antigens

It was just a few years ago, however, that Ludwig Institutes Dr. Thierry Boon, the symposiums first lecturer, identified and sequenced a tumor antigen. Since then, he has used the genetic-based approach he developed to clone several more antigens that can potentially serve as immunotherapeutic targets. More recently, Dr. Michael Pfreundschuh, of the Universitat des Saarlandes in Germany, created an alternative method called SEREX (Serological Analysis of Recombinantly Expressed Clones), with which he has successfully isolated additional immunogenic peptides.

This is just the first glance through the serological looking-glass, said Dr. Pfreundschuh, one which may well lead to clinically successful immunotherapy for a wide spectrum of cancers, he said.

Dr. Pramod Srivastava, of Fordham University, has taken a different path to probing what he called the vast and variable repertoire of human antigens. He has discovered that a group of proteins -- called heat shock proteins (HSPs) -- act as antigen chaperones, picking up cellular peptides and delivering them to MHC molecules for presentation on the cell surface. Because a given HSP binds with several different antigens, the HSP-antigen complex can serve as a polyvalent vaccine, thus providing one means of dealing with the challenge of immune escape -- the cancer cells tactics for evading the immune response.

Principles of Immune Recognition and Effector Functions

The second day of the meeting focused on ways to augment and track the immune systems attack on cancer cells. In the past, most research has concentrated on mediating the response of cytotoxic T cells (CTLs), which target and eliminate specific antigens. But Dr. Phillipa Marrack, of the National Jewish Center for Immunology and Respiratory Medicine in Denver, admonished her audience of the critical importance of eliciting helper T cells, which transmit the growth signals that sustain CTLs.

This sentiment was underscored by several speakers, including University of Washington researcher Dr. Philip Greenberg. He had isolated CTLs from a patient with cytomegalovirus, cloned them, and administered them to 14 CMV patients -- preventing recurrence of the disease in all of them. But he found that unless his patients began to produce their own helper T cells, their adopted CTLs all disappeared within a few weeks. Dr. Greenberg is now genetically modifying CTLs to enable them to survive without the stimulus of helper-T-cells.

Construction & Testing of Tumor Vaccines

The critical question -- how to apply these findings toward the construction of tumor vaccines -- loomed large in everyones minds, and on the final day of the conference, several speakers provided answers. Dr. Steven Rosenberg, of the National Cancer Institute, who pioneered the use of tumor infiltrating lymphocytes (TIL) in identifying the antigens displayed by tumor cells, is now conducting several clinical trials using the genes that encode these antigens as the basis for his therapeutic vaccines. In patients who receive IL-2 -- a cytokine whose only function is to stimulate the immune system -- 20% see even bulky tumors shrink and then disappear altogether, said Rosenberg. This shows me that the immune system can reject large tumors. The question is how?

Several other speakers, including Dr. Alexander Knuth, from Krankenhaus Nordwest in Germany, and Dr. Craig Slingluff, of the University of Virginia, described their current clinical trials testing the efficacy of peptide-based vaccines in the treatment of metastatic melanoma. Pittsburgh Cancer Institute researcher Dr. John Kirkwood, on the other hand, is currently accruing 851 patients for the trial of a vaccine that uses GM2, a carbohydrate, rather than a peptide, antigen. This is the largest specific vaccination trial ever, he said.

The final speaker of the symposium, Johns Hopkins researcher Dr. Drew Pardoll, described his creation of a tumor cell vaccine genetically modified to secrete GM-CSF, a cytokine. GM-CSF attracts antigen-presenting cells to come to the tumor site, picking up and presenting antigens far more efficiently than the tumor cells themselves. Dr. Pardoll administered a random double-blinded trial of Stage IV renal cancer patients, and has seen positive clinical responses, including inflammation and infiltration of immune cells at the injection site, in subjects who received the GM-CSF transduced vaccine.

Dr. Pardoll concluded by summarizing the advances and challenges that had come out of Cancer Vaccines 1996. We have been presented with so much good science, he said, and although in many areas there is no consensus, it is a healthy lack of consensus. We have seen how rapidly the field is evolving. We have the power to manipulate the immune system -- and we are learning how to wield this power.

The Cancer Research Institute supports leading-edge research based on the premise that the human immune system is capable of fighting, and winning, the battle against cancer. The Institute was founded in 1953. Since that time it has provided funding for more than 700 scientists around the world who have contributed to achieving the goal of mobilizing the immune system against cancer.

CONTACT: Cancer Research Institute, New York Brian Quinn, 212/688-7515

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