http://news.bmn.com/news/story?day=030702&story=2

1 July 2003 17:00 GMT

by Hillary E. Sussman, Drug Discovery Today

A personalized, therapeutic vaccine has recently been shown to eliminate cancer in a Phase I clinical study of patients with chronic myelogenous leukemia (CML) who are also being treated with Gleevec.

Although approaches to manufacturing cancer vaccines vary and include - but are not limited to - the use of whole cells, peptides, genetically-modified tumor cells and apoptotic tumor cells, they are all geared toward the same end; namely, to stimulate the host immune system to respond to antigens characteristic of cancer cells.

Pramod Srivastava, professor of immunology and director of the Center for Immunotherapy of Cancer and Infectious Diseases at the University of Connecticut School of Medicine, believes "cancers are as unique as a fingerprint" and, therefore, the approach "has to be personalized." Srivastava is also the co-founder of Antigenics, the company that develops the research for this vaccine, designated AG858, and for other cancer vaccines based on heat shock protein technology, such as Oncophage. His data were presented in June at the American Society of Clinical Oncology Annual Meeting in Chicago, Illinois.

The Gleevec club

CML is a cancer of the blood characterized by the unchecked proliferation of transformed bone marrow stem cells. It accounts for 15-20% of all adult leukemias, with a median age of diagnosis of 50 years. Patients with CML usually progress through three phases: chronic, accelerated and blast crisis. Most patients are diagnosed by a routine blood test in the chronic phase wherein many are asymptomatic, but after a few years patients are likely to experience fatigue, weight loss, abdominal distention, bleeding and/or night sweats due to an excess of white blood cells in the peripheral blood and bone marrow.

The leukemic cells of almost all CML patients contain the Philadelphia chromosome (Ph), an acquired mutation that is the result of a reciprocal translocation between chromosomes 9 and 22. Ph encodes the fusion gene, Bcr-Abl whose translated product is a constitutively active tyrosine kinase that drives the growth of the leukemic cells.

"CML is one of a handful of diseases where we clearly know that the immune system plays a major role in its treatment," said Brian Druker, a medical oncologist at the Oregon Health & Science University Cancer Institute in Portland, Oregon. CML can be cured by bone marrow transplantation but donor availability and patient age limits the number of patients who are eligible.

Interferon-alpha and chemotherapeutic agents are also used to treat CML but since 2001 the treatment of choice has been Gleevec, a Bcr-Abl tyrosine kinase inhibitor. David Scheinberg, Chairman of the Molecular Pharmacology and Chemistry Program and Chief of the Leukemia Service at Memorial Sloan Kettering Cancer Center, whose group has shown that a tumor-specific, Bcr-Abl peptide-derived vaccine can elicit measurable peptide specific T-cell immune responses in CML patients notes; "While Gleevec is effective in inducing a cytogenetic remission, nearly all patients are left with minimal residual disease - a state that is ideal for exploring the use of a vaccine to clear the final cells." Druker, who was in large part responsible for the development of Gleevec, adds; "That's the whole point behind the Antigenics study... if you could figure out a way to get a patient's own immune system to help attack their leukemia you might have a much more effective treatment by adding it to the available treatments."

Heat shock-ing discovery

AG858 consists of autologous heat shock protein 70 (HSP70)-peptide complexes purified from the peripheral blood mononuclear cells of CML patients. According to Garo Armen, Chairman and CEO of Antigenics, HSPs have the role of intracellular 'schleppers' by shuttling peptides from one compartment of the cell to another. If the contents of the cell spill into the extracellular environment, during necrosis for example, HSPs send out a danger signal, basically recruiting antigen-presenting cells (APCs), such as dendritic cells (DCs), which internalize the HSP-peptide complexes. "There is evidence that when APCs take up HSPs together with the peptides they chaperone, the accompanying peptides are delivered into the antigen-processing pathways, leading to peptide presentation by major histocompatibility complex (MHC) molecules," explains Emmanuel Katsanis, associate professor of pediatrics and pathology at the Children's Research Center, University of Arizona, Tucson, who has studied tumor-derived chaperone-rich cell lysate (CRCL) and CRCL-pulsed DCs in a mouse model of CML. When DCs travel to the lymph nodes T cells recognize the antigenic peptides and are specifically activated against cancer cells bearing these peptides.

Custom cancer cure?

Armen believes that the antigenic repertoire that is bound to heat shock protein is unique to the source from which the HSP is extracted. But, "in a disease like CML where there is the same identifiable oncogene and oncoprotein target found in 100% of the cancer cells of the patients, it is possible to target nearly everyone with the disease, with one vaccine," said Scheinberg. Srivastava argues that one person's cancer is different from another person's because "as cancer cells divide, there is the generation of random diversity inherent in the process of cell division."

In the Phase I trial designed to determine the feasibility of making the vaccine, seven out of eight patients experienced cytogenetic remission following a course of eight weekly injections, demonstrating measurable reduction in leukemic cells. Two patients experienced molecular remission, indicating the elimination of cancer cells. According to Srivastava, "Molecular remission with Gleevec is extremely rare," but because these patients were not necessarily Gleevec resistant, a large, multicenter Phase II trial of AG858 in formally Gleevec-resistant patients has begun "to leave no doubt as to where the activity is coming from," he said. "If the magnitude of the response is similar to what we have observed in this trial we should be in good shape." The investigators hope to see results of the Phase II trial by the middle of 2004.

This article was originally published in Drug Discovery Today.

© Elsevier Limited 2003