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Immunostimulatory Therapies

Overview

The subject if immune surveillance as a defense against cancer has been debated since the 1950s. Knowledge of the genetic basis of cancer and immune processes has expanded significantly since that time and allowed researchers to manipulate tumor-specific characteristics as targets for the immune system. The idea of activating a specific immune response against cancer is an attractive one, and scientific research in this area is making its way into the clinic.

Mechanism Of Action

Immunostimulatory TherapiesThe immune system has developed a safety mechanism that allows it to mount appropriate responses to pathogens while maintaining tolerance to self-tissue. When this tolerance breaks down, autoimmunity occurs. The safety mechanism works by allowing only a specific subset of cells known as antigen-presenting cells (APCs) to induce an immune response by delivering two signals.

The primary signal comprises an antigen bound to a major histocom-patibility (MHC) molecule, which engages the T-cell-receptor (TCR) complex on the surface of the responding T cell. The secondary, or costimulatory, signal results when molecules on the surface of the APC interact with their ligands on the T-cell surface. These initial steps must occur to drive an immune response; the delivery of one signal without the other can result in anergy (a state of nonre-sponsiveness). In cancer, it is thought that the immune system ignores malignant cells because one or both signals are missing.

Xcellerate

Xcyte Therapies and the University of Chicago were developing Xcellerate, a cocktail of immunostimulatory antibody-coated beads, which are used to stimulate patients’ T cells ex vivo before being reinfused. Xcellerate is in Phase I/II studies for prostate cancer, multiple myeloma, and chronic lymphocytic leukemia in the United States. Xcyte technologies has eventually sold this technology to Invitrogen.

Inadequate or impaired antigen-presentation and/or the delivery of costimulatory signals appear to play a role in the failure of the immune system to detect and eradicate cancer cells. This scenario is particularly true in chronic lymphocytic leukemia, where the number of circulating T cells is reduced and those that do exist can be anergic (nonresponsive) due to the tumor burden. Xcellerate aims to overcome these problems of immune inaction by delivering such signals ex vivo. Blood is collected from the patients and sent to Xcyte Therapies’ cell manufacturing facility, where Xcellerate-activated T cells are generated by stimulation with CD3 (part of the TCR complex) and CD28 (costimulatory signal) antibody-coated beads. The product is then returned and administered in an outpatient setting.

Three clinical trials in the United States are investigating Xcellerate. A Phase I trial in hormone-refractory prostate cancer patients has been completed, and Phase I/II trials in multiple myeloma and chronic lymphocytic leukemia are ongoing.

In 2003, at ASH, researchers presented data from the Phase I/II study of Xcellerated T cells in chronic lymphocytic leukemia patients. Eleven patients received varying doses of activated T cells. There were no grade 3 or 4 infusion toxicities. Lymph node and spleen size fell by more than 50% in 10/11 patients, although this decline was not associated with a corresponding fall in circulating lymphocyte count. Further follow-up is needed to determine the clinical significance of these data.

ISF-154

ISF-154 is a personalized, cellular therapy being developed by the University of California at San Diego (UCSD) and Tragen for B-cell malignancies. It is in Phase II trials for chronic lymphocytic leukemia in the United States.

B cells are one of the three types of professional APCs, but chronic lymphocytic leukemia B cells are known to be poor at presenting antigen because of their lack of surface costimulatory molecules. In an attempt to overcome this defect and potentially induce an immune response against the malignant cells themselves, ISF-154 therapy involves collecting chronic lymphocytic leukemia cells from the patient and transducing them with CD40L, a critical molecule for T-cell activation, using a recombinant adenovirus vector. These transduced cells are then readministered to the patient.

Phase II trial data were presented at ASH in 2003. In this multidose trial, seven patients received five courses of 3  —  6 x 108 ISF-154 transduced cells given at two-week intervals, and trial endpoints aimed to evaluate safety and relative tumor load reduction. All patients had intermediate -or high-risk disease classified by the modified Rai system. Six of seven patients received all five courses of therapy; one patient withdrew after suffering grade II adverse events consisting primarily of flu-like symptoms after the second course of therapy. All patients (7/7) responded to therapy, experiencing transient falls in B-cell counts and lymph node size reductions of more than 50%. Durable responses were achieved in 5/6 patients who received all five courses of therapy. Two of these five patients achieved a PR; a third patient’s disease declined progressively over six months as the circulating B-cell count fell by 60% following the last infusion.

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