Review
Immunotoxins in cancer therapy

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Abstract

Immunotoxins are composed of a protein toxin connected to a binding ligand such as an antibody or growth factor. These molecules bind to surface antigens (which internalize) and kill cells by catalytic inhibition of protein synthesis within the cell cytosol. Immunotoxins have recently been tested clinically in hematologic malignancies and solid tumors and have demonstrated potent clinical efficacy in patients with malignant diseases that are refractory to surgery, radiation therapy and chemotherapy — the traditional modalities of cancer treatment. This therapy is thus evolving into a separate modality of cancer treatment, capable of rationally targeting cells on the basis of surface markers. Efforts are underway to obviate impediments to clinical efficacy, including immunogenicity and toxicity to normal tissues. Immunotoxins are now being developed to new antigens for the treatment of cancer.

Introduction

It has been estimated that — in the year 1999 — 1,228,000 people in the US will be diagnosed with invasive cancer and 564,800 people are expected to die of it [1]. Treatment of cancer classically consisted of surgery, radiation therapy and chemotherapy — the latter having had the sole task of treating widespread disease that usually afflicts the dying cancer patient. The success of chemotherapy requires the malignant cells to be sensitive by virtue of intracellular metabolic processes or growth rates that are different from those of normal cells.

Section snippets

A different modality for cancer treatment

Human cancer is becoming more definable by surface proteins displayed on the malignant cell surface. Targeting cells selectively via these surface proteins is inherently different from surgery, radiation and chemotherapy and is often considered a new modality for cancer therapy. Targeted therapy can be accomplished by using monoclonal antibodies (MAbs) alone or MAbs armed with radionuclides or toxins. The Food and Drugs Administration (FDA) recently approved the MAbs Rituximab and Herceptin,

Immunotoxins targeting hematologic tumors

Hematologic malignancies are easier to target than solid tumors for many reasons, including easy access of the immunotoxin to intravascular tumor cells and improved penetration of lymphomatous tumor cells without tight junctions. Moreover, fresh cells may be easily tested for immunotoxin binding and cytotoxic activity. Immunotoxins have also been developed for indirect treatment of malignancies by their killing of T cells that mediate graft-versus-host disease (GVHD) in the setting of

Solid tumors

The treatment of solid tumors with immunotoxins is challenging due to tight junctions between tumor cells, high interstitial pressure within tumors and heterogeneous blood supply [46]. As described below, to deal with these obstacles some immunotoxins are being administered locally to solid tumors. Nevertheless, some systemically administered immunotoxins have recently shown efficacy in patients with solid tumors.

Targeting tumors in the central nervous system

Since the transferrin receptor (TfR) is expressed on tumor and normal hepatic cells but not in normal brain, several trials have targeted anti-TfR immunotoxins to brain tumors. The conjugate 454A12–rRA — composed of an anti-TfR MAb, 454A12, and recombinant ricin A chain — was used for intraventricular therapy of patients with leptomeningeal cancer and cleared > 50% of the malignant cells from the cerebrospinal fluid (CSF) in half of the patients [54]. These same investigators have also targeted

Immunogenicity

Although durable partial and even complete responses have resulted from one cycle of immunotoxin therapy, immunogenicity is considered a major barrier to the clinical utility of chimeric toxins. Table 1 includes immunogenicity data from recent clinical trials, indicating that patients with solid tumors become immunized much more readily that those with hematologic tumors. Some hematologic tumors may be associated with less immunogenicity than others. None of 14 patients with chronic lymphocytic

Conclusions

Chimeric toxins have become a new modality for the treatment of cancer. Despite difficulties with immunogenicity, toxicity to normal tissues and limitations in tumor penetration, they are unique in their ability to rationally target tumor cells via cell surface receptors. The ability to kill a cell with only one or a few molecules of toxin in the cytoplasm permits successful targeting of cells displaying only a limited number of antigen molecules. Several immunotoxins can target cells mediating

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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