When No Response Is a Good Thing

An immuntoxin homes to a cancer cell by way of a surface-specific antibody (blue) and, once there, the immunotoxin gets taken inside where it can deliver a lethal blow to the cell.

An immuntoxin homes to a cancer cell by way of a surface-specific antibody (blue) and, once there, the immunotoxin gets taken inside where it can deliver a lethal blow to the cell.

Custom-designed therapies that target cell-surface antigens or receptors represent a promising immunological approach in cancer therapy. Antibodies that bind these targets are the starting point.  Potent toxins can then be added to them by fusing antibody fragments to powerful bacterial toxins such as Pseudomonas exotoxin (PE). This recombinant immunotoxin combines antibody selectivity with toxin cell-killing potency.

PE–based immunotoxins have triggered effective antitumor responses in clinical trials, but they also trigger immune reactivity to the PE component, causing patients’ immune systems to generate neutralizing antibodies long before they can receive the full series of immunotoxin doses needed for optimal anticancer effects. In fact, in clinical trials evaluating the antimesothelin PE recombinant immunotoxin called SS1P, many patients began to produce neutralizing anti-SS1P antibodies after only one round of immunotherapy. This is the bad news.

The good news is that, Miriam Mossoba, Ph.D., and Massanori Onda, Ph.D., working with Daniel Fowler, M.D., in CCR’s Experimental Transplantation and Immunology Branch and Ira Pastan, M.D., Chief of CCR’s Laboratory of Molecular Biology, have found an induction chemotherapy regimen that can overcome this therapeutic obstacle. They recently published their findings in Clinical Cancer Research.

Induction chemotherapy is sometimes necessary during a patient’s medical care.  It is treatment designed to prevent a response from a patient’s immune system for a brief critical time period, such as when a patient is receiving a transplanted organ.

Working in mice, the team found that induction chemotherapy using pentostatin plus cyclophosphamide (PC) at the correct intensity could safely and completely stop the animals from producing anti-SS1P neutralizing antibodies.  This made it possible to deliver weekly repeated doses of SS1P. 

Mice in the control group received no induction therapy and uniformly developed anti-SS1P antibodies after the third recombinant immunotoxin exposure. 
Experimental groups of mice received PC induction chemotherapy prior to their initial exposure to SS1P; some groups received further PC maintenance therapy of varying intensities just prior to each weekly SS1P injection.

PC induction therapy reduced the frequency of mice with circulating anti-SS1P antibodies. PC induction therapy followed by intensive maintenance PC therapy worked best: nearly 100 percent of recipients who received this regimen were free of anti-SS1P antibodies after 9 weeks of receiving recombinant immunotoxin doses. This most effective PC regimen caused B-cell depletion, moderate T-cell depletion, and minimal myeloid cell depletion in the mice.

Induction and maintenance PC chemotherapy safely prevented anti-immunotoxin antibody formation in mice. These data suggest that, in patients,  immunotoxin therapy might be used in combination with pentostatin plus cyclophosphamide chemotherapy to improve the targeted therapy of cancer.

Summary Posted: 06/2011

Reference

Reviewed by Donna Kerrigan PubMed Link