title: Pentostatin plus cyclophosphamide safely and effectively prevents immunotoxin immunogenicity in murine hosts.
abstract: OBJECTIVE
  The success of immunotoxin therapy of cancer is limited by host production of neutralizing antibodies, which are directed toward the Pseudomonas exotoxin A (PE) component. In this proof-of-principle study using a well-established murine model, we hypothesized that a newly developed immune depletion regimen consisting of pentostatin plus cyclophosphamide would abrogate anti-immunotoxin reactivity.
  
  
  METHODS
  BALB/c hosts were injected weekly with recombinant immunotoxin (RIT) SS1P, which is an antimesothelin Fv antibody fragment genetically fused to a 38 kDa portion of PE, and has been evaluated in clinical trials. Experimental cohorts received induction chemotherapy consisting of pentostatin (P) plus cyclophosphamide (C) prior to initial RIT exposure; some cohorts received further maintenance PC therapy of varying intensity just prior to each weekly RIT challenge. Cohorts were monitored for T, B, myeloid cell depletion, and for total anti-SS1P antibody (Ab) formation.
  
  
  RESULTS
  Controls uniformly developed anti-SS1P Ab after the third RIT exposure. Induction PC therapy reduced the frequency of hosts with anti-SS1P Ab. Abrogation of antibody generation was improved by maintenance PC therapy: nearly 100% of recipients of intensive PC maintenance were free of anti-SS1P Ab after 9 weekly RIT doses. The most effective PC regimen yielded the greatest degree of host B-cell depletion, moderate T-cell depletion, and minimal myeloid cell depletion.
  
  
  CONCLUSIONS
  Induction and maintenance PC chemotherapy safely prevented anti-immunotoxin antibody formation with uniform efficacy. These data suggest that immunotoxin therapy might be used in combination with pentostatin plus cyclophosphamide chemotherapy to improve the targeted therapy of cancer.
authors.affiliation: Center for Cancer Research, National Institutes of Health, Experimental Transplantation and Immunology Branch, and Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Miriam E
authors.initials: ME
authors.lastname: Mossoba
authors.forename: Masanori
authors.initials: M
authors.lastname: Onda
authors.forename: Justin
authors.initials: J
authors.lastname: Taylor
authors.forename: Paul R
authors.initials: PR
authors.lastname: Massey
authors.forename: Shirin
authors.initials: S
authors.lastname: Treadwell
authors.forename: Elad
authors.initials: E
authors.lastname: Sharon
authors.forename: Raffit
authors.initials: R
authors.lastname: Hassan
authors.forename: Ira
authors.initials: I
authors.lastname: Pastan
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Fowler
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology*; D057134:Antibodies, Neutralizing; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000276:immunology; D003520:Cyclophosphamide / Q000009:adverse effects / Q000494:pharmacology*; D055808:Drug Discovery; D004797:Enzyme-Linked Immunosorbent Assay; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology; D015649:Pentostatin / Q000009:adverse effects / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000970:Antineoplastic Agents; D001426:Bacterial Proteins; C474515:SS1(dsFv)PE38; C111749:pseudomonas exoprotein A protein, Pseudomonas aeruginosa; D015649:Pentostatin; D003520:Cyclophosphamide