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Pentostatin plus cyclophosphamide safely and effectively prevents immunotoxin immunogenicity in murine hosts.

ABSTRACT: PURPOSE: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. EXPERIMENTAL DESIGN: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.

SUBMITTER: Mossoba ME

PROVIDER: S-EPMC3107891 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Pentostatin plus cyclophosphamide safely and effectively prevents immunotoxin immunogenicity in murine hosts.

Mossoba Miriam E ME Onda Masanori M Taylor Justin J Massey Paul R PR Treadwell Shirin S Sharon Elad E Hassan Raffit R Pastan Ira I Fowler Daniel H DH

Clinical cancer research : an official journal of the American Association for Cancer Research 20110426 11

<h4>Purpose</h4>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.<h4>Experimental design</h4>BALB/c hosts were injected weekly with recombinant immuno ...[more]

PMID: 21521777

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Dataset Information

Pentostatin plus cyclophosphamide safely and effectively prevents immunotoxin immunogenicity in murine hosts.

Publications

Pentostatin plus cyclophosphamide safely and effectively prevents immunotoxin immunogenicity in murine hosts.

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