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Augmented HER-2–Specific Immunity during Treatment with Trastuzumab and Chemotherapy

Authors' Affiliations: Departments of ¹ Microbiology and Medicine and ² Pathology, College of Physicians and Surgeons and ³ Department of Biostatistics, Mailman School of Public Health, Columbia University; ⁴ Division of Hematology/Oncology, Department of Medicine, Weill Cornell University Medical Center, New York, New York; ⁵ Department of Medicine, University of California at Los Angeles School of Medicine, Los Angeles, California; and ⁶ Department of Immunology, Mayo Clinic, Rochester, Minnesota

Requests for reprints: Raphael Clynes, Departments of Microbiology and Medicine, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY 10027-6902. Phone: 212-305-5289; Fax: 212-305-1392; E-mail: rc645{at}columbia.edu.

Purpose: Passive immunotherapy with antitumor antibodies has the potential to induce active tumor immunity via the opsonic enhancement of immunogenicity of tumor antigen. We have assessed whether immune sensitization to the HER-2/neu tumor antigen occurs during treatment with the anti-HER-2/neu monoclonal antibody trastuzumab.

Experimental Design: Twenty-seven patients treated with trastuzumab and chemotherapy were assessed for the induction of HER-2/neu–specific immunity. Sera and peripheral blood mononuclear cells obtained before and after trastuzumab therapy were compared for the presence of anti-HER-2/neu endogenous Ig antibodies and HER-2/neu–specific CD4 responses by ELISA and enzyme-linked immunospot, respectively.

Results: Anti-HER-2/neu antibodies were detectable in 8 of 27 (29%) patients before trastuzumab treatment and in 15 of 27 (56%) patients during trastuzumab treatment. In the overall study population, anti-HER-2/neu humoral responses significantly increased during therapy (P < 0.001) and were not associated with development of an anti-idiotypic response. In 10 evaluable individuals, 6 showed augmented HER-2/neu–specific CD4 T-cell responses during therapy. Of the 22 individuals treated for metastatic disease, those patients showing objective clinical responses exhibited more frequent (P = 0.004) and larger (P = 0.006) treatment-associated anti-HER-2/neu humoral responses.

Conclusion: Humoral immune sensitization occurs during treatment with chemotherapy and trastuzumab. Further studies are warranted to investigate whether augmented anti-HER-2/neu humoral and cellular immunity contributes mechanistically to clinical outcome.

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