Induction of Active Immunity in Cancer Patients Undergoing Passive Immunotherapy with Antitumor Antibodies

Raphael Clynes, M.D., Ph.D.

Columbia University

Funded in June, 2007: $600000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY .

LAY SUMMARY

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Does Anti-Tumor Antibody Treatment Improve Immune Responses and Outcomes of Breast Cancer?

This consortium will determine whether improved clinical outcomes in patients with HER-2 breast cancer is correlated with strengthened immune CD4 T responses produced by monoclonal antibody treatment (Trastuzumab).

Anti-tumor antibody treatments have improved clinical outcomes for breast cancer and lymphoma patients. Researchers have thought that the monoclonal antibody breast cancer treatment Trastuzumab works by interfering with processes that regulate tumor growth. Animal model studies suggest that anti-tumor antibodies prevent tumor growth by inducing anti-tumor immune responses, but evidence of this has been lacking in human patients. Preliminary patient data from the collaborating investigators suggests this may be the case; those patients who experience a strong therapeutic effect from Trastuzumab are those who are developing their own antibody immune response to the target HER-2.

They now will determine whether Trastuzumab treatment induces significantly greater immune CD4 T cell responses and is associated with better clinical outcomes. They also will determine which innate immune cells stimulate the strengthened CD4 T cell attacks. Columbia and University of Miami researchers will enroll study participants.  Even though the approximately 50 patients entered into the study will be treated with standard-of-care therapies in addition to Trastuzumab, the study is designed specifically to assess Trastuzumab’s effects. University of Miami and Columbia will provide the clinical testing resources, Mayo researchers will assess CD4 T cell responses, and Columbia researchers will study the antibody responses and the role of innate immune cells.

Significance:  The study may provide direct evidence in breast cancer patients of immune responses stimulated by Trastuzumab, facilitating development of newer combination therapies designed to further strengthen these immune responses.

ABSTRACT

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Induction of Active Immunity in Cancer Patients Undergoing Passive Immunotherapy with Antitumor Antibodies

The therapeutic mechanism(s) of Trastuzumab alone, or in combination with chemotherapies are unknown.  Our preliminary studies demonstrate that HER-2 specific humoral immunity occurs commonly in Trastuzumab-treated patients and that the appearance of HER-2 humoral immunity occurs more commonly in clinically responding patients.  Importantly, we have shown in a small series of patients that concomitant CD4 HER-2 specific responses are also induced, and the principal goal of this proposed study is to determine the magnitude and breadth of these responses and to determine whether immunological CD4 responsiveness correlates positively with favorable clinical outcomes.  We will further address whether this association is causal rather than being merely a marker of tumor responses, by determining whether patients with favorable high affinity FcgR polymorphs are more likely develop both clinical and immunological responsiveness.

INVESTIGATOR BIOGRAPHIES

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Raphael Clynes, M.D., Ph.D.

Dr. Raphael Clynes is an Assistant Professor in Medicine and Microbiology at Columbia University, College of Physicians and Surgeons, and an Attending Physician in Medical Oncology at Columbia-Presbyterian Hospital. He received his M.D./Ph.D. at SUNY Stony Brook and trained in Internal Medicine at Washington University and in Medical Hematology/Oncology at Memorial Sloan-Kettering Cancer Center. He has a longstanding interest in antitumor antibodies, having defined the required role of Fc receptor engagement in the laboratory of Jefffey Ravetch at the Rockefeller University. His work at Columbia University continues to investigate the protective immunological mechanisms of antitumor antibody therapeutics.

Dr. Keith L. Knutson is currently an Assistant Professor in the Department of Immunology at the Mayo Clinic.  He received his Ph.D. from the University of Georgia in Physiology and Pharmacology in 1995 and completed two post-doctoral fellowships in immunology, one at the University of British Columbia and the other at the University of Washington.  Dr. Knutson’s current interests and research focuses on the immunology and immunotherapy of breast and ovarian cancers, in both the basic immunobiology and clinical translation, including clinical trials. 

The laboratory conducts research on cancer vaccines focuses on augmenting CD4 “helper” T cell immunity using peptide epitopes.  These vaccine strategies are aimed at preventing the patients from relapsing after optimal conventional therapies.  Adoptive T cell therapy is also being examined, a strategy that involves infusing high numbers of T cells into patients with active bulky malignancy.  Work in the lab important to adoptive T cell therapy includes methods of T cell expansion and in vitro generation of memory T cells.  Lastly, research is also aimed at understanding how tumors evade the immune system. A number of different mechanisms and several areas of immune escape are being investigated including cellular reprogramming and recruitment of regulatory T cells into the tumor microenvironment. 

Dr. Pegram received his M.D. degree from the University of North Carolina at Chapel Hill in 1986. He went on to complete an internship and residency in Internal Medicine at University of Texas Southwestern Medical School at Dallas, and a Fellowship in Hematology/Oncology at UCLA School of Medicine in Los Angeles, California, where he studied HER2 activity and therapies targeting HER2 for the treatment of breast cancer under Dr. Dennis Slamon. In 1993 he joined the faculty of UCLA as an Assistant Professor of Medicine; in 1999 he was promoted to Associate Professor and in 2005 to Professor of Medicine. From 2001 to 2007 he served as Director of the Women’s Cancer Program Area at UCLA Jonsson Comprehensive Cancer Center.  Dr. Pegram was a co-investigator on the trials that yielded Herceptin, the first FDA approved targeted therapy for use in early stage HER-2 positive breast cancers.

Dr. Pegram recently moved to the University of Miami’s Sylvester Comprehensive Cancer Center, where he works to coordinate efforts with the Braman Family Breast Cancer Institute with the goal of integrating basic science and clinical research to rapidly introduce clinical application of scientific advances.  Dr. Pegram’s specific research interests are focused on new understanding of the HER2/neu receptor and pathway in breast cancer and on identifying new drugs to block the pathway for improved outcomes in HER2+ disease.