Philip O. Livingston, MD

Tumor cells can be killed in the test tube and in mice by antibody or T cell mediated mechanisms. We have focused on optimiziation of vaccines that induce antibody responses.

Vaccines that Induce Antibodies

A large-scale immunohistology screen was performed to identify the dominant cell-surface antigens expressed by common human cancers; and a series of studies was conducted in mice and in patients to identify the most-potent vaccines for inducing antibodies against these antigens. In every case, the best antibody response was induced by covalently linking antigen to the large carrier molecule keyhole limpet hemocyanin (KLH), which is obtained from the keyhole limpet, a mollusk. The optimal adjuvants in each case were purified saponin fractions or semisynthetic saponins, all derived from the bark of a South American tree. These vaccines have induced consistent antibodies against a series of cell-surface carbohydrate and protein antigens. These include GM2, GD2, GD3, fucosyl GM1 and sialyl Lewis a (also known as CA19.9) gangliosides, the neutral glycolipid globo H, blood-group-related antigens Tn, sialyl Tn, and Thompson Friedenreich antigen (TF), and mucin 1 (MUC1). Recently, these individual monovalent vaccines have been combined into polyvalent vaccines containing three to seven different conjugates. A series of phase II trials in patients with melanoma, neuroblastoma, small cell lung cancer, ovarian cancer, and breast cancer were designed to determine whether vaccine-induced antibodies against multiple cell-surface antigens are able to prolong disease-free survival and overall survival after surgical resection or chemotherapeutic response of all known disease. Multicenter randomized trials in ovarian cancers in second complete remission and stage IV sarcoma patients postsurgical resection were initiated in 2010 by the Gynecologic Oncology Group and MabVax Therapeutics, respectively. Smaller trials in patients with small cell lung cancer and neuroblastoma were also initiated at Memorial Sloan-Kettering Cancer Center in 2010, and a phase II trial comparing chemotherapy alone to chemotherapy plus vaccine in breast cancer patients with measurable disease is scheduled to begin in the first half of 2011. The vaccines for these trials were prepared by Govind Ragupathi of the Clinical Grade Production Facility.

Projects

• Investigations into class, subclass, and functional characteristics of polyvalent vaccine-induced antibodies over time with repeated vaccinations as well as into the correlation of these responses to clinical outcome is under way in laboratories at this center and at MabVax Therapeutics, Inc. These sera are available for the use of investigators at this institution and elsewhere.
• Collaborating with David Gin, we are testing the adjuvant potency of a series of synthetic saponin molecules with the intent of preparing a more stable, more active and less toxic adjuvant. These studies, conducted in mice, involve a series of antigens ranging from carbohydrate and peptide cancer antigens to malarial and other infectious disease antigens.
• Collaborating with Samuel Danishefsky, we are testing a series of unimolecular polyvalent antigen constructs. A clinical trial with the initial unimolecular polyvalent construct was initiated in ovarian cancer patients in 2010.

Vaccines that Induce T-cell Immunity

CA-125 (MUC16) and PSMA are the major cell surface glycoproteins of ovarian cancers and prostate cancer (respectively). These were initially cloned at this Center. We are exploring a variety of approaches in the mouse to increasing the antibody, CD8 and CD4 T cell responses to these glycoproteins. These include comparing the impact of peptides and proteins mixed with different adjuvants or conjugated to different carrier proteins and DNA vaccines. DNA vaccine followed by protein vaccine prime/boost combinations will be tested. The antibody response is measured in ELISA, FACS, and cytotoxicity assays. T cell responses are tested in ELISPOT and intracellular cytokine assays. Clinical trials should commence late in 2007.

Projects

• Impact of different adjuvant combinations or conjugation to carrier proteins on immune response to MUC16 and PSMA peptide and protein vaccines.
• Impact of hybridization with different carrier proteins or electroporation on response to DNA vaccines.
• Impact of different prime/boost combinations on antibody and T cell responses.