Lloyd J. Old - Major Discoveries

Major Discoveries

His findings and achievements include:

• Introduced Bacille Calmette-Guérin (BCG), the tuberculosis vaccine, into experimental cancer research as a way to stimulate non-specific resistance to tumor growth. BCG was FDA-approved in 1991 and is now widely used as a first line treatment for superficial bladder cancer (1959).

• Discovered the first linkage between the major histocompatibility complex (MHC) and disease—mouse leukemia—opening the way for the recognition of the importance of the MHC in the immune response (1964).

• Identified the first cell surface antigens distinguishing cells of different lineages, introducing the concept of cell surface antigens that could differentiate different cell types. First coined TL (for “thymus-leukemia” antigen in mice) then later as the Ly series (originally named Ly-A and Ly-B and later called Ly-1, Ly-2, and Ly-3), this discovery led directly to the wide use of cell surface markers to distinguish and classify normal and malignant cells and the development of CD classification (for “clusters of differentiation”). Most notably, Dr. Old discovered the LY-B antigen, later renamed CD8 in humans. CD8 cells, often referred to as “killer” T cells, are one of the major cells of the adaptive immune response, and are capable of directly killing dangerous or foreign cells (1964-1968).

• Discovery of the association between Epstein-Barr Virus (EBV) and nasopharyngeal cancer (1966).

• Discovery of tumor necrosis factor (TNF), a key immune signaling molecule (cytokine) that, in addition to its promise for the treatment of cancer and other diseases, has provided a powerful research tool in biomedicine (nearly 88,000 articles in PubMed as of May 25, 2011) (1975).

• Identification (independently, along with two other groups) of the p53 protein, the gene for which is mutated in approximately 50 percent of cancers (1979).

• Conducting of the most comprehensive dissection of the cell surface of human cancers using monoclonal antibodies, with the identification of an array of cell surface antigens as targets for antibody-based therapies of human cancer. Of the monoclonal antibodies developed in Dr. Old’s laboratory, thirteen have been licensed and seven are in clinical trials. These include:
  • MORAb-003 (farletuzumab), currently in a phase III trial for ovarian cancer sponsored by Morphotek, which licensed the antibody from LICR. MORAb-003 targets the folate receptor alpha, which is overexpressed on a number of epithelial cancers, including ovarian, breast, renal, lung, colorectal and brain cancers.
  • the anti-EGFr antibody Hu806, which Abbott acquired exclusive world-wide rights to develop in a major licensing deal in 2008. Hu806 targets the overexpressed form of the epidermal growth factor receptor (EGFr) present in 50 percent of all cancers of epithelial origin.
  • cG250 (girentuximab, Rencarex®/Redectane®), which targets the CA-IX molecule/G250 antigen, expressed on over 90 percent of clear cells renal cell carcinomas (RCC, kidney cancer), and is in phase III clinical trials as a diagnostic tool and as a therapeutic modality (also iodine-131-G250).
  • hu3S193, which targets the LeY antigen, an oligosaccharide epitope expressed on glycolipids and glycoproteins by a wide range of epithelial cancers, is in phase II clinical trials being conducted by LICR spin-off company Recepta Biopharma.
  • huA33, which targets the A33 antigen present on colorectal cancer cells. The antibody has been licensed to LICR spin-off company Life Sciences Pharmaceuticals, and the mAb’s therapeutic potential is being tested as a stand-alone antibody, as a radioimmunotherapy agent, and in combination with chemotherapy.

• Establishment of the autologous typing system as the methodology leading to the identification of the first specific human tumor antigens recognized by antibodies and T cells, created 150 separate cancer cell lines, and laid the groundwork for the development of SEREX by Pfreundschuh in 1995.

• Discovery and naming of several members of the CT (cancer/testis) family of human tumor antigens, including New York-ESO-1 (NY-ESO-1). NY-ESO-1 is one of the most immunogenic human tumor antigens discovered to date and is expressed in approximately 35 percent of melanomas, 30 percent of breast cancers, 30 percent of liver cancers, 25 percent of lung cancers, less than five percent of colon cancers.

• Contribution to the resurrection of the cancer immunosurveillance hypothesis and to the development of the expanded model of cancer immunoediting.

• Establishment in 2001 of the Cancer Vaccine Collaborative (CVC), the world's first network of clinical trial sites closely linked with immunological monitoring laboratories with the goal to develop effective therapeutic cancer vaccines by first understanding the fundamental immunological implications of vaccination and applying that knowledge toward the rational design of optimal vaccine formulations. A joint program of the Cancer Research Institute and the Ludwig Institute for Cancer Research, the CVC conducts parallel, early phase, single variable clinical trials of various cancer vaccine formulations and combinations composed of cancer-specific antigen, immunological adjuvant, vaccine delivery platforms, and modulators of immune suppression.