Lloyd J. Old, MD, Father of Modern Tumor Immunology, Dies at 78 of Prostate Cancer

The Cancer Research Institute (CRI), a U.S. nonprofit organization dedicated to transforming cancer patient care by supporting and coordinating global research in tumor immunology, announced today that CRI founding scientific and medical director Lloyd J. Old, MD, regarded as the “Father of Modern Tumor Immunology,” died early this morning at his home in New York City from prostate cancer. He was 78 years old. 

Dr. Old is internationally recognized as one of the founders and standard-bearers of the field of tumor immunology, the study of the interaction between cancer and the immune system. Nearly every major advance, scientist, and research program in the field can somehow trace its lineage back to him, either through his discoveries, his mentorship, the grant programs he established through the Cancer Research Institute, the immense translational research infrastructure he built as director of the Ludwig Institute for Cancer Research, or the many other ways he worked to build and advance the field.

When Dr. Old began his research career in 1958, tumor immunology was still on the margins of scientific credibility. Today, the immune system’s role in cancer control and development is a fundamental component of the modern cancer paradigm, and nearly every major biomedical research institute or academic medical center around the world has a dedicated research or training program in cancer immunology or cancer immunotherapy. Over the past two years, with the approvals of the first therapeutic cancer vaccine, Provenge®, in 2010 for advanced prostate cancer and of the immunotherapy Yervoy™ for advanced melanoma in 2011, cancer immunotherapy is starting to make its first solid steps into mainstream cancer treatment and is now considered to be one of the most promising cancer treatment modalities to emerge since the advent of chemotherapy in the 1940s and 1950s.

Birth and Education

Lloyd J. Old was born in San Francisco on September 23, 1933, the son of John Hans Old and Edna Marks Old. He attended public schools in Burlingame, California, a town about eight miles south of the San Francisco city limits. Although Dr. Old would eventually go into science, his first aspiration was to be a violinist. He became concertmaster of his high school orchestra and, following graduation in 1951, went to Paris to study violin with European masters. After a year in France, he returned to the United States to attend the University of California at Berkeley, where he trained and played with the Griller String Quartet, Berkeley’s resident ensemble. At Berkeley, Dr. Old’s fascination for science grew. While continuing to perform as a musician, he simultaneously began pre-med studies. He graduated Phi Beta Kappa, with a degree in biology, in three years and then attended medical school at the University of California, San Francisco.

A Passion for Cancer Research

In 1958, Dr. Old graduated first in his class from medical school, and joined Memorial Sloan-Kettering to train in tumor immunology. Shortly after, Dr. Old penned the three questions that would serve as the roadmap for the nascent field: (1) “Is there an immune reaction to cancer?; (2) “If there is, what are the targets?; and (3) “How can you stimulate that immunity?” Over the course of the next five decades, the work of Dr. Old and many others would provide experimental validation for each of the three questions, which now form the foundation for the rational design of therapeutic cancer vaccines and other targeted immunotherapies for cancer. 

“In each and every one of the six decades since the 1950s, Lloyd Old has made seminal contributions to our understanding of how the immune system interacts with cancer cells,” says James Allison, PhD, head of the immunology program at Memorial Sloan-Kettering Cancer Center, who succeeded Dr. Old as director of the Cancer Research Institute Scientific Advisory Council on October 1, 2011.

Pioneer in Immunotherapy for Cancer

Shortly after joining Sloan-Kettering, Dr. Old began a collaboration with Baruj Benacerraf, MD, who would go on to share the 1980 Nobel Prize in Physiology or Medicine and who would later be recruited by Dr. Old to serve as a founding member of CRI’s Scientific Advisory Council, to test the cancer fighting ability of tuberculosis vaccine Bacille Calmette-Guérin (BCG). Their results, published in Nature in 1959, showed that BCG could confer protection against tumors and prolong survival times in experimental mouse models. The paper was one of the first times that the phrase “tumor immunity” appeared in the scientific literature, and it is today considered a classic in the early history of cancer immunology and one of the fountainheads for the field. BCG was approved by the FDA in 1990 and is now widely used as a first-line treatment for superficial bladder cancer.

Dr. Old then turned his attention to the search for tumor-specific antigens. In collaboration with Edward A. Boyse, MD, he identified the first cell surface markers, or antigens, that could distinguish different functional subsets of immune cells.  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. This is now known as the “cluster of differentiation,” or CD, system in humans, with the most recognized being CD8 to identify “killer” T cells, which Dr. Old discovered as Ly-B in mice, and CD4 to distinguish “helper” T cells, which has become widely known because of the role of CD4 T cells in the development and classification of HIV/AIDS. This research laid the groundwork for identifying the molecular markers on the surfaces of cells that allow them to be experimentally and diagnostically separated and distinguished, revolutionizing immunology and medicine as it is practiced today.

Dr. Old also identified the p53 protein, the gene for which is now known to be mutated in more than half of all cancers. Several other groups identified the p53 protein simultaneously, however, Dr. Old was “unequivocally the first to show that the protein was abnormally expressed in human tumors,” says Bert Vogelstein, MD, the Clayton Professor of Oncology and Pathology and Director of the Ludwig Center for Cancer Genetics and Therapeutics at the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, who clarified the tumor suppressive role of the p53 gene.

Among his scientific discoveries, Dr. Old is perhaps best known for the discovery of tumor necrosis factor (TNF), a key immune signaling molecule (cytokine) that has opened several lines of inquiry across diverse fields of science and has led to important therapies. TNF was first discovered by Dr. Old and Elizabeth Carswell, who noted its ability to cause tumors to turn black and die, or necrose. Although its promise was apparent, therapeutic advances were hampered by limits in technology and did not happen until the TNF molecule was identified, purified, and its gene cloned, in the mid-1980s—ten years after TNF’s initial discovery. “It was Dr. Old’s work that encouraged people to try to purify and clone the gene,” says Jan T. Vilcek, MD, who helped develop the anti-TNF-alpha monoclonal antibody Remicade. “If it weren’t for his leadership, the development in the field and the new knowledge that was gained after the purification and cloning of TNF would not have occurred for maybe another ten years or so.”

More recently, Dr. Old pioneered the identification and classification of cancer-testis antigens, which are providing researchers with a unique group of molecular markers for therapies that can be selectively targeted to cancer cells and not to healthy cells (except for those in the testis)—a goal that many refer to as “the holy grail” of cancer therapy. “These cancer testis antigens represent, in my view, the best opportunity for immunotherapy targets that can be selective for the cancer and that can avoid toxicity to normal tissues,” says Steven A. Rosenberg, MD, PhD, the head of tumor immunology and chief of surgery at the National Cancer Institute, who recently reported that T cells genetically engineered to recognize the NY-ESO-1 cancer-testis antigen, which Dr. Old discovered with Yao-Tseng Chen, MD, PhD, in 1997, could induce significant regressions in patients with metastatic melanoma and synovial sarcoma. In addition to their potential as targets for immunotherapy, cancer-testis antigens may prove to be highly promising targets for small molecule drugs as their precise functions become further elucidated.

A Visionary Leader

As the Cancer Research Institute’s (CRI) founding scientific and medical director, since 1971 Dr. Old helped create, build, and sustain cancer immunology on a field-wide scale. “For the past four decades Dr. Old and the Cancer Research Institute have been synonymous,” says Jill O’Donnell-Tormey, PhD, CRI’s chief executive officer and director of scientific affairs. “He has been the visionary architect who shaped CRI’s programmatic agenda and who is responsible for the respected place that the Institute now holds among the scientific and not-for-profit communities serving both as a funding source and thought leader.” 

With CRI’s establishment of the first postdoctoral fellowship program in immunology and tumor immunology in 1971, Dr. Old helped seed the field with more than 1,000 investigators to date, a great number of whom have established or are leading major cancer centers and cancer immunology programs across the world. Through initiatives such as CRI’s annual William B. Coley Award for Distinguished Research in Tumor Immunology, Dr. Old helped recognize and codify important individuals and discoveries in cancer immunology and raised the credibility and visibility of the field, and through the naming of the award raised awareness and appreciation of the history of the field and the seminal role of Dr. William B. Coley, whose daughter, Helen Coley Nauts, founded CRI in 1953.

In 2001, Dr. Old led a new partnership between the CRI and the Ludwig Institute for Cancer Research to establish the Cancer Vaccine Collaborative (CVC), which he considered his greatest accomplishment. The CVC was a manifestation of Dr. Old’s vision that, in order to understand and optimize strategies for therapeutic vaccination, single-variable clinical trials needed to be carried out to identify the approaches most likely to achieve success. These trials would be supported with world-class immunological monitoring laboratories skilled in analyzing the human immune response to cancer vaccination. To date, the CVC has conducted nearly 50 early-phase clinical trials, generated significant insights into how to enhance patient responses to therapeutic cancer vaccination, and created a network comprising 19 sites across four continents that serves as an international model for the way to marshal the efforts of both fundamental scientists as well as clinicians in order to move the field forward. A decade after the founding of the CVC, the U.S. National Cancer Institute launched in 2010 a similar program with the establishment of its Cancer Immunotherapy Trials Network, which plans to start conducting trials next year.

A Distinguished Career

Prior to his death, Dr. Old held the William E. Snee Chair of Cancer Immunology at Memorial Sloan-Kettering Cancer Center (MSKCC), where he was director of the Ludwig Institute for Cancer Research (LICR) New York Branch. He was also a trustee of the LICR Charitable Trust, and a trustee of the Virginia & D.K. Ludwig Fund for Cancer Research, which created the Ludwig Cancer network in 2006. From 1971 to 2011, he served as the founding scientific and medical director of the Cancer Research Institute, where from 2001 to 2011 he also served as director of the CRI/LICR Cancer Vaccine Collaborative (CVC).

Dr. Old was the recipient of numerous awards and honors, including the Alfred P. Sloan Award in Cancer Research, the inaugural William B. Coley Award for Discoveries in Basic and Tumor Immunology from the Cancer Research Institute, which honored him as one of the “Founders of Tumor Immunology,” the Robert Koch Prize from the Robert Koch Society, the Charles Rodolphe Brupbacher Prize for Cancer Research, and, most recently, the 2011 C. Chester Stock Award Lectureship from Memorial Sloan-Kettering Cancer Center. He was elected to the U.S. National Academy of Sciences in 1978.

Dr. Old is survived by sister, Constance Old, of New York, NY; nephews Christopher John Rowe of Ashland, OR, and Albert Holmes Rowe of Oakland, CA; niece, Letitia Rowe Maun of New York, NY; and six grandnieces and grandnephews.

In lieu of flowers, donations may be made to the Cancer Research Institute Lloyd J. Old Endowed Fellowship Fund, One Exchange Plaza, 55 Broadway, Suite 1802, New York, NY 10006; or to the Lloyd Old and Constance Old Lecture Series, “21st Century Music in Society,” The Graduate Center Foundation, City University of New York, 365 5th Avenue, New York, NY 10016.