Cancer Immunity 12:9 (2012)

When Dr. Lloyd J. Old referred to the goals and objectives of his laboratory of Human Cancer Immunology, he typically just said, “A major objective of the laboratory is the identification of suitable targets for cancer immunotherapy with monoclonal antibodies and vaccines.” This key objective remained unchanged for more than three decades, and I think I have referred to this sentence uncountable times in our scientific reports, in grant applications, in manuscripts, presentations, or in just talking about the laboratory. What at a first glance apparently seems a “simple” and “narrow” objective actually perfectly describes his quest for understanding the immune system and utilizing its enormous power to control cancer. This sentence is rooted in the four key questions of cancer immunology that Lloyd Old outlined when he began to consider entering this field in 1958 and that he continued asking throughout his entire life: 1. Does the immune system recognize cancer as foreign? 2. What are the targets of recognition? 3. Does immune recognition lead to tumor protection? 4. How can immune protection be strengthened? He had a lifelong fascination with the extraordinary power of the immune system to make the finest distinctions between molecules (antigens) and thus potentially between normal cells and cancer cells. In the 1970s and 1980s, this power of distinction was most inherent in antibodies, which could do so quickly and with great sensitivity. Based on this idea, his laboratory developed during this time potent serological tools to identify molecules on cancer cells that could be recognized by antibodies and began the challenging process of characterizing and dissecting the antigenic systems on the cellular, tissue, and molecular level. The principle of his approach was “let the immune system decide what antigen it would recognize on a tumor cell and then carefully analyze the immune response and find those antibodies that show selective reactivity with tumors.” Practically, this meant that mice were immunized with tumor cells, monoclonal antibodies (mAbs) were generated from the immunized mice, and the mAbs were then subjected to elaborate screening for reactivity with the cell surface of a broad range of living tumor cells. Using this approach, a huge panel of antibodies and antigenic targets was identified for a large variety of solid tumors, the tumor stroma, and tumor endothelium. The antibodies with the highest selectivity for cancer were then prepared and studied in early-phase clinical trials in cancer patients. For an antigenic system to become really exciting, a high degree of specificity was of utmost importance to Lloyd Old, and his quest for specificity became legendary. More then a dozen of these antibodies have been licensed by large and small pharmaceutical companies and are in various stages of clinical development for the treatment of patients with cancer. This is unrivaled for a single academic laboratory, and when this success was to be pointed out by someone, quite atypical for him, he could not resist occasionally showing some pride in his unique and industrious “academic biotech” approach. How did I get involved in Lloyd Old’s antibody program? For me, it all began with a phone call. One evening in early fall of 1993, my phone rang at my then home in Italy. The caller did not identify himself initially but just said “Hello” in a very unmistakable intonation. I had not really talked with Lloyd Old since I left his and Herbert Oettgen’s laboratory at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York about three years earlier to pursue an exciting scientific endeavor in Italy. But in an instant I knew who was on the other side, playing one of his little phone games by trying to coax the person he called to guess who would be on the line. At that time, he called to invite me to come back to New York and join his just three year old unit (later the New York Branch) of the Ludwig Institute for Cancer Research (LICR) at MSKCC to pursue research in antigen-specific cancer immunotherapy. And involved I got, hands-on from day one in the purification of a humanized antibody (huA33) for the first clinical trials in patients with colon cancer. But more about this antibody later. Lloyd Old loved a good one-liner, idiom, proverb, or pun. He drew on them frequently and sporadically repeated them in a mantra-like fashion to underscore or illustrate a key point, bring out the quintessence of a topic, or just help an audience better remember or connect a scientific or historical fact or view. He made use of them to hold up a mirror or courteously tease himself or the team, but also occasionally to convey what seemed absurd or bizarre to him as it presented an unnecessary hurdle to a development path that was so straightforward to him but took years for others to comprehend. There are still many of these one-liners and the topic they are associated with that come into my mind, several of them uttered many years ago—but these are the memories a fine teacher and mentor leaves you with. Hence, I selected a few that I personally associate with him and his vision and stewardship of the targeted antibody cancer