Cancer Immunity 12:7 (2012)

The first time I met Lloyd Old was in late 1976, several weeks after I had started a fellowship at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York City. With the adventure of experiencing life in New York City as my major goal, I had come to MSKCC without clearly defined plans, only with a vague idea to study immunology in the context of the pathogenesis and therapy of cancer. The idea to employ immunology for the diagnosis and treatment of cancer was not widespread at that time in clinical medicine when densitygradient isolation of peripheral blood mononuclear cells by Ficoll-Hypaque was just introduced and T lymphocytes were defined by forming rosettes with sheep erythrocytes. As an M.D., I wanted to study human tumor immunology and, to this end, the lab of Bob Good, who at that time was president of MSKCC, seemed to be the appropriate place. Meanwhile, the lab of MSKCC’s vice president Lloyd Old had the reputation to be not very profitable for foreign fellows because it was well known that a publication (without which you would not dare return to Europe) with Dr. Old would take years and was not achievable without the sacrifice of late hours and work during the weekends. While the latter did not deter me, it was the fact that Dr. Old’s reputation was based on his excellent work on tumor immunology in the mouse that made me hesitate when Herbert Oettgen invited me to join Dr. Old’s group. I eventually accepted when Dr. Oettgen told me that I could work on a project on human tumor immunology without any “mouse work.” Dr. Old, together with Tom Carey and Toshitada Takahashi, had just published their Proceedings of the National Academy of Sciences paper in which they described for the first time antibody reactivity in the serum of a patient with melanoma that recognized a tumor-specific antigen on the surface of cultured melanoma cells. This was the first convincing evidence that a serological immune response existed in patients with malignant tumors against antigens expressed on the surface of the tumor cells (1). A second paper with Hiroshi Shiku as the first author was under way, where additional surface antigens on human malignant melanoma cells were described (2). The specificity of the observed reactions was characterized by absorption studies with a wide range of malignant and benign cell lines. “Autologous typing”—the immunological characterization of a tumor by means of its reactivity with antibodies in the serum of the autologous patient, i.e., the patient from which the tumor under study was derived—was thus born. These two papers signified a new era in human tumor immunology and called for expansion. We all knew that melanoma was special with respect to the immunobiological relationship between the tumor and the tumor-bearing patient because there was no other malignancy associated with such a prevalence of autoimmune phenomena and a comparatively high rate of spontaneous regression. With the contagious enthusiasm that Dr. Old spread, however, we refused to acknowledge that specific anti-tumor reactions would be much harder to demonstrate in other human tumors; on the contrary, we were convinced to find tumorspecific immunoreactions in many (and secretly hoping in all) patients with cancer. Yet, the expansion of autologous typing to other types of human tumors was limited by the fact that we needed tumor cell lines that grew permanently in vitro from the patients who were to be studied for tumor-specific antibodies in their blood. Fresh tumor biopsies did not provide enough cells for the primary testing and were completely insufficient for the exhaustive absorption studies necessary to determine the specificity of an observed antibody response. Thus, the establishment of a tumor cell line was the prerequisite and the bottleneck to embarking on autologous typing of a patient’s tumor. Dr. Old inaugurated a tumor procurement system with surgeons at Memorial Hospital and with the surgical and neurosurgical departments of several other New York City hospitals. We accepted any tumor specimen that we could acquire, but we had to learn fast that, apart from melanoma—at a time when no growth factors or other cytokines had been identified—only renal cancer and malignant brain tumors yielded permanent cell lines in vitro at a rate high enough to start a tumor type-specific effort at autologous typing. Under the supervision of Dr. Shiku, Ryuzo Ueda and I (they used to call us the “serology twins”) did everything in the lab together. I do not know when we decided that my subject should be the autologous typing of brain tumors (3), and Dr. Ueda’s project, the autologous typing of kidney cancers. Maybe it was when it became clear that the kidney cancer project was lengthier and Dr. Ueda not as eager to return home as I was. We worked hard to make our “babies,” the fresh tumor samples, survive and grow in cell culture and hardly dared to ask for a vacation, which was socially problematic anyway with my Japanese co-workers and Dr. Old, who—if my memory does not deceive me—did not have a single vacation during the two years that I spent in his lab. When Dr. Old showed up in the lab, it was usually in the evening. We always wondered whether this was due to his busy schedule during normal working hours or because of his curiosity. He was always well informed on the state of every project pursued in the lab and knew when new results would be ready. He enjoyed most when he was present at the very moment the results of our experiments came out. When the results were not as expected (which was the case with most of our experiments), Dr. Old comforted us with his standard comment on negative or disappointing results: “There are no negative results, there are only interesting results” or alternatively, “These results are important because they teach us a lot.” Positive results