From stress protein biochemistry to novel immunotherapeutics

John R. Subjeck, PhD – Recipient of the 2012 J. Eugene Robinson Award.

I am pleased to have the opportunity to briefly describe some of the achievements of John Subjeck that led to his selection by the Society of Thermal Medicine (STM) to be the recipient of our highest honour, the J. Eugene Robinson Award, presented at his lecture on 15 April 2012, at the annual meeting in Portland, Oregon, USA. First, a bit of important history: in 1974 John received his PhD in biophysics from the University of New York at Buffalo. His doctoral dissertation research was done in the laboratory of Leonard Weiss at Roswell Park Memorial Institute (later known as Roswell Park Cancer Institute (RPCI)) in the area of metastasis. From there he joined the Department of Radiation Medicine at Roswell (chaired by Richard Johnson) to study in the areas of medical physics and radiation biology. He was trained as a medical physicist and later became certified by the American Board of Radiology. Over the years, John has frequently mentioned how much he enjoyed working in the clinic and interacting directly with patients and how different this work was compared to supervising a research laboratory. It was in this environment at Roswell Park that John learned about heat shock and began to study the heat protective roles of heat shock proteins (HSPs).

The seminal research for which John was honoured represents decades of work, which can be traced to when John first began regularly attending hyperthermia sessions while they were still part of the Radiation Research Society, which he joined in 1978. Even earlier, John recalls presenting his research at RTOG (Radiation Therapy Oncology Group) hyperthermia meetings, while Dr Johnson was the chairman of that group. As John mentioned during his Robinson Lecture, a sad loss early in his career came with the untimely death, in 1985, from renal cell cancer, of Dr Johnson. John credits Dr Johnson for much of his early inspiration to focus his research in the hyperthermia/heat shock protein fields. John was an original member of STM or, as it was known then, the North American Hyperthermia Group.

John carried out some of the original experiments in defining cellular stress responses at the molecular level. In some of his earliest studies on hyperthermia, John observed the expression of a major protein of Mr 110 kDa which came to be called hsp110 [1]. In parallel, he was also examining a second set of proteins inducible by a different stress, glucose starvation and which became known as glucose regulated proteins, or GRPs. His earliest study in this area identified a GRP of approximately 170 kDa that he called grp170. In addition, another important observation from his laboratory was that chronic anoxia/hypoxia could be an inducer of GRPs. In parallel with the thermoprotective role of HSPs, he postulated roles for the GRPs in drug resistance and evasion of ischaemic cell death [2,3]. He then focused on the biochemistry and cell biology of the large stress proteins, hsp110 and grp170, that had been largely overlooked by others. Both the hsp110 and grp170 genes were first cloned in his laboratory. Surprisingly, when their sequences were examined, both genes were shown to be distantly related to members of the Hsp70 family. This new information created a much broader appreciation of the variation that exists in what is now referred to as the hsp70 ‘super-family.’ [4,5]. His group then demonstrated that hsp110 and grp170 were extremely efficient molecular chaperones that could inhibit the aggregation of heat-damaged substrate proteins in a highly effective manner. Then in the late 1990s, John took a turn in direction and suggested that the strong chaperoning properties of large HSPs might be used to construct recombinant chaperone vaccines for the treatment of cancer. This approach was based on studies of others showing that certain stress proteins, after biochemical purification from tumour specimens, possessed anti-cancer vaccine activities based on their ability to carry tumour peptide antigens. In his recombinant large stress protein technology, John employed full-length tumour protein antigens such as melanoma antigen gp100. Thus the possession of tumour specimens to prepare vaccine was not required. Heat was used to damage the tumour protein in the presence of hsp110 or grp170 leading to the formation of the chaperone complex vaccine [6]. The preclinical results based on this technology were highly impressive and led to a Rapid Access to Intervention and Development grant from the NCI (National Cancer Institute) to facilitate the translation of this novel technology into the clinic. A clinical trial for the treatment of melanoma using a hsp110-gp100 vaccine is currently in progress at Roswell under the direction of John’s clinical collaborators.

Today, John is Professor of Oncology in the Department of Cell Stress Biology at Roswell Park Cancer Institute. He has mentored many graduate students and post-docs, several of whom have gone on to make important contributions of their own in the area of heat shock protein biology/immunology and are current members of STM. For many years he also served as the Director of Graduate Studies, followed by serving as chairman of the academic programme in biophysics and he has held many other positions of responsibility at Roswell Park.

In summary, John’s contributions to the field of stress protein biology began more than three decades ago and continue today in his studies of the roles of stress proteins in the immune response. John’s ground-breaking and sustained research has thus ranged all the way from deep basic biochemical analysis of the stress response to the treatment of cancer patients with unique immunotherapy agents. John represents our Society in areas of biomedical research that today extend far beyond the traditional areas that represented the interests of our Society at its beginning.