With the Click of a Mouse: A 35-Year History of Success in Immunology
From left to right: Lisa Min Cao, Dr. Shuhua Cheng, Dr. Hsiou-Chi Liou, Dr. Zoran Popmihajlov, Dr. Kendall Smith, Nadine Mclaughlin, Dong Xu, Catherine Sharoky
"Most of the knowledge of the immune system has accumulated only within the past 20 to 30 years," explains Dr. Kendall A. Smith, who has been at the forefront of the field since 1972 when he began a 20-year period of intense basic research at Dartmouth Medical School. During that time, he and his team carried out experiments that led to the discovery of the molecule interleukin-2 (IL2) and its receptor that revolutionized the study of T cells. Dr. Smith prefers the name T cell Growth Factor (TCGF) since it reflects the capacity of IL2 to activate a beneficial immune response, namely, the growth of T cells. In 1993, Dr. Smith was recruited to Cornell's Department of Medicine with the goal of establishing clinical trials.
Today, with the click of a mouse, patients, doctors and the public alike may access the web for a wealth of information bearing the fruit of some 35 years of research and clinical trials by Dr. Smith and his colleagues.
During the initial bench research phase, Dr. Smith solidified the notion that it might be feasible to administer IL2 therapeutically to boost T cell growth with only low doses being required. In therapeutic experiments at the National Cancer Institute in 1985, IL2 was administered for the first time to humans only four years after the first identification of the molecule. Unfortunately, these early clinical experiments did not apply Dr. Smith's reasoning based on his IL2 receptor experiments that only low dosages should be used, and instead, followed chemotherapy principles of "more is better" to gauge the amount of the dosage. Also, purified IL2 was not used; so that the end result was the dosages were much too large and caused septic shock.
From Cancer, to Leprosy, to HIV, to HCV
Surmising that a lower dosage was the way to go, Dr. Smith collaborated with Dr. Zanvil Cohn, Rockefeller University, who was also experimenting with IL2 by the 1980s. In 1989, they used low IL2 doses to treat leprosy in Nepal with positive results. Subsequently, Dr. Smith began to work with Dr. Jerome Ritz of Harvard Medical School, using low doses of IL2 given intravenously to bone marrow transplant recipients. These experiments also led to beneficial results and further elucidation of the mechanisms of IL2 action.
After enjoying these initial successes in translating his bench findings to the clinical arena, Dr. Smith joined Cornell ready to move into a highly productive phase of clinical trials. One of the pivotal questions in the field of Human Immunodeficiency Virus (HIV) had involved whether to try to purge, or eradicate the virus, or boost the host defenses. There are antiviral drugs aimed at killing the virus, but they cannot completely eliminate the virus and cure the infection, so they must be given for the rest of the life of the patients. Moreover, they can have serious side negative effects, such as abnormal blood lipids and premature heart disease. Dr. Smith's goal was to utilize IL2 in an effort to boost the host immune system in order to fight the virus, while using drugs to inhibit viral replication. The experiments he initiated in 1994 ultimately proved that the low IL2 doses used with leprosy and bone marrow transplant patients could also be administered to patients with HIV-safely and without systemic side effects. Between 1994 and 1999, Smith's team performed 3 phase I/II clinical trials; the first was with 16 subjects, then 40, and finally, more than 100 subjects in a randomized controlled trial. Results showed that the immune system could indeed be augmented to fight HIV.
IL2 Alone Insufficient: Yet Another Approach Sought
However, IL2 alone was insufficient. Trying yet another approach, Dr. Smith sought to combine IL2 as an immunological adjuvant, or booster, together with a candidate HIV vaccine as a new form of immunotherapy. Utilizing a new clinical trial design, whereby volunteers were immunized and given IL2 while receiving antiviral drugs, Smith's team then tested their therapeutic vaccine approach by discontinuing the antiviral therapy, initially for 12 weeks. They found that this clinical trial design yielded very rapid and accurate analysis of the capacity of the immune system to control the virus. However, after more than 40 volunteers had been enrolled in the study, it was clear that neither the vaccine nor IL2, nor their combination could prevent viral replication when the antiviral drugs were discontinued. From the data, it appeared that the vaccine was relatively weak, and that it was necessary to improve the vaccine before initiating another clinical trial.
Back to the Bench
As a result of these findings, Smith again reversed course, and together with Marc Feldman, Director of Rheumatology Division of the Kennedy Institute of Rheumatology at Imperial College London, has focused on fundamental research in vaccines since 2006. With grant support, Smith and Feldman have combined forces with develop more effective therapies and vaccines for the influenza virus. The London group had already done a series of experiments showing new ways to increase the efficacy of vaccines, so that now experiments are underway to investigate whether IL2 added to their vaccine can improve the results even further. Currently they are using mouse models, but if results are promising, the plan is to proceed to human trials soon with a new flu vaccine first, and then a new HIV vaccine.
A Fruitful Journey: Branches of Support
Dr. Smith's journey in immunology has been remarkably fruitful. His first four HIV trials were funded with aid from the Department of Medicine and through basic science research grants from the National Institutes of Health. Funding has also come in the form of an RO1 single investigator award, which is unusual for clinical trial research, and from the Belfer family. Dr. Smith notes the NIH grant that established Cornell's GCRC (General Clinical Research Center) and the efforts of Dr. Julianne Imperato-McGinley, Director, and Dean Antonio M. Gotto as instrumental to ongoing success. A critical component of the GCRC are the NewYork-Presbyterian Hospital inpatient and outpatient clinical research units. "These units have been totally renovated and provide for an ideal modern facility to conduct clinical research." He also acknowledges his "accomplished" Clinical Trials Team and superb support staff.
Electronic databases have been created for his trials by Elizabeth Wood, the information technologist of the GCRC. These databases are secure and compliant with FDA guidelines, replacing hard copy records with computerized records. The data entered serves as the source documents for trials and substitutes for the patient chart and lab notebook. Hospital laboratory test results are downloaded daily, available with the click of a mouse. The NewYork-Presbyterian Hospital Investigative Pharmacy is instrumental in receiving, storing, dispensing and recording all experimental drugs administered. "Without this infrastructure in place," explains Dr. Smith "the conduct of clinical trials would be much more difficult." A close collaborative relationship has been formed with Dr. Paul Bellman, whose large Greenwich Village-based practice in HIV medicine, has been added as a "Downtown Site." This development has significantly increased subject enrollment rates. Additionally, through NewYork-Presbyterian Hospital's marketing efforts, direct advertising to the community through radio and the TV news station NY-1 has "gotten the word out on clinical trials."A wealth of information may be found at Dr. Smith's web site located at www.kendallasmith.us. He has also opened an on-line journal at www.medimmunol.com. "It's time to begin the dialogue so that all people have access to the same information and can understand how the immune system functions. Until now, physicians and scientists have separated themselves from the lay population by using a special vocabulary. It's akin to the middle ages when only the educated spoke Latin, while everyone else spoke the lingua franca."
A Comprehensive Future: Focus on Basic Research & Clinical Research
"Clearly, the conduct of clinical trials, even more so than basic science, requires the combined efforts of many individuals with different expertise," observes Dr. Smith. "The clinical investigator must acquire a different set of skills than does the practitioner or the basic scientist. The education of the physician and the basic scientist has been perfected in the United States. Now, the education of the clinical researcher must be emphasized. Clinical research is the pinnacle of the medical and graduate institutional effort, and only the very best institutions will be able to perform clinical trials well. Immunology is ripe for clinical research opportunities, and over the last 20 years, many new agents have been made available to test, including cytokines, anti-cytokines, antibodies, and clones of specific T cells. Research is needed to find new ways of suppressing, as well as augmenting, the immune system, and there are a multitude of diseases waiting to benefit from new immunostimulatory therapies, as well as immunosuppressive therapies."