Dr. Gold comments on this article from the Globe and Mail Jan. 9, 2015: Scientists unleash the power of immunotherapy on stubborn cancers
Perhaps the earliest attempt at the immunotherapy of human cancer, in the ‘modern era’, can be traced to William Coley who had seen tumour regression in patients with erysipelas near head and neck cancers. Extending this observation, Coley’s toxin, as it came to be called, was a mixture of killed bacteria that he injected directly into the tumours of patients with head and neck cancer. In a significant number of cases, a regression of the tumour was seen, although seldom “cured”. This work was done in the 1890’s at Memorial Hospital in New York and it’s interesting that Anton Chekhov, in his capacity as a physician rather than a composer, had recorded similar findings in the late 1880’s in his patients in Russia.
Moving rapidly forward to the mid-20th century, with increasing knowledge of the mechanisms whereby the immune system functions, two pathways of investigation were undertaken. One line of study was a search for tumour-specific, or tumour-associated, antigens that might be used as therapeutic targets, without endangering normal cells. Such early tumour antigens discovered were the Carcinoembryonic Antigen (CEA) and Alpha-Fetoprotein (AFP). Although neither has yet become a clear target for therapy, they are widely used in the diagnosis and then post-therapeutic surveillance of patients with cancer of various organs. Other such molecules, subsequently found, are PSA, CA19-9 and CA125, amongst many others.
The other immunologic approach taken in the study of human cancers was that of attempting to utilize immunologic mechanisms, albeit non-specifically, to somehow enhance that body’s immune response against the invasion by a genetically altered and, therefore, putatively foreign, malignant tumour. For the most part, these studies have involved 3 different approaches:
The first is cell-based therapies, often referred to as cancer vaccines, which involved exposure of a patient’s own lymphocytes and/or dendritic cells to her tumour cells after removal of that tumour at surgery. It was hoped that such exposure would then further stimulate and expand the already putatively cancer-activated dendritic and/or T lymphocytes. These cells were then reinfused into the patient, often with significant regression of the tumour. One such therapy, currently approved for use, is Dendreon’s Provenge, which has been employed in the treatment of prostate cancer, with some success.
The second approach was that of the use of humoral antibody immunotherapy, the success of which awaited the discovery, in the 1970’s, of the Nobel Prize-winning studies of monoclonal antibody technology by Kohler and Milstein. Amongst the very successful monoclonal antibody therapies that have evolved from this work are such materials as Herceptin, now widely used in HER2-positve breast cancers, and now extended to other tumours as well. Similarly, the monoclonal anti-B lymphocyte antibody, Rituximab, has been used with significant success in B-cell leukemias and lymphomas. A variety of comparable monoclonal antibodies have been developed for other tumours (and, indeed, other diseases) as well.
The third approach has been that of using different pro-inflammatory cytokines to expand the, putatively, naturally activated anti-cancer immune T lymphocyte populations. Such biological materials have been employed either in vivo or in vitro and have included Interferon alpha (INFα), Tumour Necrosis Factor (TNF) and Interleukin-2 (IL2), amongst others. The in vitro approach avoids the very significant adverse side effects seen with in vivo cytokine therapy. The expanded T-cell population is then reinfused into the patient. Once again, significant tumour regression has frequently been seen and, indeed, some patients have gone on to multi-year survival.
More recently, a fourth, and very exciting approach, has been forthcoming from the ongoing fundamental studies of the normal immune response. It has been learned that a specific immune response, once initiated, continues for a finite period of time until checkpoint inhibitors arise that effectively stop the progression of the immune response. At least two (2) molecules of major importance in this inhibition of the immune response have been identified and designated CTLA4 and PD1. These molecules normally interfere with the activation linkage that occurs between dendritic cells and CD4-positive helper T (Th) cells that initiate immune reactivity. Hence, by using monoclonal antibodies against either CTLA4 or PD1, any ongoing anti-tumour immune response is allowed to go forward without inhibition. A number of very encouraging results of studies employing this technology have been published in a number of medical journals, and these observations have recently been reported in the popular press. Much of this work has been forthcoming from studies in patients with malignant melanoma where a number of tumour-associated molecules have been described.
Obviously, now, the search will continue for more tumour-associated or tumour-specific molecules, such as the ones noted earlier (e.g. CEA, AFP etc.) that can be incorporated into an approach employing immune checkpoint inhibitors. In most cases, chemotherapy will likely continue in conjunction with the immunotherapy in the hope that we may finally have reached a point where even the most aggressive malignant tumours can be brought under control.
Phil Gold CC, OQ, MD, PhD – Editor, Current Oncology and CKN
Dr. Philip Gold, C.C., O.Q., M.D., Ph.D., is a pioneer in cancer research with nearly 50 years of clinical and teaching experience under his belt. As one of the most prominent clinical investigators in Montreal, Dr. Gold has demonstrated a steadfast commitment to bettering patient care through the development of innovative therapies. Dr. Gold’s early research led to the discovery and definition of the carcinoembryonic antigen (CEA), the blood test most frequently used in the diagnosis and management of patients with cancer. Dr. Gold has received numerous international awards and honors and has been elected to a wide variety of scientific organizations. He was named Companion of the Order of Canada, an Officer of the Ordre Nationale du Québec, a member of the Academy of Great Montrealers, and is also the recipient of the Gold Medal Award of Merit of the Graduate Society of McGill University. He is the recipient of such prestigious awards as the Gairdner Foundation’s Annual International Award, The Isaak Walton Killam Award in Medicine of the Canada Council and the National Cancer Institute of Canada R.M. Taylor Medal. He has been elected to membership in the Royal Society of Canada, the Association of American Physicians and Mastership in the American College of Physicians.