Year: 2019
Type: editorial
Abstract: At the turn of the last century, William Coley observed that sarcoma patients developing postoperative infections occasionally experienced spontaneous regression of residual tumor. Based on this observation, he went on to treat patients with fluid (“Coley's Toxin”) from these infections resulting responses in some patients. The unpredictability of responses in patients treated by William Coley and the more predictable responses to irradiation, a competing therapeutic modality at the same hospital, damped enthusiasm for Coley's Toxin (Reviewed in “A Commotion in the Blood: Life, Death and the Immune System,” Stephen S. Hall). This lack of enthusiasm was certainly amplified by the fundamental lack of understanding of the immune response at the time. Approximately 50 years later, Foley and Gross,1 followed by a number of other investigators, observed that chemically induced tumors could be rejected in mice if animals were first given killed tumor cells, thus leading to a resurgence in studies on the interaction between tumors and host immune system. The next clinical demonstration of the effectiveness of the immune system against cancer came from two clinical situations in the 1970s and 1980s, over 50 years after Cooley's initial observations. This first was allogenic transplantation for hematologic malignancies where it was recognized that the donor immune system contributed to the control of malignancy in recipients via allorecognition of the tumor cells.2 The second was in patients with metastatic melanoma where responses were observed following the administration of IL-2 and/or autologous lymphocytes.3 Unfortunately, while there were iterative improvements in the effectiveness of immunotherapeutic approaches in patients with cancer over the next 20 years, this progress was limited and robust responses outside of melanoma and allogeneic HSCT were uncommon. Thus, few considered immunotherapy to be a legitimate component of the anti-cancer treatment armamentarium. During this time, continued efforts in the basic and preclinical scientific arena markedly expanded the mechanistic understanding of the immune response against tumors and led to two major breakthroughs. The first was the identification of immune checkpoints as negative regulators4 of the immune response and the demonstration that agents that blocked these immune checkpoints induced regression of solid tumors in mice,5 resulting in Nobel prizes for Tasuku Honjo and Jim Alison. The second was enabled by technological advances in gene therapy that enabled the redirection of T-cell specificity toward desired antigens on the surface of tumor cells through genetic manipulation. Somewhat fortuitously, these breakthroughs enabled clinical success across a broad spectrum of cancers. For checkpoint inhibitors, success occurred mainly in adult epithelial cancers where a higher frequency of mutations conferred immunologic distinction between tumor and host that allowed for “natural” recognition by adaptive immune cells that could be unleashed by inhibition of negative immune regulators.6 For mutationally (and immunologically) “bland” cancers, redirection of immune effector cell specificity has enabled recognition of targets selected for on the surface of cancer cell. Within a relatively short period of time, multiple agents targeting the CTLA4 and PD1/PDL1 immune checkpoint pathways have been approved by regulatory agencies for the treatment of adult cancers.7 Simultaneously, T cells genetically modifying to express chimeric antigen receptors have been approved for the treatment of B-cell malignancies in children and adults and there are now hundreds of clinical trials testing this CAR T cells in other cancers.8 These dramatic successes in immunotherapy has ushered in a new era in cancer treatment in which immunotherapy is firmly planted as a therapeutic option in patients with cancers refractory to initial treatment and rapidly being discussed as a consideration in a upfront therapy. However, we are rapidly learning that we are at the beginning of cancer immunotherapy as a clinical practice and that we will need to go back to roots in basic immunology to move to the next generation. This volume of Immunological Reviews contains a series of chapters prepared by the authors with broad expertise ranging from basic immunology to translational science and early clinical investigations in patients. The first chapter focuses on the current status of immune checkpoint inhibitors in the clinic with an emphasis on rational combinations that will likely be required for success in more cancer subtypes followed by a chapter on preclinical and early clinical experience with a more recently identified immunologic pathway that has demonstrated early promise. The subsequent chapters discuss the status of adoptive cellular therapies including CAR T-cell therapies for liquid and solid tumors followed by a chapter on the rapidly evolving field of adoptive NK cell therapy enabled by technological advances in the ability to generate large numbers of these cells ex vivo. The next two chapters address the emerging challenges facing the field of cellular therapy—relapse and toxicity. These chapters are presented with a “bedside to bench” structure informed by growing experience in patients in the context of mechanistic immunology. Finally, as a way of going back to the beginning, the issue closes with a discussion of how the physiologic T-cell receptor offers tremendous opportunities for success in the next era of cancer immunotherapy. The authors declare no conflict of interest.
Source: Immunological Reviews
DOI: 10.1111/imr.12797
Author: Terry J. Fry
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2964775692