Research reviewImmunotherapy for solid tumors—a review for surgeons
Introduction
Our understanding of the dialog between cancer and our immune systems has evolved considerably over the past decade. With recent scientific and conceptual advances, novel immunotherapeutic approaches have emerged as effective and promising treatments against cancer. Immunotherapy is rapidly being incorporated into everyday clinical care and is no longer relegated to the realm of the esoteric. Therefore, clinicians must understand the basic principles of immunotherapy and how it will be integrated it into multidisciplinary cancer care.
Section snippets
Historial perspective
The clinical relevance of the bidirectional crosstalk between immune cells and cancer cells has been the subject of considerable controversy. In 1891, Dr William B. Coley published a remarkable account of an unresectable neck sarcoma that regressed completely after a severe episode of erysipelas [1]. Based on this observation, Coley speculated that the patient's response to the infection mediated tumor regression. In one of the first ventures into the realm of immunotherapy, Coley prepared a
Immune system overview
A basic understanding of how the immune system functions and interacts with tumor cells is necessary to appreciate the clinical application of immunotherapy. The immune system can be broadly divided into innate and adaptive components. Innate immunity refers to the nonspecific first line of defense against danger signals from pathogens or tumor cells. Triggers for innate immune cells include bacterial cell wall products, endotoxin, and pathogen nucleic acids. The innate response is mediated by
Tumor evasion and immune escape
The presence of immunogenic tumor antigens is not sufficient to induce a clinically meaningful immune response in most patients. Tumor cells actively influence their microenvironment, promoting an immunosuppressive milieu (Table 1, Fig.). Tumors not only evade cytotoxic responses but also actively produce immunosuppressive factors with local and systemic effects. These factors, through a variety of mechanisms, promote tumor growth and prevent eradication. As such, effective immunotherapy will
Immunotherapy approaches
Numerous immunotherapy strategies have undergone extensive development and clinical testing. Approaches range from nonspecific immunostimulation to the production of exquisitely specific genetically modified T cells. The first FDA approved immunotherapies include IL-2 and interferon-α2b used for melanoma [61], [62]. These approaches have yielded durable results in a select group of patients, with tumor regression in 10%–15% of melanoma and renal cell carcinoma (RCC) patients [62].
Combining immunotherapy with conventional treatment
The notion that chemotherapy is strictly immunosuppressive is no longer valid, and evidence exists to support the notion that the effect of cytotoxic agents on antitumor immunity is complex. Suppression of Treg has been seen with low doses of cyclophosphamide [84]. Gemcitabine has been shown to reduce the number of MDSC [85]. Oxaliplatin has been linked to favorable cytokine release within the tumor microenvironment with the activation of dendritic cells and cytotoxic T cells [86]. Therefore,
Trials evaluating immune checkpoint blocking agents
As reviewed earlier, CTLA-4 and PD-1 represent critical immune checkpoint molecules and their inhibition can activate antitumor T cells. Initial studies evaluating the activity of ipilimumab as a single dose in patients with advanced tumors, showed increased T cell reactivity suggesting increased antitumor immunity with the drug [90]. Later reports from the National Cancer Institute demonstrated a 12.5% ORR in stage IV melanoma patients when used with gp100 vaccine [91]. A phase III trial for
Summary and conclusions
Cancer immunotherapy has evolved significantly, from the time of Coley's observations of a spontaneous sarcoma regression to the recent clinical testing of immune checkpoint blockade and genetically modified T cells. Our increased understanding of lymphocyte biology and immunosuppressive pathways has facilitated translation of animal work into groundbreaking clinical trials. For patients with solid tumors resistant to conventional therapy, immunotherapy alone or in combination with traditional
Acknowledgment
Author contributions: A. S. was responsible for conception, writing and revision; V.G. was involved in design, writing, and revision; S. C. Katz was responsible for conception, design, writing and critical revision.
Support for this work was provided by the National Institutes of Health (1K08CA160662-01A1) and the Society of Surgical Oncology Clinical Investigator Award.
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