Research review
Immunotherapy for solid tumors—a review for surgeons

https://doi.org/10.1016/j.jss.2013.12.018Get rights and content

Abstract

Immunotherapy has evolved considerably in the last decade and is becoming an integral component of the armamentarium for the treatment of patients with advanced solid tumors. It is important for clinicians, especially surgeons, to understand the basic principles of novel immunotherapies and the immune system. This review summarizes the evolution of the most relevant immunotherapies, their mechanisms of action, the data supporting their clinical use, and integration of immunotherapy into multidisciplinary management of solid tumors. This review should serve as a primer for clinicians and surgeons to understand the rapidly evolving field of immunotherapy.

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.

References (109)

  • J. Kao et al.

    Targeting immune suppressing myeloid-derived suppressor cells in oncology

    Crit rev oncology/hematology

    (2011)
  • P. Gould

    Sipuleucel-T shows partial advantage in prostate cancer

    Lancet Oncol

    (2006)
  • W.M. Liu et al.

    Pre-treatment with chemotherapy can enhance the antigenicity and immunogenicity of tumours by promoting adaptive immune responses

    Br J Cancer

    (2009)
  • S.F. Slovin et al.

    Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: results from an open-label, multicenter phase I/II study

    Ann Oncol

    (2013)
  • W.B. Coley

    II. Contribution to the knowledge of sarcoma

    Ann Surg

    (1891)
  • K.W. Clauberg

    [The immunobiological legacy of Emil von Behring and Paul Ehrlich]

    Dtsch Med J

    (1954)
  • M. Burnet

    Cancer—a biological approach

    Br Med J

    (1957)
  • L. Thomas et al.

    Cellular and humoral aspects of the hypersensitive states

    (1959)
  • O. Stutman

    Immunodepression and malignancy

    Adv Cancer Res

    (1975)
  • R.D. Schreiber et al.

    Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion

    Science

    (2011)
  • S.A. Rosenberg et al.

    Adoptive cell transfer: a clinical path to effective cancer immunotherapy

    Nat Rev Cancer

    (2008)
  • A. Knuth et al.

    T-cell-mediated cytotoxicity against autologous malignant melanoma: analysis with interleukin 2-dependent T-cell cultures

    Proc Natl Acad Sci

    (1984)
  • U. Sahin et al.

    Human neoplasms elicit multiple specific immune responses in the autologous host

    Proc Natl Acad Sci

    (1995)
  • I. Nukaya et al.

    Identification of HLA-A24 epitope peptides of carcinoembryonic antigen which induce tumor-reactive cytotoxic T lymphocyte

    Int J Cancer

    (1999)
  • M.A. Cheever et al.

    The prioritization of cancer antigens: a national cancer institute pilot project for the acceleration of translational research

    Clin Cancer Res

    (2009)
  • S.C. Katz et al.

    Regulatory T cell infiltration predicts outcome following resection of colorectal cancer liver metastases

    Ann Surg Oncol

    (2013)
  • T.F. Gajewski

    Failure at the effector phase: immune barriers at the level of the melanoma tumor microenvironment

    Clin Cancer Res

    (2007)
  • S.C. Katz et al.

    T cell infiltrate predicts long-term survival following resection of colorectal cancer liver metastases

    Ann Surg Oncol

    (2009)
  • J. Galon et al.

    Type, density, and location of immune cells within human colorectal tumors predict clinical outcome

    Science

    (2006)
  • L. Zhang et al.

    Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer

    New Engl J Med

    (2003)
  • J.F. Vansteenkiste et al.

    Association of gene expression signature and clinical efficacy of MAGE-A3 antigenspecific cancer immunotherapeutic (ASCI) as adjuvant therapy in resected stage IB/II non-small cell lung cancer (NSCLC)

    J Clin Oncol

    (2008)
  • B. Mlecnik et al.

    Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction

    J Clin Oncol

    (2011)
  • S. Bodmer et al.

    Immunosuppression and transforming growth factor-beta in glioblastoma. Preferential production of transforming growth factor-beta 2

    The J Immunol

    (1989)
  • Y.Y. Wan et al.

    TGF-β and regulatory T cell in immunity and autoimmunity

    J clin immunol

    (2008)
  • D.B. Constam et al.

    Differential expression of transforming growth factor-beta 1,-beta 2, and-beta 3 by glioblastoma cells, astrocytes, and microglia

    The J Immunol

    (1992)
  • G.Y. Chau et al.

    Serum interleukin-10 but not interleukin-6 is related to clinical outcome in patients with resectable hepatocellular carcinoma

    Ann Surg

    (2000)
  • S. Viviani et al.

    Elevated pretreatment serum levels of Il-10 are associated with a poor prognosis in Hodgkin’s disease, the Milan cancer institute experience

    Med Oncol

    (2000)
  • M.R. Young et al.

    Mechanisms of immune suppression in patients with head and neck cancer: influence on the immune infiltrate of the cancer

    Int J Cancer

    (1996)
  • H. Sheng et al.

    Modulation of apoptosis and Bcl-2 expression by prostaglandin E2 in human colon cancer cells

    Cancer Res

    (1998)
  • M. Huang et al.

    Non-small cell lung cancer-derived soluble mediators and prostaglandin E2 enhance peripheral blood lymphocyte IL-10 transcription and protein production

    The J Immunol

    (1996)
  • D.C. Gondek et al.

    Cutting edge: contact-mediated suppression by CD4+ CD25+ regulatory cells involves a granzyme B-dependent, perforin-independent mechanism

    The J Immunol

    (2005)
  • F. Fallarino et al.

    Modulation of tryptophan catabolism by regulatory T cells

    Nat immunol

    (2003)
  • F. Ghiringhelli et al.

    CD4+ CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor–β–dependent manner

    The J Exp Med

    (2005)
  • A.L. Mellor et al.

    IDO expression by dendritic cells: tolerance and tryptophan catabolism

    Nat Rev Immunol

    (2004)
  • O. Janssen et al.

    Regulation of activation-induced cell death of mature T-lymphocyte populations

    Cell Tissue Res

    (2000)
  • O.J. Finn

    Cancer immunology

    N Engl J Med

    (2008)
  • F.S. Hodi et al.

    Improved survival with ipilimumab in patients with metastatic melanoma

    New Engl J Med

    (2010)
  • J.R. Brahmer et al.

    Safety and activity of anti-PD-L1 antibody in patients with advanced cancer

    N Engl J Med

    (2012)
  • T.J. Curiel et al.

    Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity

    Nat Med

    (2003)
  • M. Kojima et al.

    Association of enhanced cyclooxygenase-2 expression with possible local immunosuppression in human colorectal carcinomas

    Ann surg oncol

    (2001)
  • Cited by (0)

    View full text