Immunotherapy of cancer in 2012

Abstract

The immunotherapy of cancer has made significant strides in the past few years due to improved understanding of the underlying principles of tumor biology and immunology. These principles have been critical in the development of immunotherapy in the laboratory and in the implementation of immunotherapy in the clinic. This improved understanding of immunotherapy, enhanced by increased insights into the mechanism of tumor immune response and its evasion by tumors, now permits manipulation of this interaction and elucidates the therapeutic role of immunity in cancer. Also important, this improved understanding of immunotherapy and the mechanisms underlying immunity in cancer has fueled an expanding array of new therapeutic agents for a variety of cancers. Pegylated interferon-α2b as an adjuvant therapy and ipilimumab as therapy for advanced disease, both of which were approved by the United States Food and Drug Administration for melanoma in March 2011, are 2 prime examples of how an increased understanding of the principles of tumor biology and immunology have been translated successfully from the laboratory to the clinical setting. Principles that guide the development and application of immunotherapy include antibodies, cytokines, vaccines, and cellular therapies. The identification and further elucidation of the role of immunotherapy in different tumor types, and the development of strategies for combining immunotherapy with cytotoxic and molecularly targeted agents for future multimodal therapy for cancer will enable even greater progress and ultimately lead to improved outcomes for patients receiving cancer immunotherapy.

FIGURE 1

Key Events in the History of Cancer Immunotherapy.^– An earlier publication for Coley can be found at: Coley WB. The treatment of inoperable sarcoma by bacterial toxins (the mixed toxins of the Streptococcus erysipelas and the Bacillus prodigiosus). Proc R Soc Med. 1910;3(Surg Sect):1–48. BCG indicates Bacillus Calmette-Guerin; mAbs, monoclonal antibodies; IFN-α, interferon-α; HCL, hairy cell leukemia; IL-2, interleukin-2; RCC, renal cell carcinoma; Peg IFN, pegylated IFN; CTLA-4, cytotoxic T lymphocyte antigen-4; MAGE-1, melanoma-associated antigen 1. Adapted from Kirkwood JM, Tarhini AA, Panelli MC, et al. Next generation of immunotherapy for melanoma. J Clin Oncol. 2008;26:3445^–3455.

FIGURE 2

Cross-Presentation/Determinant Spreading. Self-antigen cross-presentation is thought to be a mechanism for inducing autoimmunity, which can involve tumor antigens (and determinant spreading from an antigen immunized against to self-antigens not specifically immunized against) and normal self-antigens (such as thyroid antigens). Cell lysis in an immunogenic milieu allows endogenous antigen-presenting cells (APCs) to take up these self-antigens, cross-present them, and activate T cells with new specificities.

FIGURE 3

Different Tasks of Preventive Versus Therapeutic Vaccines. Therapeutic vaccines need to function despite tumor-induced dysfunction of endogenous dendritic cells (DCs) and in the presence of tumor-induced suppressive cells such as regulatory T cells (T_reg). Their roles go beyond the induction of long-lived memory cells, because cancer is a poor source of proinflammatory alarm signals capable of inducing effector functions and peripheral homing potential in antigen (Ag)-specific T cells. The effectiveness of therapeutic vaccines may require the provision of such signals by the vaccines themselves or by additional factors used in combination with the vaccines. Some tumors show limited production of the chemokines capable of attracting effector cells (cytotoxic T lymphocytes [CTLs], T helper-1 [Th1-], and natural killer [NK] cells), and rather produce T_reg-attracting chemokines. Effective immunotherapies for cancer may benefit from the combination of vaccines with additional modulation of the production of the effector cell-attracting versus T_reg-attracting chemokines within tumor tissues.

FIGURE 4

Dendritic Cells Provide Different Types of Information to Tumor-Specific T Cells. Dendritic cells (DCs) provide T cells with antigenic “signal 1” and costimulatory “signal 2,” which are needed for the activation and expansion of pathogen-specific T cells. DCs have also been shown to provide T cells with an additional polarizing “signal 3,” driving the development of different effector mechanisms and activating various subsets of immune cells with different abilities to induce cancer rejection. Recent studies have indicated that DCs also provide T cells with an additional signal (“signal 4”) regulating the organ-specific trafficking of immune cells. DCs regulate the expansion and acquisition of effector functions, as well as tumor-relevant homing properties for the development of effective immunotherapy. Th indicates T helper; NK, natural killer; CTLs, cytotoxic T lymphocytes; IL-12, interleukin-12; IFNs, interferons; Vit A, vitamin A; Vit D, vitamin D; T_regs, regulatory T cells.

FIGURE 5

Mechanisms Used by Monoclonal Antibodies to Mediate Antitumor Effects. Multiple roles of monoclonal antibodies (mAbs) in cancer therapy are shown.

FIGURE 6

Mechanisms Underlying the Antitumor Activity of Monoclonal Antibody-Based Immunotherapy. TA indicates tumor antigens; FcR, Fc receptor; NK, natural killer; DC, dendritic cell; VEGF, vascular endothelial growth factor.

FIGURE 7

Genetic Immunization. Plasmid DNA and viral vectors can be utilized for vaccination by direct injection, often into muscle or skin. While direct transfection/transduction of antigen-presenting cells (APCs) at the injection site can occur, the transfected tissue serves as a source of vaccine protein that can be taken up as cross-presented by host APCs to activate antitumor immunity.

FIGURE 8

Immunologic Monitoring. Cross-talk between the tumor and the immune system can be examined in tumor tissue and blood. From tumor tissue, infiltrating cells can be identified. From blood, a variety of assays can be performed, some of which require fresh blood. Others can be performed from frozen/cryopreserved samples and batched for directly compared analysis. TIL indicates tumor-infiltrating lymphocyte; PBMC, peripheral blood mononuclear cells; NK, natural killer; DC, dendritic cell; T_reg, regulatory T cells; MDSC, myeloid-derived suppressor cells.