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Review
. 2016 May 5:14:73.
doi: 10.1186/s12916-016-0623-5.

Cancer immunotherapy: the beginning of the end of cancer?

Sofia Farkona  1   2 , Eleftherios P Diamandis  1   2   3 , Ivan M Blasutig  4   5   6
Affiliations
Review

Cancer immunotherapy: the beginning of the end of cancer?

Sofia Farkona et al. BMC Med. .

Abstract

These are exciting times for cancer immunotherapy. After many years of disappointing results, the tide has finally changed and immunotherapy has become a clinically validated treatment for many cancers. Immunotherapeutic strategies include cancer vaccines, oncolytic viruses, adoptive transfer of ex vivo activated T and natural killer cells, and administration of antibodies or recombinant proteins that either costimulate cells or block the so-called immune checkpoint pathways. The recent success of several immunotherapeutic regimes, such as monoclonal antibody blocking of cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD1), has boosted the development of this treatment modality, with the consequence that new therapeutic targets and schemes which combine various immunological agents are now being described at a breathtaking pace. In this review, we outline some of the main strategies in cancer immunotherapy (cancer vaccines, adoptive cellular immunotherapy, immune checkpoint blockade, and oncolytic viruses) and discuss the progress in the synergistic design of immune-targeting combination therapies.

Keywords: Adoptive cellular therapy; Cancer; Cytotoxic T lymphocyte-associated protein 4; Immune checkpoint blockade; Immunotherapy; Programmed cell death protein 1; T cells.

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Figures

Fig. 1
Fig. 1
Dendritic cell (DC) based vaccines. CD34+ hematopoietic progenitor cells or monocytes are isolated from the patient’s peripheral blood by cytapheresis. Monocytes are cultured in the presence of Granulocyte macrophage colony-stimulating factor (GM-CSF) and IL-4 to induce differentiation into immature DCs, while CD34+ cells are differentiated when cultured in the presence of GM-CSF, Flt3 ligand and TNF-α. Immature DCs are then loaded with antigen in the form of proteins, peptides or tumor cells either with or following their maturation with proinflammatory cytokines. Once loaded with antigen, DCs can be re-introduced to the patient or frozen in aliquots and thawed before vaccination. (Adapted from [17])
Fig. 2
Fig. 2
Genetic T cell engineering for the improvement and broadening of tumor-infiltrating lymphocyte (TIL) therapy. Chimeric antigen receptors (CARs) consist of an Ig variable extracellular domain fused to a T cell receptor (TCR) constant domain. The engineered T cells obtain the antigen-recognition properties of antibodies and thus are targeted against any potential cell surface target antigen. The expression of the TCR confers the engineered T cell with the antigen specificity of the transferred TCR. TIL therapy with TCRs is feasible for patients whose tumor harbors the human leukocyte antigen (HLA) allele and expresses the target antigen recognized by the TCR
Fig. 3
Fig. 3
T cell activation in the lymph node. a Both immunological signal 1 (T cell receptor (TCR) recognition of antigens) and immunological signal 2 (stimulation of CD28 by B7 costimulatory molecules) are required for T cell activation in the lymph node. The interaction between the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) receptor and B7 expressed on T cells and antigen presenting cells, respectively, prevents T cells from becoming fully activated by blocking immunologic signal 2. b Antibodies that block the CTLA-4 pathway (e.g. ipilimumab) permit T cell activation by derepressing signaling by CD28. MCH, Major histocompatibility complex. (Adapted from [77])
Fig. 4
Fig. 4
T cell activation in the tumor milieu. a Programmed cell death protein 1 (PD1) receptor is an inhibitory receptor expressed by antigen-stimulated T cells. Interactions between PD1 and its ligand, PD-L1, expressed in many tumors activate signaling pathways that inhibit T-cell activity and thus block the antitumor immune response. b Antibodies targeting PD1 or PD-L1 block the PD1 pathway and reactivate T cell activity. MCH, Major histocompatibility complex; TCR, T cell receptor. (Adapted from [77])
Fig. 5
Fig. 5
Combination therapy of immune checkpoint inhibitors with conventional therapies may enhance antitumor responses. Molecularly targeted therapies attack cells with specific genetic characteristics resulting in the release of multiple tumor neoantigens. Tumor neoantigens are taken up by antigen presenting cells that then present them in the context of B7 costimulatory molecules and major histocompatibility complex to T cells. T cells are partially activated but overexpress checkpoint molecules, such as CTLA-4 and PD1, which prevent them from becoming fully activated at the tumor site. Immune checkpoint blockade unleashes pre-existing anticancer T cell responses and licenses T cells to attack the cancer cells. CTLA-4, Cytotoxic T lymphocyte-associated protein 4; MCH, Major histocompatibility complex; PD1, Programmed cell death protein 1; PD-L1, PD1 ligand; TCR, T cell receptor. (Adapted from [4])
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