Focus: Combining immunotherapy and targeted therapies in cancer treatment.

Abstract | During the past two decades, the paradigm for cancer treatment has evolved from relatively nonspecific cytotoxic agents to selective, mechanism-based therapeutics. Cancer chemotherapies were initially identified through screens for compounds that killed rapidly dividing cells. These drugs remain the backbone of current treatment, but they are limited by a narrow therapeutic index, significant toxicities and frequently acquired resistance. More recently, an improved understanding of cancer pathogenesis has given rise to new treatment options, including targeted agents and cancer immunotherapy. Targeted approaches aim to inhibit molecular pathways that are crucial for tumour growth and maintenance; whereas, immunotherapy endeavours to stimulate a host immune response that effectuates long-lived tumour destruction. Targeted therapies and cytotoxic agents also modulate immune responses, which raises the possibility that these treatment strategies might be effectively combined with immunotherapy to improve clinical outcomes.

Table: Effects of approved and experimental targeted agents on tumour cells and immune cells

Drug	Effect on tumour	Effect on the immune system
Trastuzumab	Blocks growth signalling through HER2	Primes anti-tumour CTLs, and boosts NK cell secretion of IFNγ and ADCC
Bevacizumab	Neutralizing antibody against VEGF: blocks angiogenesis	Increases DC maturation, shifts DC differentiation towards mature DCs instead of MDSCs and increases DC priming of T cells
Cetuximab	Neutralizing antibody against EGFR: blocks growth signals	• Immune activating: complement fixation, ADCC, increases MHC class I and MHC class II expression and augments DC priming of tumour-specific CTLs • Immunosuppressive: activates M2 macrophages
Temsirolimus, rapamycin and other mTOR inhibitors	Blocks mTOR pathway	• Immunostimulatory: enhances CD8+ T cell activation and IFNγ production, augments CD8+ T cell differentiation into memory T cells, impairs the homeostasis of TReg cells and decreases IDO expression • Immunosuppressive: augments the responsiveness of TReg cells to antigen
Sunitinib	Blocks multiple tumour-associated tyrosine kinases, including VEGFR and PDGFR	Blocks STAT3, decreases numbers and effectiveness of MDSCs and TReg cells, and blocks VEGF signalling
Imatinib	Blocks multiple tumour-associated tyrosine kinases, including ABL and KIT	Blocks IDO, decreases numbers and effectiveness of TReg cells, promotes DC cell–NK cell crosstalk, and increases the numbers of B‑1 B cells and the amount of ‘natural’ anti-tumour carbohydrate antibodies
Vemurafenib	Blocks BRAF‑V600E	Increases expression of gp100, MART1 and other antigens, and decreases tumour secretion of immunosuppressive cytokines
Bortezomib	Blocks 26S subunit of the proteasome	Sensitizes tumour cells to CTL-mediated lysis, sensitizes tumour cells to NK cell-mediated lysis by downregulating MHC class I molecule expression and boosts antigen-specific T cell response to vaccination
JAK2 inhibitors	Block JAK2 signalling in tumour cells	Enhances DC maturation, bolsters DC‑mediated antigen presentation and T cell priming, decreases immunosuppressive STAT3 signalling, decreases IAP expression and decreases tumour cell PDL1 expression
HSP90 inhibitors	Blocks HSP90, which increases unfolded protein-associated stress in tumour cells	• Immunostimulatory: increases expression of NKG2D ligands and boosts CTL recognition of tumour cells • Immunosuppressive: decreases cytokine secretion from macrophages and T cells, decreases expression of co-stimulatory molecules on DCs and decreases antigen presentation by DCs
PI3K–AKT inhibitors	Decreases PI3K–AKT signalling in tumour cells	Increases tumour susceptibility to perforin and granzyme-mediated lysis (mediated by CTLs and NK cells), decreases pro-survival signalling and decreases tumour-promoting inflammation
Lenalidomide	Not well understood	Pleiotropic: increases co-stimulatory molecules on tumour cells, modulates SOCS1 expression to increase cytokine secretion, decreases PDL1 expression on tumour cells, increases NK cell cytotoxicity and cytokine secretion, and increases NKG2D ligand expression
GSK3β inhibitors	Blocks GSK3β-mediated signalling of tumour cell growth	Facilitates differentiation towards ‘stem-cell’ memory T cell population and augments TLR4 signalling
IAP inhibitors	Sensitizes tumour cells to apoptosis	Increases T cell, NK cell and NKT cell responses to stimulation

ADCC, antibody-dependent cellular cytotoxicity; CTL, cytotoxic T lymphocyte; DC, dendritic cell; EGFR, epidermal growth factor receptor; GIST, gastrointestinal stromal tumour; GM‑CSF, granulocyte–macrophage colony-stimulating factor; GSK3β, glycogen synthase kinase 3β; HSP90, heat shock protein 90; IAP, inhibitor of apoptosis protein; IDO, indoleamine-pyrrole 2,3-dioxygenase; IFN, interferon; JAK2, janus kinase 2; MART1, melanoma antigen recognized by T cells 1; MDSC, myeloid-derived suppressor cell; MHC, major histocompatibility complex; NK, natural killer; NKG2D, natural killer group 2, member D; PD1, programmed cell death protein 1; PDGFR, platelet-derived growth factor receptor; PDL1, PD1 ligand 1; STAT3, signal transducer and activator of transcription 3; SOCS1, suppressor of cytokine signalling 1; TLR4, Toll-like receptor 4; TReg cells, regulatory T cells; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor.

Source: Combining immunotherapy and targeted therapies in cancer treatment. Matthew Vanneman and Glenn Dranoff. Nature Reviews Cancer. Volume 12 April 2012  237-251.

Free paper available at:

http://www.nature.com/nrc/journal/v12/n4/pdf/nrc3237.pdf