jeudi 29 mars 2012

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

Effect on tumour
Effect on the immune system


Blocks growth signalling through HER2
Primes anti-tumour CTLs, and boosts NK cell secretion of IFNγ and ADCC

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

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

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

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 B1 B cells and the amount of ‘natural’ anti-tumour carbohydrate antibodies

Blocks BRAFV600E
Increases expression of gp100, MART1 and other antigens, and decreases tumour secretion of immunosuppressive cytokines

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

Block JAK2 signalling in tumour cells

Enhances DC maturation, bolsters DCmediated antigen presentation and T cell priming, decreases immunosuppressive STAT3 signalling, decreases
IAP expression and decreases tumour cell PDL1

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

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

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

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; GMCSF, 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.
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