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Cancer and Innate Immune System Interactions: Translational Potentials for Cancer Immunotherapy

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Posted 12 Jun 2012 — by James Street
Category Immune System
Journal of Immunotherapy:
May 2012 – Volume 35 – Issue 4 – p 299–308
doi: 10.1097/CJI.0b013e3182518e83
Review Article

Liu, Yanan; Zeng, Gang

Free Access
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Author Information

Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA

Reprints: Gang Zeng, Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1738 (e-mail:

Received February 2, 2012

Accepted February 22, 2012

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Passive immunotherapy, including adoptive T-cell therapy and antibody therapy, has shown encouraging results in cancer treatment lately. However, active immunotherapy of solid cancers remains an elusive goal. It is now known that the human innate immune system recognizes pathogen-associated molecular patterns conserved among microbes or damage-associated molecular patterns released from tissue injuries to initiate adaptive immune responses during infection and tissue inflammation, respectively. In contrast, how the innate immune system recognizes endogenously arising cancer remains poorly understood at the molecular level, which poses a significant roadblock to the development of active cancer immunotherapy. We hereby review the current knowledge of how solid cancers directly and indirectly interact with cells of the human innate immune system, with a focus on the potential effect of such interactions to the resultant adaptive immune responses against cancer. We believe that understanding cancer and innate immune system interactions may allow us to better manipulate the adaptive immune system at the molecular level to develop effective active immunotherapy against cancer. Current and future perspectives in clinical development that exploits these molecular interactions are discussed.

Despite a predominantly immunosuppressive tumor microenvironment,1,2 spontaneous T-cell and antibody responses against tumor-associated antigens (TAAs) can be induced in tumor-bearing hosts.3–5 In a small fraction of patients, antitumor immunity may lead to spontaneous tumor regression or control of tumor expansion, with perhaps the most compelling evidence documented in patients with melanoma3 and paraneoplastic neurological disorders.6

The ultimate goal of active cancer immunotherapy is to achieve the antitumor immunity that has been demonstrated in the sporadic examples of spontaneous tumor regression/containment and recent success of passive immunotherapy such as adoptive T-cell therapy and antibody therapy.7–10 Recent advances in basic science have defined several ligand/receptor interactions and molecular pathways that have significant effect on subsequent adaptive immune responses in various circumstances. For example, it is now known that the human innate immune system, through its cell-surface pattern recognition receptors, recognizes pathogen-associated molecular patterns conserved among microbes or damage-associated molecular patterns (DAMPs) released from tissue injuries to initiate adaptive immune responses during infection and tissue inflammation, respectively.11,12 Despite this wealth of knowledge, how spontaneous antitumor immune responses are initiated is still poorly understood at the molecular level, which poses a major obstacle in developing effective active immunotherapy.

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The major effector cells of the immune system that directly target cancer cells include natural killer cells (NK), dendritic cells (DCs), macrophages, polymorphonuclear leukocytes (PMN including neutrophils, eosinophils, and basophils), mast cells, and cytotoxic T lymphocytes. NK cells, DCs, PMN, mast cells, and macrophages are first-line effectors to damaged cells and cancer cells. NK T cells and γδ T cells play roles as both innate and adaptive components, through close interactions with cells of the adaptive immune system, such as CD4+ and CD8+ T lymphocytes with cytotoxic effects and memory.13 The importance of innate immune system in limiting cancer progression has been highlighted recently with the following direct molecular interactions between cancers and innate immune effector cells.

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NK Cells

NK cells constitute the primary innate immune cell type responsible for killing nonmajor histocompatibility complex (MHC) expressing cancer cells, releasing small cytotoxic proteins such as perforin and granzyme that cause apoptosis in target cells. There are 2 functional types of receptors on the NK-cell surface: stimulatory receptors and inhibitory receptors. Natural killer group 2D (NKG2D) molecule is perhaps the best known stimulatory receptor.14 The ligands on tumor cells for NKG2D include MHC class-I-chain-related protein A,15 MHC class-I-chain-related protein B,16,17 UL16 binding protein18 in human, and minor histocompatibility molecule H60, retinoic acid early transcript 1 protein, UL16 binding protein-like transcript 1 protein in mice.19–22 Figure 1 shows the interactive diagram of such interactions in humans. The binding of the previously mentioned stress-related ligands with NKG2D stimulate NK cells, leading to secretion of interferon-γ (IFN-γ) and perforin, release of inflammatory cytokines, and the induction of apoptosis in cancer cells. Other NK stimulatory receptors have also been characterized, such as NKp30,23 NKp44,24 and NKp4625 in humans, NK-cell receptor protein 1,26,27 Ly49d/h,28,29 and NKG2C/E-CD94 in mice,14,30 and DNAX accessory molecule31 in both humans and mice. The inhibitory receptors of NK cells consist of the human killer-cell immunoglobulin-like receptors (KIRs),32,33 the mouse Ly49a/c/g2,34–36 and NKG2A-CD94 lectin-like receptors shared by both humans and mice.37 The nonclassical MHC class I molecule, HLA-G, on tumors also functions as a ligand for KIRs that can inhibit cytotoxicity mediated by NK cells. Ly49 family receptors specifically recognize MHC class I or MHC class I-like molecules. The nonclassical MHC class I molecule HLA-E is the ligand for human NKG2A/CD94 heterodimer receptors.38

Figure 1

Figure 1
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Tumor necrosis factor (TNF) family ligands are widely expressed on the NK-cell surface: TNF, TNF-related apoptosis-inducing ligand (TRAIL), lymphotoxin, Fas ligand, 4-1BB ligand, lymphotoxin-like inducible protein that competes with glycoprotein D for binding herpesvirus entry mediator (HVEM) on T cells (LIGHT), OX40 ligand, CD40 ligand, CD30 ligand, and CD27 ligand. In parallel, the TNF family of receptors, TNF receptor, TRAIL receptor, lymphotoxin receptor, Fas, 4-1BB, HVEM/LTβ receptor, OX40, CD40, CD30, and CD27 are expressed in many tumor cell lines.39–43 The complementary binding between TNF ligands and TNF receptors can efficiently induce tumor cell apoptotic death. Hence, engineered or induced expression of TNF family receptors on cancer cells represents 1 avenue being actively pursued for active immunotherapy. Moreover, LIGHT/HVEM (LTβR) signaling helps develop the adaptive immune response through priming and recruiting tumor-specific T cells.44–46 NK cells, activated by LIGHT, produce IFN-γ to directly promote the expansion and differentiation of T cells. Studies from mouse LIGHT tumor model suggest that intratumoral NK cells and local IFN-γ are required for priming cytotoxic T cells and tumor rejection.46

Tumors coated with antibodies against cell-surface molecules can be directly recognized by several innate immune cells through Fc receptors (FcR), the receptors for immunoglobulin. The FcR for IgG (FcγR) include 2 functional types of receptors, activating and inhibitory receptors. Antibody-coated tumor cells can be killed by NK cells or macrophages with activating FcγR, termed antibody-dependent cell-mediated cytotoxicity.47,48 NK cells solely express the activating FcγR CD16 for IgG49 without inhibitory FcγR detected.

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Apoptotic tumor cells can be efficiently eliminated by macrophages to avoid autoimmunity. These tumor cells express the so-called “eat me” molecules at cell surface (Fig. 1) for recognition and phagocytosis by macrophages. These signals include lipid phosphatidylserine (PS), oxidized PS, oxidized low-density lipoprotein, and the multifunctional protein calreticulin (CRT).50 These molecules are translocated or redistributed to expose at the tumor cell surface during apoptosis.51,52 CRT is also associated with the CD91 receptor on macrophages and involved in the engulfment of apoptotic cells through interaction with soluble complement protein C1q and its ligand PS. Scavenger receptors, such as SR-A, CLA-1, CD36, CD68, LOX-1, and stabilin-2, can bind oxidized PS and oxidized low-density lipoprotein motifs on apoptotic tumor cells. T-cell immunoglobulin mucin (TIM) proteins (TIM-1, TIM-3, and TIM-4) were recently identified as critical receptors for PS to mediate uptake of apoptotic cells.53–55 CD36 may also form complex receptors with αvβ3 integrin on macrophages, whereas CD14 on macrophages can serve as the receptor for intercellular adhesion molecule-3, and trigger phagocytosis and clearance of apoptotic cells.56 Under normal circumstances in the tumor environment, the interaction between apoptotic tumor cells and macrophage phagocytes leads to immune tolerance without provoking significant proinflammatory cytokines. Unlike NK cells, macrophages express both activating and inhibitory FcγR simultaneously. Activating FcγR stimulate cytotoxicity to tumor cells. In contrast, FcγRIIB is the only inhibitory receptor on macrophages in mice, which is responsible for inhibitory effects on macrophage including inhibition of phagocytosis, decreased cytokine release, superoxide production, and blocking Toll-like receptor 4 (TLR4) signaling pathway.57

In the tumor milieu, macrophages are believed to be major contributors to the chronic inflammation that renders an immune suppressive environment benefiting tumor growth.2 Direct and indirect interactions of macrophages and cancer cells in the previously mentioned and following sections provide molecular mechanisms underlying such effects.

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DCs are perhaps the most potent professional antigen-presenting cells, and bridge between innate and adaptive immune system. The 2 major groups of DCs are known as the myeloid DCs and the plasmacytoid DCs. Functional subsets of myeloid DCs in the skin, epidermal Langerhans cells, and dermal interstitial DCs are also characterized with distinct immune induction potentials. Activated epidermal Langerhans cells secret interleukin 15 (IL-15) and induce CD4+ and CD8+ T-cell priming to elicit cellular immunity. Dermal interstitial DCs stimulate B-cell priming to produce humoral immunity.58,59 Engaging DCs using different receptors and subpopulations may stimulate different inflammation responses, producing multiple T-cell outcomes including T-helper cells of type 1 (Th1), Th2, Th17, Th21, and T-regulatory cells.

With respect to direct interactions with cancer cells, DCs phagocytose apoptotic cancer cells using αvβ5 integrin and CD36 receptors.60 Similar to macrophages, DCs can recognize the so-called “eat me” signals on apoptotic cells through endocytotic receptors, scavenger receptors, and TIM receptors. In addition, the apoptotic cell marker PS can be captured by TAM receptor protein tyrosine kinases (TYRO3, AXL, and MER) on DCs and macrophages using molecular linkers Gas6/protein S, and through αvβ3 integrin using linker MFG-E8. TAM receptors promote phagocytosis of apoptotic tumor cells and inhibit inflammation in DCs and macrophages.61–63 The integrin αvβ3 complex is able to mediate engulfment of apoptotic cancer cells.64,65 Similar to macrophages, phagocytosis of apoptotic tumor cells by DCs in the absence of danger signals generally leads to immune tolerance.

DCs also express both activating and inhibitory FcγR. Comparing to other fashions of antigen uptake, antibody-coated tumor cells are more efficiently internalized into DCs through activating FcγR, leading to more efficient MHC class I and II-restricted antigen presentation and induction of tumor-specific effector and memory T cells.66 Therefore, inflammation and adaptive immune response could be trigged by DC-cancer cell encountering through activating FcγR signaling pathway, and this process is negatively modulated by coexpression of inhibitory FcγRIIB and TAM receptors on DCs. However, it is necessary to note that uptake of antigens does not accompany induction of effector T cells. The induction of active adaptive immunity requires danger signals or maturation of DCs during antigen encountering as discussed in the following sections.

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PMN and Mast Cells

Tumor-associated PMN and mast cells can have a significant role in tumorigenesis and metastasis.67 However, fewer studies have been focused on the direct molecular recognition between tumor cells and PMN. The known examples are activating and inhibiting FcγR on PMN and mast cells to interact with antibody-coated antigens on tumor cells. Activating FcγR induces neutrophils to release cytokines and chemoattractants which influence recruitment and activation of DCs and macrophages in tumor environment.48,68,69 Activation of inhibitory FcγRIIB on neutrophils decreases products of reactive oxygen species, which are cytotoxic against tumors. Although in mast cells, stimulating FcγRIIB can decrease IgE-mediated release of granular molecules, IL-4 cytokine, and histamine which trigger inflammatory response in tumor environment.57 One study has shown that increased direct contact between tumor cells and PMN plus macrophages in mice is responsible for resisting lethal doses of cancer cells.70,71 However, the molecular mechanism for such efficacy remains unclear.

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A few NK–cell-based cancer therapies are now being tested in clinical trials, most of which utilize direct cytotoxic activity of NK cells against cancer, such as activation of NK–cell-surface stimulatory receptors or blocking surface inhibitory receptors. On the basis of preclinical studies showing tumor regression induced through genetic overexpression of NKG2D, several drugs that selectively upregulate NKG2D ligands on tumor cells are introduced to complement chemotherapy such as DNA damage-inducing cisplatin and 5-fluorouracil,72 the histone deacetylase inhibitor sodium valproate.73 Low-dose proteasome inhibitor bortezomib has also been applied in human breast cancer74 and hepatocellular carcinoma75 to increase NK-activating ligands and subsequent tumor lysis. TRAIL on NK cells can efficiently trigger cancer cell apoptosis even after chemotherapy, which induces resistance to intrinsic apoptotic process in cancer. Thus, modulating TRAIL pathway on NK cells is also a new approach combining NK–cell-based therapy with chemotherapy.76,77 In addition to activation of NK-surface stimulatory receptors, therapeutic monoclonal antibodies such as the anti-KIR monoclonal antibody blocking inhibitory signaling in NK cells have been tested in clinical trials on acute myeloid leukemia and multiple myeloma patients.78

Several clinically useful monoclonal antibodies have now been approved for lymphoma and leukemia, with some functioning in part through antibody-dependent cell-mediated cytotoxicity, such as B-lymphocyte antigen CD20-targeted humanized monoclonal antibodies rituximab, tositumomab, and veltuzumab.79,80

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In addition to the direct cancer/innate immune system interactions, a large number of molecules released due to cancer cell death, may function as DAMPs and interact with innate immune cells (Table 1). Such cancer-derived DAMPs include both intracellular molecules and extracellular matrix (ECM) molecules released from apoptotic and necrotic tumor cells. Intracellular molecules that can function as DAMPs include heat shock proteins (HSPs), high-mobility group box-1 protein (HMGB1), adenosine triphosphate (ATP), mitochondrial formyl peptides, mitochondrial DNA, and uric acid. Special attention is given to NY-ESO-1 and possibly others, which are initially identified as TAAs but lately have been recognized with similar properties as DAMPs. ECM danger molecules include hyaluronan and heparan sulfate fragments, S100 family proteins, fibronectin, surfactant protein A, biglycan, versican, and so on. TLRs on innate immune cells represent the major pattern recognition receptors sensing DAMP-related danger signals.11 Other receptors such as cytoplasm NOD-like receptors and RIG-I-like receptors also play significant roles in responding to DAMPs derived from cancers.115

Table 1

Table 1
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The exact nature of these DAMPs in the cancer microenvironment and their contributions to the cancer-associated inflammation and immunity are yet to be clearly understood, which are now an active area of investigation. Nevertheless, it is believed that cancer-derived DAMPs and their partner receptors represent new molecular targets with potentially significant immunological outcomes upon intervention.

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HSPs are house-keeping proteins that are widely expressed in most cells, and are molecular chaperones under normal and stressed conditions. HSPs from necrotic tumor cells display immunological properties characterized by induction of DC maturation, inflammatory cytokine production, and stimulation of NK-cell cytotoxicity.116 Some of these activities are related to promoting tumor growth,117 whereas others contribute to antitumor immunity. HSP90, Gp96, CRT, HSP70, HSP110, and Grp170 can function as chaperones of polypeptides in cancer. Tumor-derived HSP-peptide complexes can be taken up by antigen-presenting cells such as macrophages and DCs and cross-presented by MHC class I molecules, which makes HSPs excellent carriers for cancer vaccines. Scavenger receptors and CD91 are common recognition receptors for HSPs on macrophage and DC surface.81 Among various HSP family members, HSP70, GRP78, and Gp96 have been found immunogenic in cancer patients, and also qualify as TAAs.118–120 TLR2/TLR4 have been indicated as the major receptors involved in HSP70-mediated and Gp96-mediated DC activation through the MyD88/NF-κB pathway,82 although conflicting data suggested that stimulation of TLR2 or TLR4 could be caused by microbial contaminants in the purified HSP preparations. Other cell-surface receptors are also indicated in HSP signaling, such as CD14 and CD40 in HSP70-mediated DC activation and scavenger receptor LOX-1 in HSP70-mediated antigen cross-presentation.83

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HMGB1 is a widely expressed protein normally located in the cell nucleus and functions as a DNA-binding transcriptional factor. However, it can be released as a secreted protein from necrotic and apoptotic cancer cells.121 In necrotic cell death, emitted HMGB1 contributes to inflammation in activating DC/macrophage to secret IFN-α, TNF-α, IL-12, and IFN-γ, upregulate CD80 and CD86 costimulatory molecules, and induce adaptive CD8+ T cells.121,122 In contrast, oxidized HMGB1 delivers tolerogenic signals during apoptosis. Extracellular HMGB1 usually associates with other molecules correlating with differential binding to DC/macrophage cell surface receptors. For example, HMGB1/DNA/RNA complex signals through receptor for advanced glycation end products.84 HMGB1/IL-1β associates with the IL-1R/IL-1RAcP complex.85 HMGB1 and lipopolysaccharide complex can activate TLR4,86,87 whereas HMGB1/nucleosome preferentially engages TLR2.88 HMGB1/CXCL12 associates with receptors CXCR4, TLR4, and receptor for advanced glycation end products.89 HMGB1 has also been reported to directly bind to triggering receptor expressed on myeloid cell-1.90 Proinflammatory responses are usually caused by the previously mentioned HMGB1 and associated partners, whereas several binding receptors of HMGB1 suppress its proinflammatory effects, such as CD24 and thrombospondin.91

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ECM Components

Multiple ECM components are upregulated or degraded in cancer, serving as proinflammatory mediators mostly through pattern recognition receptors TLR2 or TLR4 or both. Biglycan, an ECM proteoglycan liberated during inflammation, activates p38, ERK, and NF-κB signaling pathway through receptors TLR2 and TLR4 in macrophage and induces the production of inflammatory cytokines TNF-α and chemokine macrophage inflammatory protein-2.92 ECM degradation product of polysaccharide fragments derived from hyaluronic acid93 and heparan sulfate94 have revealed new roles for immunomodulatory signals eliciting DC maturation using TLR4. S100A8/S100A9 proteins, another family of endogenous DAMP molecules, can specifically interact with the TLR4-MD2 complex on phagocytes, which results in elevated expression of TNF-α and stimulation of chemotactic response. This includes the secretion of proinflammatory chemokines IL-8, upregulation of adhesion molecule intercellular adhesion molecule-1 and adhesion receptor CD11b/CD18.95,96 Fibronectin and surfactant protein A may also be recognized by TLR4 promoting expression of genes involved in the inflammatory response.97,98 Recent studies suggest that versican, a large ECM proteoglycan that accumulates in the mouse Lewis lung carcinoma microenvironment, stimulates tumor infiltrating macrophages (using TLR2, and coreceptors TLR6 and CD14) to produce IL-6 and TNF-α, and accelerates Lewis lung carcinoma metastasis.99 Versican is also accumulated in stroma surrounding human skin tumors induced by UV, colocalizing with infiltrating neutrophils.100

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Recent evidence show that high levels of extracellular ATP can function as an endogenous danger signal and proinflammatory factor.101 High concentrations of extracellular ATP are quickly detected after tumor death induced by stress and chemotherapeutic agents.102 ATP is believed to play an important role in rendering the “immunogenic” death of tumor (late-stage apoptosis and necrosis) and induction of anticancer immune response accompanied with chemotherapy.103 After chemotherapy, ATP emitted from dying cancer cells engages the purinergic receptor P2X7 on immature DCs, activating the NOD-like receptor family, pyrin domain containing-3 protein (NLRP3) inflammasome, and driving the secretion of IL-1β. IL-1β then contributes to adaptive immunity against cancers, including priming IFNγ-producing CD8+ T cells.104

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Mitochondrial DAMPs

Mitochondrial DAMPs are newly identified intracellular DAMPs that can be released into the circulation from shock-injured tissues, which can elicit significant immune consequences.123 Among them, mitochondrial formyl peptides activate human PMN through formyl peptide receptor-1105; mitochondrial DNA, which are evolutionarily derived from bacteria, is recognized by innate immune system using TLR9, that similarly binds bacterial DNA. Mitochondrial DAMPs promote PMN Ca2+ flux, activate p38 mitogen-activated protein kinase107 and p44/42 mitogen-activated protein kinase,106 and induce PMN to secrete IL-8 and matrix metalloproteinase-9. This has lead to PMN migration, degranulation, and contribute to systemic inflammatory responses in vivo. Dying tumor cells may also release mitochondrial debris containing formyl peptides and DNA, producing similar immune outcomes.

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Uric Acid

Uric acid is a by-product of nucleic acid metabolism, which can be released from dying tumor cells and serve as a DAMP alert, shaping both the innate and adaptive immune responses.108 First, uric acid crystals may form in tumor cells with high contents of nucleic acids, which are able to upregulate costimulatory molecules on immature DCs and subsequently prime CD8+ T cells.109 Second, in cooperation with NF-κB activation (such as that caused by lipopolysaccharide), uric acid crystals have recently been shown to induce DCs to secrete IL-1α/β, IL-6, and IL-23, which subsequently drive proinflammatory Th17 differentiation of naive CD4+ T cells.110 IL-1 then binds to the IL-1 R and signals through MyD88 to amplify proinflammatory responses, including neutrophil recruitment.111 The effect of Th17 differentiation is dependent on the NLRP3 inflammasome, and cytokines IL-1α/β and IL-18. The receptor that identifies uric acid crystals is not clear. The binding of uric acid crystals with immature DCs seems not to be mediated by a specific receptor on the cell surface, but instead depends on directly engaging the cholesterol-rich membrane lipid rafts and Syk kinase activation.112

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TAAs and DAMPs

TAAs are usually defined based on their recognition by spontaneous T-cell and antibody responses in cancer patients. When encountering antigen-presenting cells, TAAs themselves are generally perceived as by-standers that rely on the previously referenced “danger signals” to initiate adaptive immune responses. According to this paradigm, TAAs will be mostly resulted from the neopeptides of genetic mutations in cancer cells. However, human TAAs identified to date are commonly seen as nonmutated self-proteins.3 It is speculated that direct interactions may exist between some TAAs and the innate immune cells, which may play a role in the initiation of adaptive antitumor immunity in vivo. In search of intrinsic factors derived from TAAs that contribute to antitumor immune responses, our laboratory has been focused on NY-ESO-1, a nonmutated cancer/testis antigen with distinctively strong immunogenicity.124 Spontaneous antibody and T-cell immune responses against NY-ESO-1 are readily detectable in a wide spectrum of cancer patients with NY-ESO-1-expressing tumors, including older patients with late-stage cancers, whose immune systems are known to be less responsive. The immunogenicity of NY-ESO-1 is not due to its higher level of expression compared with other TAAs. Indeed, at least in melanoma, the expression of NY-ESO-1 is much lower than that of melanocyte differentiation antigens such as gp100, MART-1, TRP-1, and TRP-2, as well as other cancer/testis antigens, such as MAGE-1 and MAGE-3.125 Our recent investigation of the specific interaction between polymeric NY-ESO-1 and TLR4/CRT on the surface of immature DCs, macrophages, and monocytes indicates a unique interaction between NY-ESO-1 and the innate immune system.113,114 Although the exact signaling events of NY-ESO-1/DC interactions still need to be elucidated, NY-ESO-1 is shown to serve as an endogenous molecular adjuvant in antitumor immune responses. Expression plasmids encoding NY-ESO-1 fused with TAA carbonic anhydrase 9 generated robust antibody responses against the otherwise nonimmunogenic protein in mice.114

NY-ESO-1 thus represents the first example of a cancer/testis antigen that is also a DAMP. In contrast, antibody (and maybe T cell) responses against well-known protein DAMPs, such as HSP70, GRP78, and HMGB1 are present in various cancer patients.118–120 These DAMPs are thus also TAAs, supporting the cross-over roles between TAAs and DAMPs, that is, certain TAAs may serve as DAMPs and certain protein DAMPs may serve as TAAs.

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Targeting TLRs

Current strategies in clinical development include: (1) TLR functional blockade using neutralizing antibodies and antagonists; (2) TLR signaling pathway inhibitors; and (3) the use of TLR agonists alone or as vaccine adjuvants.126–129 We emphasize on TLR agonists in immunotherapy of solid cancers in the following paragraph.

Because of complicated and sometimes adverse immune effects of TLR agonists, their overall use as cancer monotherapies is limited locally but not systematically. So far, TLR agonists approved by the Food and Drug Administration for clinical use in cancer treatment consist of the classic Bacillus Calmette-Guein (mycobacterium mixture) targeting TLR2, TLR4, and TLR9 for bladder cancer,130 imiquimod (small-molecule single-stranded RNA) targeting TLR7 for superficial basal cell carcinoma,131,132 and the AS04 adjuvant system (detoxified lipid A on aluminum hydroxide) targeting TLR4 for human papillomavirus as a prophylactic cervical cancer vaccine.127 Several other TLR agonists, such as CpG oligodeoxynucleotides targeting TLR7, polyriboinsinic-polyribocytidylic acid targeting TLR9, and flagellin-protein fusions targeting TLR5 are being actively evaluated as adjuvants in multiple cancer indications.133 For example, a small single-stranded RNA molecule-based TLR7 agonist, 852A, stimulates immature DCs to produce multiple cytokines including IFNα in vitro and in vivo. It is now being evaluated in a phase II clinical trial for treatment of inoperable melanoma.134 There are also numerous efforts to discover new TLR agonists with low toxicities and improved systemic antitumor effects from natural product extracts analysis and structural modifications. TLR agonists are being exploited as adjuvants in cancer vaccines based on their ability to induce maturation of antigen-presenting cells.133 They can also combine with chemotherapy, radiotherapy, or monoclonal antibodies to improve efficacy.

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Molecular Adjuvant Effect of HSPs and Other DAMPs

HSPs have been applied as carriers/adjuvants for cancer vaccines in clinical trials. The most commonly used approaches include autologous tumor-derived HSP-polypeptide complexes and chimeric HSP-TAA fusion proteins. Promising effects are being obtained in clinical trials using Gp96 complex purified from patients’ own cancers including glioma, renal cell carcinoma, melanoma, and pediatric neurological cancer patients. For example, in a phase II trial carried out in stage IV melanoma patients treated with autologous tumor-derived Gp96, 28 among 39 patients had residual measurable disease, whereas 11 were disease free after surgery.135 In another phase II study of HSP-polypeptide complex for patients with metastatic renal cell carcinoma, 2 patients had a partial remission, 1 had a complete remission and 18 had stable disease, among 61 patients treated. These HSP-based vaccines exhibit minimal toxicity and promising antitumor activity.83 Phase III clinical trials have been initiated in advanced melanoma and kidney cancer with earlier stage disease.136

Preclinical studies have indicated potential advantages in cancer vaccine-induced helper T cells and cytotoxic T cells generated through activating immature DCs directly with DAMPs rather than indirectly using proinflammatory or activating cytokines provided by neighboring cells.137,138 In particular, after the recognition of the mechanism of immunogenicity, HMGB1 and NY-ESO-1 are being studied in preclinical investigations as immune adjuvants with perspectives as potential vaccine adjuvants in human trials in the future.114,139 DAMPs, due to its limited toxicity comparing with bacterial and viral products, are attractive candidates of molecular adjuvant development.

Other areas of clinical development exploiting cancer/innate immune cell interactions, such as blocking DAMPs that are associated with chronic inflammation for the prevention and treatment of cancer, blocking or enhancing cytokines/chemokines in cancer biotherapy, utilization of growth factors to increase the number of DCs, and other antigen-presenting cells, have been the subject of other review articles1,2,140 and not explicitly discussed here.

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Spontaneous immune responses against cancer are complex and can be well summarized in the immune editing model.5 In most patients present at the clinic, chronic inflammation and immune suppression are the dominant effects in the tumor microenvironment. However, this does not exclude the existence of cancer-derived intrinsic factors that may have a powerful activation effect to the immune system. By dissecting the molecular details of cancer and innate immune system interactions as summarized in Figure 1 and Table 1, we hope to individually identify cancer-derived intrinsic factors involved in this complex network and point to areas with the potential of tipping the balance through immunological interventions. These factors are composed of certain cancer-derived DAMPs as well as their partner receptors on the immature DCs, which represent new molecular targets for immunotherapy of cancer in the future.

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The authors are thankful to the support of the NIHR21CA137651 Grant under the American Recovery and Reinvestment Act and the Research Scholar Award (#RSG-08-070-01-LIB) from the American Cancer Society. Robert M. Prins, PhD and David H. Nguyen, PhD of UCLA provided helpful discussions for the draft of this manuscript.

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This study was funded by the National Institutes of Health (NIHR21CA137651) and the American Cancer Society (RSG-08-070-01-LIB).

The authors declare that there are no financial conflicts of interest in regard to this work.

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innate immune system; apoptosis; necrosis; damage-associated molecular pattern; immunotherapy; dendritic cell; tumor-associated antigen

© 2012 Lippincott Williams & Wilkins, Inc.

Study Provides Insight Into Pancreatic Cancer Progression, New Target for Treatment

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Posted 12 Jun 2012 — by James Street
Category Immune System, Pancreatic
Released: 6/11/2012 12:10 PM EDT
Source: NYU Langone Medical Center

Mystery of How Pancreatic Cancer Escapes Immune Detection is Unraveled,
Offering Hope for Treatment

Newswise — NEW YORK, June 11, 2012 – Researchers at NYU School of Medicine have made a key discovery that could help doctors treat one of the deadliest cancers.

A new study reveals a strategy used by pancreatic cancer cells to tinker with the immune system in a way that enables them to escape destruction by specialized immune cells.

The study, funded by the National Institutes of Health, The Pancreatic Cancer Action Network and by The Irvington Institute Postdoctoral Fellowship Program of the Cancer Research Institute, appears in the June 12 issue of Cancer Cell.

Pancreatic cancer is known for its aggressive nature. Only four percent of patients survive past five years from the time of diagnosis, and currently available therapies are largely ineffective.

“It is extremely important that we learn how the advancement of pancreatic cancer is being regulated in an effort to interrupt the progression of the disease,” said senior author Dafna Bar-Sagi, PhD, senior vice president and vice dean for Science and chief scientific officer at NYU School of Medicine.

Using mouse models of pancreatic cancer, Dr. Bar-Sagi and colleagues found that a mutation of the KRAS gene, present in 95 percent of all pancreatic cancers, triggers the expression of a protein called GM-CSF. The tumor-derived GM-CSF then directs accumulation of myeloid-derived suppressor cells in the area surrounding the tumor. These cells suppress the body’s natural immune defense reaction to growing tumor cells. In this way, pancreatic cancer cells escape being seen by the body’s immune system and are free to grow and divide. Establishment of an immunosuppressive environment around pancreatic cancer cells, therefore, prevents their prompt rejection by the immune system.

By blocking production of GM-CSF in pancreatic cancer cells, the researchers found that they were able to disrupt accumulation of myeloid-derived suppressor cells, liberating the tumor-killing immune response. “Our study suggests a therapeutic strategy for harnessing the anti-tumor potential of the immune system,” Dr. Bar-Sagi explained.

“Our findings should be applicable to a significant proportion of human pancreatic cancer cases, as the vast majority of human pancreatic cancer samples that we tested express the GM-CSF protein prominently,” Dr. Bar-Sagi added. The researchers are hopeful that their findings will open new doors in therapeutic research, eventually leading to new drug therapies that block the production or function of the GM-CSF protein to allow anti-tumor immune cells to attack the cancer cells and halt tumor development.

Although the study focuses on pancreatic cancer, KRAS mutations are prevalent in a number of other cancers, including colon and lung cancer. “From a research standpoint, the contribution of KRAS mutation to the production of GM-CSF is a very exciting find, as it may have important implications for the therapeutic management of other cancers, as well,” Dr. Bar-Sagi said.

Co-authors on the study include first author Yuliya Pylayeva-Gupta, PhD, Kyoung Eun Lee, PhD, Cristina H. Hajdu, MD, and George Miller, MD, all of NYU School of Medicine.

About NYU School of Medicine:
NYU School of Medicine is one of the nation’s preeminent academic institutions dedicated to achieving world class medical educational excellence. For 170 years, NYU School of Medicine has trained thousands of physicians and scientists who have helped to shape the course of medical history and enrich the lives of countless people. An integral part of NYU Langone Medical Center, the School of Medicine at its core is committed to improving the human condition through medical education, scientific research and direct patient care. The School also maintains academic affiliations with area hospitals, including Bellevue Hospital, one of the nation’s finest municipal hospitals where its students, residents and faculty provide the clinical and emergency care to New York City’s diverse population, which enhances the scope and quality of their medical education and training. Additional information about the NYU School of Medicine is available at

The Ludwig Institute for Cancer Research announces launch of iTeos Therapeutics SA

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Posted 06 May 2012 — by James Street
Category Immune System

May 3rd, 2012

The Ludwig Institute for Cancer Research (LICR) announced today the launch of a private biotechnology enterprise, iTeos Therapeutics SA, to develop a novel pre-clinical pipeline of immunomodulators to stimulate the immune system’s ability to attack cancer. Founded by LICR with the de Duve Institute at the Université catholique de Louvain (UCL), iTeos is led by a team experienced in tumor immunology, immunotherapy, drug discovery, business development and entrepreneurship. iTeos is the ninth new company formed based on innovative cancer research discoveries licensed from LICR.

The field of cancer immunotherapy has come to the fore in the last two years with the approval of drugs and vaccines that harness the power of the immune system to treat cancer patients more safely, efficiently and effectively. However, therapeutic uses of these treatments can be limited as the tumors often develop mechanisms that enable them to escape the immune system. iTeos brings together world-class expertise in tumor immunology and immunotherapy, with a focus on developing small molecule immunomodulators to counteract cancer immunosuppression.

“Immunotherapy – boosting the body’s natural immune system to fight cancerous tumors – is the next frontier in life-extending cancer treatment,” said Benoît Van den Eynde, M.D., Ph.D., Brussels Branch Director at LICR, UCL Professor and co-founder of iTeos. “Effective immunotherapy treatments enable the body’s immune system to ‘re-engage’ in destroying tumor cells, thereby potentially creating better patient outcomes with fewer side effects when compared to conventional cancer treatments.”

“iTeos’ mission is to translate pioneering scientific discovery into meaningful treatments for people living with cancer,” said iTeos co-founder and CEO Michel Detheux, Ph.D. “We now know that combination treatments are likely to be more effective than single therapies in controlling and eventually eliminating cancer. iTeos will pursue this approach by combining existing vaccines with new immunodulatory compounds based on research that has just emerged from the Ludwig Institute.”

iTeos’ initial goals are to reach a proof of concept in humans by completing a Phase I/IIa study for the first compound program and to submit an Investigational New Drug application for a second candidate in four years.

Ludwig and UCL scientists, led by Dr. Van den Eynde, recently made the breakthrough discovery of the potential role of TDO in immunotherapy. TDO is a critical enzyme that is produced by a significant number of human tumors. In research published in the 30 January 2012 issue of Proceedings of the National Academy of Sciences, Dr. Van den Eynde’s team showed that blocking TDO with a novel inhibitor promotes tumor rejection in mice. This team was also responsible for recognizing the role that a similar enzyme, IDO, plays in tumor growth. TDO and IDO inhibitors are now in preclinical development at iTeos.

“Preclinical studies suggest that TDO inhibition may be beneficial in treating bladder, liver and melanoma skin cancers. Suppressing IDO may help to positively impact ovarian, prostate, pancreatic and colorectal cancer treatment among others,” said Dr. Detheux. “iTeos’ focus is to bring these and other truly novel compounds to become part of the standard of care for cancer treatment.”

“LICR has the expertise to conduct and administer its own early phase clinical trials as part of its technology development process,” said Jonathan Skipper, Ph.D., Executive Director of Technology Development at LICR. “Spin-off companies, such as iTeos, have access to this infrastructure so that candidate therapeutics can be further tested. This allows LICR to continue to have input into the development of its discoveries and, more importantly, ensure promising new therapies will eventually reach patients.”

Strong third-party endorsement is behind iTeos, including early funding by the Belgian Walloon Government. In fact, the creation of the spin-off was made possible by the grant from a Walloon FIRST spin-off mandate. Then, in December 2011, the Walloon Government awarded iTeos a research grant for $8M (€6M). This support builds upon the progress of an earlier government program, the Biowin Pole of “Plan Marshall,” aimed at the development of small molecule inhibitors.

Provided by Ludwig Institute for Cancer Research

Insight: New doubts about prostate-cancer vaccine Provenge

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Posted 31 Mar 2012 — by James Street
Category Immune System, Prostate Cancer, Provenge, vaccination

Fri, Mar 30 2012

By Sharon Begley

NEW YORK (Reuters) – Prostate cancer vaccine Provenge has long incited passions unlike any other cancer therapy.

Doctors who raised doubts about it received death threats. Health regulators and lawmakers faced loud protests at their offices. A physician at the American Cancer Society was so intimidated by Provenge partisans that he yanked a skeptical discussion of it from his blog.

The vitriol dissipated in April 2010, when the U.S. Food and Drug Administration approved Provenge for advanced prostate cancer, satisfying investors in manufacturer Dendreon and patients who for years had demanded it be put on the market.

But the bell on Round Two sounded when Marie Huber, a trained scientist and former hedge-fund analyst, made it her mission in the last year to analyze what she believes are deadly flaws in the studies that led to the approval of Provenge by the FDA.

She argues that the main reason Provenge seemed to extend survival – a crucial factor in the FDA’s decision – was that older men in the study who did not receive Provenge died months sooner than similar patients in other studies.

She raises the possibility the “placebo” they received was actually harmful and made Provenge, known scientifically as sipuleucel-T, look better by comparison.

As Huber gains traction, most notably with a February paper in the prestigious Journal of the National Cancer Institute, she, too, is receiving threats. One post on an investors’ message board last month suggested that “somebody smack her with a rubber hose.” An email said “don’t think you will be unscathed in this battle you waged on Provenge.”

Provenge is Dendreon’s only product and the company’s stature with investors has waned with disappointing sales. In 2011, product revenues totaled $213.5 million, far from the $400 million Dendreon initially projected.

The company insists Huber’s analysis is flawed and that Provenge has helped thousands of men with prostate cancer.

“I’m looking forward to getting this to patients around the world,” said President and Chief Executive John Johnson.


Since it won FDA approval two years ago, Provenge has been Exhibit A for the idea that a patient’s immune system can control or cure cancer. The first therapeutic cancer vaccine to reach the market, Provenge tries to engineer white blood cells, part of the immune system, to vanquish prostate cancer, which killed an estimated 33,720 men in the United States last year.

Its path to approval has all the features of a heavyweight healthcare fight – desperate patients demanding access to a promising therapy, a very expensive drug that extends life only a few months and efficacy data open to interpretation.

The FDA declined to approve the drug in 2007, when a clinical trial failed to show it slowed tumor growth. That incited protests, lawsuits and death threats against physicians on the FDA advisory panel who did not recommend approval, breaking with the 13-4 majority in favor.

“Provenge came along when we didn’t have much to offer for prostate cancer,” said Dr. Len Lichtenfeld of the ACS. “The advocacy community was bursting at the seams for something that worked. When you have that situation, it inflames passions and that can overtake the science.”

In the pivotal trial called IMPACT, published in July 2010, but shared with the FDA months earlier, Provenge extended median survival by 4.1 months to 25.8 months from 21.7 months. That was sufficient for FDA approval. The vaccine costs $93,000 and patients also incur physician and other charges. Medicare agreed to cover Provenge last year, as have private insurers, but doctors initially balked at a long wait for reimbursement.

Huber had long been “utterly intrigued” by Provenge and its “huge promise of harnessing the immune system to battle cancer,” she said in an interview.

In documents JNCI requires authors to sign, she declared no financial conflicts of interest. Neither she nor her former firm nor anyone else she is connected to stands to benefit financially from her analysis, she said.

Instead, she says she is motivated to help “vulnerable and desperate patients” – so much so that she gave up her job, salary and health insurance. Arguing that Provenge is harming these men, she called “the whole thing utterly horrific. The company got away with hiding data and doctors making $7,000 per prescription won’t even engage in discussion” about whether it helps their patients.

After receiving degrees in biochemistry and bioscience enterprise from Cambridge University, Huber began working as an analyst for a hedge fund in 2007. A Thomson Reuters analysis of securities filings confirmed her former firm has not held any positions in Dendreon.


Each dose of Provenge is custom-made. A nurse or technician withdraws white blood cells from a man’s arm in a three-to-four hour procedure called leukapheresis.

The cells are shipped to a Dendreon manufacturing facility, where for two days they are incubated with a “fusion protein:” One protein that stimulates the cells’ growth and maturation and another called PAP, or prostatic acid phosphatase. PAP is an antigen that studs prostate cancer cells like antennae, pieces of it sticking out of the cells’ surfaces.

Dendreon says the patients’ white blood cells take up the antigen and within hours their surfaces bristle with fragments of the telltale molecule. The cells are then shipped back to the physician and infused into the patient. A full treatment includes three such procedures, two weeks apart.

Back inside the body, Dendreon claims the modified cells trigger the immune system to produce T cells that kill any cell sporting the PAP antigen — namely, prostate cancer cells.

In principle, that should eliminate the cancer, but Provenge does not shrink either the primary tumor or metastases.

Steven Rosenberg of the National Cancer Institute, a leading tumor immunologist, says that raises doubts over whether Provenge helps patients live longer, as the IMPACT trial reported.

“We have a lot of data that supports the idea that the product works the way it was designed to,” said Dr. Mark Frohlich, Dendreon’s chief medical officer. “We’re seeing evidence of immune-system activation. The only question is whether the T cells are killing the tumor.”

The FDA acknowledges that data supporting Provenge’s approval did not show the drug shrank tumors, but says the overall survival benefit was enough to bring it to market. Spokeswoman Rita Chapelle, citing data submitted by Dendreon, said there is a “lack of evidence of anti-tumor activity,” the reason for which “is unclear.”


Huber’s analysis comes from data showing that men who received the placebo had very different survival times based on their age. Men older than 65 lived 17.3 months on placebo and 23 months with Provenge. Men younger than 65 lived 28 months after receiving placebo and 29 months after Provenge.

Other studies have shown that age generally does not affect how long a man survives with this form of prostate cancer, says Peter Iversen, a urologist and prostate-cancer surgeon at the University of Copenhagen and co-author of the paper with Huber.

Combining these findings led to the new paper’s conclusion: The four-month edge in median survival from Provenge for all patients was due to longer survival among older men who got the vaccine.

“There is no efficacy in the younger patients, the primary group where you would expect it,” said Huber.

Since the immune system weakens with age, an immune-based therapy should work better in younger men.

Some experts agree.

“If it was really a vaccine, you’d think younger men would show more response, since they are more immunocompetent,” said NCI’s Rosenberg.

On that basis, Huber and her co-authors, including two prostate-cancer specialists, argue the placebo used in the trial may have harmed the older men, cutting months off their lives and inadvertently making Provenge seem beneficial.

One way that could have occurred was through leukapheresis. That process removed about 90 percent of certain kinds of circulating white blood cells, according to calculations by immunologist Laura Haynes of the Trudeau Institute, a co-author of the JNCI paper.

The Provenge men got back about 32 percent of those cells, which had been stored at body temperature. The placebo men got back 12 percent, which had been incubated at near-freezing temperatures. Cold storage has been reported to kill “most, if not all, of those cells,” notes the JNCI paper. Moreover, said Haynes, “if you return dead and dying cells to older men you are likely to cause inflammation,” which can stoke the growth of cancerous cells.

Younger men were better able to replace the lost white blood cells, argued Iversen. Older men could not, resulting in early death.

“These cells are very specialized and there is research suggesting that removing them can harm older men,” he said.

Earlier this month, DynaMed, an online database used by physicians, added to its Provenge entry a note on the JNCI paper, but calls the concern “not substantiated.” ACS’s Lichtenfeld says the analysis “might inhibit some patients and doctors from going ahead with a very expensive drug.”

Huber says she plans to approach European regulators as they consider Dendreon’s application to approve Provenge.

Investor message boards have lit up in response to the new paper. In February, an anonymous commentator on warned that Huber’s work was about to be published “a few days before our earnings. Her agenda is obvious.”


Critics of the new analysis argue the number of cells removed is too small to suppress the immune system. Charles Drake, an oncologist and immunologist at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, said there is no evidence the placebo men in IMPACT suffered more infections or other effects of a depleted immune system than the Provenge men.

The scientist who led IMPACT, oncologist Philip Kantoff of Dana Farber Cancer Center, said colleagues in immunology “dismissed as nonsense the idea that leukapheresis could hurt individuals.”

He takes issue, too, with the statistics. Dividing the men by whether they are older or younger than 65, he said, is “arbitrary” and to pick apart data retrospectively is a statistical no-no.

Dendreon’s Frohlich also criticizes the statistics: “If you do enough of these (post-hoc analyses) then by chance alone you’d expect to get one positive finding.”

In other words, it is almost always possible to find a subset of patients who do better than others.

When Dendreon divided the men by whether they were older or younger than about 71, he added, they found no red flags.

The FDA agrees that such post-hoc statistical analyses “are exploratory” and their results “must be interpreted with caution, as acknowledged by the authors.” Yet a paid consultant to Dendreon before the IMPACT trial agreed with many of Huber’s concerns.

“The control vaccine used in IMPACT and in the predecessor trial had never been used anywhere for anything and may well have been detrimental to patients,” said Donald Berry of MD Anderson Cancer Center, a leading biostatistician. “Here’s a great way to get your drug approved: Kill the control patients.”

Despite the heated rhetoric, Provenge may go out with a whimper more than a bang. Promising new agents for advanced prostate cancer include an oral drug from Medivation Inc called enzalutamide, in the final phase of clinical trials, and Zytiga from Johnson & Johnson, which won FDA approval in 2011. A vaccine that targets PSA, from Bavarian Nordic Immunotherapy, is in late-stage trials.

Dendreon does not disclose how many patients have been prescribed Provenge. CEO Johnson said that about 70 percent of its Provenge revenue comes from sales to community hospitals and doctors and 30 percent from academic medical centers. Some of the latter decline to use Provenge, deterred by lingering concerns over whether it provides a meaningful benefit.

Three such facilities in the Midwest, contacted at random by Reuters, confirmed they do not recommend Provenge. All asked not to be named for fear of receiving threats.

“It is my policy not to make public comments about this drug,” said one oncologist. Patients who ask for it “are referred to another facility.”

(Editing by Michele Gershberg, Ed Tobin and Andre Grenon)

Stanford: Antibody offers hope against cancers

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Posted 31 Mar 2012 — by James Street
Category CD47, Immune System, Monoclonal Antibody

Victoria Colliver

Saturday, March 31, 2012

In a potential breakthrough for cancer research, Stanford immunologists discovered they can shrink or even get rid of a wide range of human cancers by treating them with a single antibody.

The experiments were done on cancerous tumors transplanted into mice, but the researchers hope to move to human clinical trials within the next couple of years.

“We have made what we think is a big advancement … and we’re going to push as hard as we can and as fast we can,” said Dr. Irving Weissman, pathology professor at the Stanford University School of Medicine and director of Stanford’s Institute of Stem Cell Biology and Regenerative Medicine.

The researchers focused on blocking a protein, which they refer to as the “don’t eat me” molecule because it sits on tumor cells signaling the body’s immune system not to attack it. By introducing the antibody, the scientists were able to block the protective signal, otherwise known as CD47, allowing the immune system to go after the cancer cells.

Broad range of cancers

Researchers say CD47 is the only target found so far on the surface of all cancer cells. That means the antibody offers hope as a weapon against a broad range of cancers – breast, ovarian, colon, bladder, brain, liver and prostate.

The research involved taking cells from Stanford cancer patients, planting them into matching locations in the bodies of mice, and then administering the antibody. The antibody completely destroyed the tumor in some cases but also prevented the cancer from spreading.

“The most common result was the tumor growth was inhibited – not fully cured – but in a few weeks dramatically decreased,” said Stephen Willingham, postdoctoral researcher and co-lead author of the study.

The study, published online this week in the journal Proceedings of the National Academy of Sciences, has drawn praise from other researchers.

“The data is indeed exciting, and the effects are significant,” said Tyler Jacks, director of the Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology, who was not involved in the study.

Research on mice

But Jacks noted that the research has been limited to mice, and disease in humans tends to be much more complex.

“That’s a commonly used preclinical model, but there are other examples when therapeutic effectiveness in such models has not translated well in real disease,” Jacks said. “We need to see what happens when the treatments are (used) in patients.”

The Stanford team said the “don’t eat me” CD47 signal has long been identified and is associated, in particular, with the treatment of leukemia. CD47 is found in healthy cells but tends to be expressed in higher levels in cancerous cells.

Limited side effects

The researchers were concerned that any treatment would single out normal cells as well as malignant ones. They discovered, however, that the antibody selected older, red blood cells, causing mild but temporary anemia and no other adverse side effects.

“That was the best moment. We found a way to utilize this antibody to treat (the cancer) without having major toxicity,” said Dr. Jens-Peter Volkmer, the study’s other lead author.

The Stanford team’s continuing research is being funded by a grant from the California Institute for Regenerative Medicine. The organization was created by Proposition 71, passed by voters in 2004 to support stem cell research.

Victoria Colliver is a San Francisco Chronicle staff writer.

Bright future ahead for antibody cancer therapy

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Posted 18 Mar 2012 — by James Street
Category CTLA-4, Immune System, ipilimumab, Melanoma, Melanoma, Monoclonal Antibody

WASHINGTON –Antibodies, once touted as the “magic bullets” of cancer care, are now fulfilling that promise and more advances are on the way, say cancer researchers at the Georgetown Lombardi Comprehensive Cancer Center

In a review article posted online March 16 in Cell, the researchers say that refinements and modifications of monoclonal antibody drugs — several of which have already revolutionized the care of breast and colon cancer –are now being tested in most tumor types.

These modifications allow antibody drugs to bind to more than one target on a cell, and to directly stimulate the body’s immune response to promote vaccine-like antitumor effects. Others have been designed to boost their killing power by carrying a payload of radiation, toxins, or other chemicals.

‘We are heading into an era where antibodies will not just be components of an effective therapeutic strategy, they will be at the core of an oncologist’s treatment plan for patients,” says the review’s lead author, Louis M. Weiner, M.D., director of Georgetown Lombardi Comprehensive Cancer Center, an internationally recognized expert in immunotherapy research.

“Advancement in antibody cancer treatment is not a minor advance or a trivial victory. This is big time stuff,” Weiner said in an interview.

His co-authors on the review are Joseph Murray and Casey W. Shuptrine, both graduate students in the Tumor Biology Training Program at Georgetown Lombardi.

A good example of the new class of antibody-based therapies is ipilimumab, a drug approved in 2011 to treat patients with metastatic melanoma, says Weiner. Ipilimumab is a fully human antibody which binds to an immune antigen (CTLA-4) on cancer cells that transmits a signal inhibiting other immune cells from destroying the tumor. Ipilimumab blocks CTLA-4, thereby inducing an active immune response.

“This agent turns off the brakes of an immune response against melanoma, liberating the body to set up long term protectiion against the cancer,” Weiner says. “About 10 percent of patients with metastatic melanoma who use it go into long-term remission, and may well be cured.”

Antigens are substances, often a cell surface receptor, which causes the immune system to produce an antibody against it, as a way to target and kill the cell. Therefore, antibody agents targeted to a receptor on a cancer cell have the unique capacity to target and kill cancer cells while activating an immune response. A monoclonal antibody (mAb) is an artificially produced antibody designed to bind to a specific cancer antigen, and currently 11 mAbs are approved for use in oncology, Most of these were approved in the last decade. The most commonly used are trastuzumab (Herceptin) to treat HER2-positive breast cancer and rituximab (Rituxan) for specific forms of lymphoma and leukemia.

Advanced antibody engineering techniques are being used to create more effective treatments, Weiner says. One group, known as bispecific antibodies (bsAbs) can bind to two different tumor antigens, or to a tumor antigen and another target in the tumor microenvironment, such as an immune system killer cell. Other mAbs are being designed as “conjugates” to carry a toxic payload, which can be a radionuclide, other drugs, toxins, or enzymes. Researchers are also now increasing the capacity of antibodies to be absorbed by cancer cells so that they can bind to antigens inside the cell – not just on the outside of the cell surface.

“The field of cancer antibodies is definitely maturing. There are scores of new cancer antibody agents now being tested in virtually every kind of solid cancer, and oncologists, researchers and pharmaceutical companies are excited about their promise,” Weiner says. “To me this is like watching a child grow up and do well — very well — in young adulthood.”


The work was supported by funding from the National Cancer Institute. Weiner serves as an expert consultant on cancer immunotherapy to several pharmaceutical companies, none of whose products are mentioned in this article.

About Georgetown Lombardi Comprehensive Cancer Center

Georgetown Lombardi Comprehensive Cancer Center, part of Georgetown University Medical Center and MedStar Georgetown University Hospital, seeks to improve the diagnosis, treatment, and prevention of cancer through innovative basic and clinical research, patient care, community education and outreach, and the training of cancer specialists of the future. Georgetown Lombardi is one of only 40 comprehensive cancer centers in the nation, as designated by the National Cancer Institute, and the only one in the Washington, DC, area. For more information, go to

About Georgetown University Medical Center

Georgetown University Medical Center is an internationally recognized academic medical center with a three-part mission of research, teaching and patient care (through MedStar Health). GUMC’s mission is carried out with a strong emphasis on public service and a dedication to the Catholic, Jesuit principle of cura personalis — or “care of the whole person.” The Medical Center includes the School of Medicine and the School of Nursing & Health Studies, both nationally ranked; Georgetown Lombardi Comprehensive Cancer Center, designated as a comprehensive cancer center by the National Cancer Institute; and the Biomedical Graduate Research Organization (BGRO), which accounts for the majority of externally funded research at GUMC including a Clinical Translation and Science Award from the National Institutes of Health. In fiscal year 2010-11, GUMC accounted for 85 percent of the university’s sponsored research funding.

Research offers new hope in cancer fight

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Posted 11 Mar 2012 — by James Street
Category Immune System, T cells
  • by: Brigid O’Connell
  • From: Sunday Herald Sun
  • March 10, 2012 10:00PM

Cancer cells

A study of the immune system has indicated ways the body fights cancer. Picture: ThinkStock

A MELBOURNE researcher has unlocked the body’s ability to kill cancer cells, paving the way to a treatment without chemotherapy or radiation.

Peter MacCallum Cancer Centre’s Jane Oliaro has deciphered the mechanics in how T-cells – the “soldiers” of the immune system – divide to produce “killer” and “memory” cells that track down and kill infected or cancerous cells.

Dr Oliaro’s work has been honoured in the top 10 research projects by the National Health and Medical Research Council in its annual awards, recognising her work as among the most important in the country.

Dr Oliaro has for the first time shown T-cells divide into two different daughter cells – “killer” and “memory” cells – which are activated by an “antigen-presenting cell” to start killing a particular infection or cancer.

“The antigen-presenting cell engulfs the bacteria and displays it to the T-cell which tells it there’s a foreign pathogen in the body,” she said.

“The T-cell gets woken up and starts multiplying cells that are designed to recognise, target and kill any cell with that bacteria inside it. That’s why our immune system doesn’t deal well with cancer, because cancer arises from our own cells and T-cells are trained not to attack anything that looks like our own cells.”

She is investigating the signals that “switch on” T-cells which determine what types of daughter cells are generated in preparation to fight.

“Our immune system does an excellent job about getting rid of infections in general, and we want to apply that knowledge to fighting cancer,” Dr Oliaro said.

“If these signals can be artificially recreated, scientists could develop a blueprint to reproduce more killer and memory cells.

“With research it’s baby steps, but the more we can learn about this, the more we can manipulate our immune system to produce more killer cells, or more memory cells the body needs to fight cancer without chemotherapy, surgery or radiation therapy.”

Research on Cancer-Fighting Shark’s Blood Gets Boost in Australia

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Posted 11 Mar 2012 — by James Street
Category Immune System, Shark Blood
March 09, 2012Phil Mercer | Sydney

A Sand Tiger Shark swims in its aquarium, File November 9, 2010.

Photo: AP
A Sand Tiger Shark swims in its aquarium, File November 9, 2010.

Australian scientists investigating the cancer-fighting qualities of shark blood have been given a significant funding boost from an international pharmaceutical giant.  The team from La Trobe University in Melbourne says trials indicate shark antibodies can be a potent weapon against malaria and breast cancer.

International pharmaceutical company Roche is funding Australian research into shark blood for six months.  During that time scientists will try to determine if shark-blood antibodies are able to lock onto and neutralize cancer cells.

Shark antibodies are very small, which researchers say makes them particularly good at seeking out and binding to target cells.   Thanks in part to funding from the Bill Gates Foundation, trials have already shown they can be an effective treatment against malaria.

The research started a decade ago and a team from Melbourne’s La Trobe University has created the world’s first ‘test-tube library’ of millions of antibodies from shark blood that could fight cancer and other diseases.  Trials into breast cancer have also started, work that will be accelerated following the deal with Roche.

“There are several-thousand million different anti-bodies,” explained associate professor Mick Foley, explaining the funding deal.  “Really we have just got to find in our library one that will bind to their target and give that to them.  We will license it to them,” he explained. “But we are hoping that, you know, this is just a sort of vote of confidence, if you like, in big pharma (large pharmaceutical companies) that we have something interesting that might be very useful to the broader pharmaceutical industry.”

Foley says his team’s work could provide a breakthrough. “We are researching into sort of, for example, cancers,” Foley said. “So, we have several antibodies that we are looking at, one of which we know in vitro, again in the laboratory, if you put it into breast cancer cells it will stop those breast cancer cells from growing.”

Sharks have immune systems similar to humans, but their antibodies – the molecules that actually fight disease – are different to human anti-bodies and are extremely resilient.

The team in Melbourne found that shark antibodies can withstand high temperatures as well as extremely acidic or alkaline conditions.

Systemic tumor disappearance following local radiation treatment reported in metastatic melanoma patient

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Posted 11 Mar 2012 — by James Street
Category Immune System, Melanoma, Radiation

March 7, 2012 in Cancer

A rarely seen phenomenon in cancer patients — in which focused radiation to the site of one tumor is associated with the disappearance of metastatic tumors all over the body — has been reported in a patient with melanoma treated with the immunotherapeutic agent ipilimumab (Yervoy). Researchers at Memorial Sloan Kettering Cancer Center shared their findings in a unique single-patient study, which could help shed light on the immune system’s role in fighting cancer. Their observations suggest that the combination of ipilimumab and radiation may be a promising approach for the treatment of melanoma. The findings are published as a brief report in the March 8 issue of the New England Journal of Medicine. The work was done at Memorial Sloan Kettering’s Ludwig Center for Cancer Immunotherapy.

Researchers report progress in cancer immunotherapy

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Posted 11 Mar 2012 — by James Street
Category Immune System, Melanoma

They say they boosted the effectiveness in melanoma patients by carefully selecting and cloning T cells from patients’ blood.

In a bid to make cancer immunotherapy more effective, researchers report they have succeeded in halting the progress of aggressive melanoma in its tracks — at least briefly — in seven patients treated with an army of cloned cancer-fighting immune cells. In one of those patients, the treatment resulted in complete remission of his metastatic melanoma and evidence that his immune system stands ready to fight any return of the cancer after three years.

The study, published Monday in the Proceedings of the National Academies of Science, contributes to hopes that a tumor-fighting strategy called immunotherapy can slow, halt or even reverse the growth of a range of cancers — and do so with fewer dangerous side effects.

Immunotherapy is one of medicine’s most promising — and most problematic — approaches to cancer treatment. It aims to charge up the patient’s immune system to attack cancer cells and halt their out-of-control growth.

The approach outlined in the new study by researchers from the Fred Hutchinson Cancer Research Center in Seattle identifies several ways to make it better, said Dr. Cassian Yee, the study’s senior author. The key is to identify specific cancer-fighting cells already circulating in the blood of patients and make thousands of copies of them in the lab.

This type of “adoptive immunotherapy” could be effective against a wide range of cancers, Yee said. His research group is making plans to try the technique on patients with advanced ovarian cancer and sarcomas — rare tumors that arise from connective tissue in bones and muscle.

Several independent researchers said the study results were promising. But they also noted that the trial involved only 11 patients and said the therapy was less effective than in other published trials.

“Someday, cell-based therapy will be mainstream in cancer therapy,” said Dr. Jeff Miller of the University of Minnesota’s cell therapy core laboratory. “Each article that shows clinical activity is giving us a piece of the puzzle” that will make it safer and more effective, he said.

Immunotherapy usually starts with clinicians harvesting immune system cells called T cells that have attached themselves to a tumor in an effort to attack. They then coax the cells to multiply, either in the lab or in the body, and let them loose in the bloodstream so they can attack cancer wherever they find it.

Yee’s team tried to do this more precisely. The researchers hoped that by choosing T cells more selectively and cloning only those judged most likely to vanquish their foe, the treatment would be more effective. Sorting through the body’s vast and diverse population of T cells to select just the right ones is a painstaking process. But Yee bet that the extra effort would pay off with better results and fewer side effects.

Researchers drew blood from patients and scoured it to find the rare type of immune cell — a melanoma-specific cytotoxic T lymphocyte cell — that specifically homes in on proteins expressed by the cancer. Then they put their harvest — as few as a few hundred cells — into a test tube and cloned them, creating millions. The last step was to infuse the resulting army of cancer-fighting clones back into the patient.

In six of the 11 patients in the trial, the melanoma stopped progressing for 12 to 19 weeks. Another patient was declared in remission because his cancer ceased to spread and, after several months, disappeared altogether. Three years later, researchers continue to detect the presence of the cloned cells they infused into the patient, 61-year-old high school history teacher Gardiner Vinnedge of North Bend, Wash.

For six years, Vinnedge endured painful rounds of chemotherapy, only to have his melanoma return. The immunotherapy allowed him to return to work three weeks after treatments began. The only side effect, he said, was a raging rash that lasted for three days.

“My back, my legs were just covered with a hot red rash,” Vinnedge said. “It meant the treatment was working — the war was on between my T cells and the melanin in my skin.” Now he says he is optimistic he may live to see retirement age, though he’s not sure he’ll ever stop teaching.

For immunotherapy to work, the manufactured T cells must survive for the months it takes to reach a tumor and dismantle it, as well as to round up migrating cancer cells and kill them. Currently, the T cells have limited staying power and often die off before their work is done. Doctors give them a boost by administering a growth factor called interleukin-2. But at high doses, it can cause dangerously low blood pressure, breathing problems, kidney failure and heart arrhythmias.

Yee’s group showed that by choosing T cells more selectively, patients can get by with much lower doses of interleukin-2, making the treatment less toxic.

The researchers also discovered another way to reduce their dependence on interleukin-2 — by selecting the most youthful T cells, which survived the longest when infused into patients.

Dr. Patrick Hwu of the MD Anderson Cancer Center in Houston said the study “adds to the wealth of what we know” about using the body’s immune system to fight cancer. But immunotherapy pioneer Dr. Steven A. Rosenberg was highly critical of the methods and results.

“Cloned cells don’t work,” said Rosenberg, who heads the National Cancer Institute’s tumor immunology section. In larger immunotherapy trials that used cultured cancer-fighting immune cells taken from patients’ tumors, Rosenberg and his colleagues achieved “durable and complete regression” in as many as 40% as patients with advanced metastatic melanoma. “These results,” he said, “are inferior.”