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Radiation therapy (RT) and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors mediate poorly overlapping cytostatic and immunostimulatory effects, suggesting that combinatorial regimens may enable supra- additive tumor control. Our preclinical findings demonstrate that administration schedule stands out as a major determinant of efficacy when RT and CDK4/6 inhibitors are combined for breast cancer therapy. [ABSTRACT FROM AUTHOR]

Type I interferon (IFN) release by irradiated cancer cells is paramount for radiation therapy to elicit anticancer immunity. Our findings demonstrate that mitochondrial outer membrane permeabilization (MOMP) triggered by RT enables exposure of mitochondrial DNA to the cytosol, hence setting off CGAS-driven type I IFN synthesis. These data point to the existence of a therapeutically actionable mitochondrial checkpoint that restricts innate immune signaling in irradiated cancer cells. [ABSTRACT FROM AUTHOR]

Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the first, rate-limiting step of the so-called "kynurenine pathway", which converts the essential amino acid L-tryptophan (Trp) into the immunosuppressive metabolite L-kynurenine (Kyn). While expressed constitutively by some tissues, IDO1 can also be induced in specific subsets of antigen-presenting cells that ultimately favor the establishment of immune tolerance to tumor antigens. At least in part, the immunomodulatory functions of IDO1 can be explained by depletion of Trp and accumulation of Kyn and its derivatives. In animal tumor models, genetic or pharmacological IDO1 inhibition can cause the (re)activation of anticancer immune responses. Similarly, neoplasms expressing high levels of IDO1 may elude anticancer immunosurveillance. Therefore, IDO1 inhibitors represent promising therapeutic candidates for cancer therapy, and some of them have already entered clinical evaluation. Here, we summarize preclinical and clinical studies testing IDO1-targeting interventions for oncologic indications. [ABSTRACT FROM AUTHOR]

Toll-like receptor 3 (TLR3) is a pattern recognition receptor that senses exogenous (viral) as well as endogenous (mammalian) double-stranded RNA in endosomes. On activation, TLR3 initiates a signal transduction pathway that culminates with the secretion of pro-inflammatory cytokines including type I interferon (IFN). The latter is essential not only for innate immune responses to infection but also for the initiation of antigen-specific immunity against viruses and malignant cells. These aspects of TLR3 biology have supported the development of various agonists for use as stand-alone agents or combined with other therapeutic modalities in cancer patients. Here, we review recent preclinical and clinical advances in the development of TLR3 agonists for oncological disorders. cDC, conventional dendritic cell; CMT, cytokine modulating treatment; CRC, colorectal carcinoma; CTL, cytotoxic T lymphocyte; DC, dendritic cell; dsRNA, double-stranded RNA; FLT3LG, fms-related receptor tyrosine kinase 3 ligand; HNSCC, head and neck squamous cell carcinoma; IFN, interferon; IL, interleukin; ISV, in situ vaccine; MUC1, mucin 1, cell surface associated; PD-1, programmed cell death 1; PD-L1, programmed death-ligand 1; polyA:U, polyadenylic:polyuridylic acid; polyI:C, polyriboinosinic:polyribocytidylic acid; TLR, Toll-like receptor [ABSTRACT FROM AUTHOR]

During the last two decades, a number of approaches for the activation of the immune system against cancer has been developed. These include highly specific interventions, such as monoclonal antibodies, vaccines and cell-based therapies, as well as relatively unselective strategies, such as the systemic administration of adjuvants and immunomodulatory cytokines. Cytokines constitute a huge group of proteins that, taken together, regulate not only virtually all the aspects of innate and cognate immunity, but also several other cellular and organismal functions. Cytokines operate via specific transmembrane receptors that are expressed on the plasma membrane of target cells and, depending on multiple variables, can engage autocrine, paracrine or endocrine signaling pathways. Perhaps, the most appropriate term for defining the cytokine network is "pleiotropic": cytokines are produced by—and operate on—multiple, often overlapping, cell types, triggering context-depend biological outcomes as diverse as cell proliferation, chemotaxis, differentiation, inflammation, elimination of pathogens and cell death. Moreover, cytokines often induce the release of additional cytokines, thereby engaging self-amplificatory or self-inhibitory signaling cascades. In this Trial Watch, we will summarize the biological properties of cytokines and discuss the progress of ongoing clinical studies evaluating their safety and efficacy as immunomodulatory agents against cancer. [ABSTRACT FROM AUTHOR]

During the last two decades, several approaches for the activation of the immune system against cancer have been developed. These include rather unselective maneuvers such as the systemic administration of immunostimulatory agents (e.g., interleukin-2) as well as targeted interventions, encompassing highly specific monoclonal antibodies, vaccines and cell-based therapies. Among the latter, adoptive cell transfer (ACT) involves the selection of autologous lymphocytes with antitumor activity, their expansion/activation ex vivo, and their reinfusion into the patient, often in the context of lymphodepleting regimens (to minimize endogenous immunosuppression). Such autologous cells can be isolated from tumor-infiltrating lymphocytes or generated by manipulating circulating lymphocytes for the expression of tumor-specific T-cell receptors. In addition, autologous lymphocytes can be genetically engineered to prolong their in vivo persistence, to boost antitumor responses and/or to minimize side effects. ACT has recently been shown to be associated with a consistent rate of durable regressions in melanoma and renal cell carcinoma patients and holds great promises in several other oncological settings. In this Trial Watch, we will briefly review the scientific rationale behind ACT and discuss the progress of recent clinical trials evaluating the safety and effectiveness of adoptive cell transfer as an anticancer therapy. [ABSTRACT FROM AUTHOR]

The success of anticancer chemotherapy relies at least in part on the induction of an immune response against tumor cells. Thus, tumors growing on mice that lack the pattern recognition receptor TLR4 or the purinergic receptor P2RX7 fail to respond to chemotherapy with anthracyclins or oxaliplatin in conditions in which the same neoplasms growing on immunocompetent mice would do so. Similarly, the therapeutic efficacy (measured as progression-free survival) of adjuvant chemotherapy with anthracyclins is reduced in breast cancer patients bearing loss-of-function alleles of TLR4 or P2RX7. TLR4 loss-of-function alleles also have a negative impact on the therapeutic outcome of oxaliplatin in colorectal cancer patients. Here, we report that loss-of-function TLR4 and P2RX7 alleles do not affect overall survival in non-small cell lung cancer (NSCLC) patients, irrespective of the administration and type of chemotherapy. The intrinsic characteristics of NSCLC (which near-to-always is chemoresistant and associated with poor prognosis) and/or the type of therapy that is employed to treat this malignancy (which near-to-always is based on cisplatin) may explain why two genes that affect the immune response to dying cells fail to influence the clinical progression of NSCLC patients. [ABSTRACT FROM AUTHOR]

The long-established notion that apoptosis would be immunologically silent, and hence it would go unnoticed by the immune system, if not tolerogenic, and hence it would actively suppress immune responses, has recently been revisited. In some instances, indeed, cancer cells undergo apoptosis while emitting a spatiotemporally-defined combination of signals that renders them capable of eliciting a long-term protective antitumor immune response. Importantly, only a few anticancer agents can stimulate such an immunogenic cell death. These include cyclophosphamide, doxorubicin and oxaliplatin, which are currently approved by FDA for the treatment of multiple hematologic and solid malignancies, as well as mitoxantrone, which is being used in cancer therapy and against multiple sclerosis. In this Trial Watch, we will review and discuss the progress of recent (initiated after January 2008) clinical trials evaluating the off-label use of cyclophosphamide, doxorubicin, oxaliplatin and mitoxantrone. [ABSTRACT FROM AUTHOR]

The author presents information on immunogenic cell death in radiation therapy. He discusses the antineoplastic effects of radiation therapy, and mentions about the cancer cell-intrinsic and extrinsic mechanism. He also discusses the radiotherapy of autophagy-incompetent tumors along with pharmacological inhibition of extracellular nucleotidases.

The article discusses several immunotherapeutic options for the treatment of castration-resistant prostate cancer (CRPC). Estimates revealed that more than 80% of men will develop prostate cancer by the age of 80. Several chemotherapeutic agents available for CRPC patients include docetaxel, cabazitaxel and bevacizumab. The U.S. Food and Drug Administration (FDA) also approved in May 2013 Bayer HealthCare's injectable solution Xofigo for the treatment of CRPC.

CTLA4 blockers have limited activity in patients with chemorefractory lung cancer. Recent clinical data demonstrate that radiation therapy combined with CTLA4 blockers enables disease control in a sizeable fraction of these patients, correlating with increased circulating levels of type I interferon and dynamic changes in the peripheral T cell repertoire. [ABSTRACT FROM AUTHOR]

Somatic gain-of-function mutations in isocitrate dehydrogenase (NADP(+)) 1, cytosolic (IDH1) or isocitrate dehydrogenase (NADP(+)) 2, mitochondrial (IDH2) are bona fide oncogenic drivers of acute myeloid leukemia and glioma because the neomorphic enzymes catalyze the synthesis of R-2-hydroxylutarate (R-2-HG), an oncometabolite with robust epigenetic effects. Recent data indicate that R-2-HG released by malignant cells can accumulate in the extracellular space and be taken up by T lymphocytes, ultimately compromising their capacity to mediate anticancer immune responses. Thus, R-2-HG drives oncogenesis and tumor progression not only as a cancer cell-autonomous epigenetic modifier, but also as an immunosuppressive metabolite. Chemical inhibitors of mutant IDH1 and IDH2, which currently are under clinical evaluation, may therefore mediate dual anticancer effects by targeting cancer cells and, at the same time, relieving R-2-HG-mediated immunosuppression. [ABSTRACT FROM AUTHOR]

While chemotherapy and radiotherapy remain the first-line approaches for the management of most unresectable tumors, immunotherapy has emerged in the past two decades as a game-changing treatment, notably with the clinical success of immune checkpoint inhibitors. Immunotherapies aim at (re) activating anticancer immune responses which occur in two main steps: (1) the activation and expansion of tumor-specific T cells following cross-presentation of tumor antigens by specialized myeloid cells (priming phase); and (2) the immunological clearance of malignant cells by these antitumor T lymphocytes (effector phase). Therapeutic vaccines, adjuvants, monoclonal antibodies, cytokines, immunogenic cell death-inducing agents including oncolytic viruses, anthracycline-based chemotherapy and radio-therapy, as well as adoptive cell transfer, all act at different levels of this cascade to (re)instate cancer immunosurveillance. Intratumoral delivery of these immunotherapeutics is being tested in clinical trials to promote superior antitumor immune activity in the context of limited systemic toxicity. [ABSTRACT FROM AUTHOR]

Epithelial ovarian carcinoma (EOC) is virtually insensitive to immune checkpoint inhibitors (ICIs). Recent findings from an innovative mouse model of EOC demonstrate that senescence induction underlies the increased sensitivity of homologous recombination-defective EOCs to platinum-based chemotherapy as it initiates tumor infiltration by immune effector cells coupled to restored sensitivity to ICIs. [ABSTRACT FROM AUTHOR]

Stimulator of interferon response cGAMP interactor 1 (STING1, best known as STING) is an endoplasmic reticulum-sessile protein that serves as a signaling hub, receiving input from several pattern recognition receptors, most of which sense ectopic DNA species in the cytosol. In particular, STING ensures the production of type I interferon (IFN) in response to invading DNA viruses, bacterial pathogens, as well as DNA leaking from mitochondria or the nucleus (e.g., in cells exposed to chemotherapy or radiotherapy). As a type I IFN is critical for the initiation of anticancer immune responses, the pharmaceutical industry has generated molecules that directly activate STING for use in oncological indications. Such STING agonists are being tested in clinical trials with the rationale of activating STING in tumor cells or tumor-infiltrating immune cells (including dendritic cells) to elicit immunostimulatory effects, alone or in combination with a range of established chemotherapeutic and immunotherapeutic regimens. In this Trial Watch, we discuss preclinical evidence and accumulating clinical experience shaping the design of Phase I and Phase II trials that evaluate the safety and preliminary efficacy of STING agonists in cancer patients. [ABSTRACT FROM AUTHOR]

Calreticulin (CALR) exposed on the surface of cancer cells succumbing to therapy delivers robust phagocytic signals that support the activation of adaptive anticancer immune responses. Recent data from our group demonstrate that spontaneous CARL exposure on leukemic blasts also supports innate anticancer immunity by natural killer (NK) cells via an indirect mechanism relying on myeloid CD11c+CD14+ cells. [ABSTRACT FROM AUTHOR]

The authors comment on the efficacy and popularity of cancer immunotherapy. The authors mention that cancer immunotherapy is deemed as the holy grail of cancer treatment because it eradicates malignant cells while it spares normal cells. They state that the treatment method is integrated in clinical routines because it is safer and more efficient. Moreover, they said that cancer immunotherapy also boost the life expectancy of patients.

The authors focus on the new immune conjugate called trastuzumab emtansine (T-DM1) which was approved by the U.S. Food and Drug Administration (FDA) on February 22, 2013 for the treatment of advanced breast carcinoma. They note that T-DM1 can exert additional antineoplastic effects by stopping the progression of cell cycle. They relate the EMILIA Phase III clinical trial which shows that T-DM1 exhibits longer progression-free survival in patients with breast cancer.

The article offers information on the clinical trial which examines the adoptive cell transfer (ACT) for the treatment of viral infections and cancer. It outlines the procedure of the clinical trial. It mentions the procedure of T cell expansion which are associated with loss of proliferative capacity, terminal differentiation and exhaustion. It suggests that rejuvenation of exhausted T cells could improve the therapeutic potential of ACT.

A paper recently published inScience Translational Medicinedescribes a next-generation antisense oligonucleotide that specifically downregulates the expression of human signal transducer and activator of transcription 3 (STAT3). Such an oligonucleotide, AZD9150, exerts antineoplastic effects on a selected panel of STAT3-dependent human cancer cells growingin vitroandin vivo(as xenografts in immunodeficient mice). Moreover, preliminary data from a Phase I clinical trial indicate that AZD9150 may cause partial tumor regression in patients with chemorefractory lymphoma and non-small cell lung carcinoma. STAT3 not only participates in cell-autonomous processes that are required for the survival and growth of malignant cells, but also limits their ability to elicit anticancer immune responses. Moreover, STAT3 contribute to the establishment of an immunosuppressive tumor microenvironment. Thus, the inhibition of STAT3 may promote immunosurveillance by a dual mechanism: (1) it may increase the immunogenicity of cancer cells via cell-autonomous pathways; and (2) it may favor the reprogramming of the tumor microenvironment toward an immunostimulatory state. It will therefore be important to explore whether immunological biomarkers predict the efficacy of AZD9150 in the clinic. This may ameliorate patient stratification and it may pave the way for rational combination therapies involving classical chemotherapeutics with immunostimulatory effects, AZD9150 and immunotherapeutic agents such as checkpoint blockers. [ABSTRACT FROM AUTHOR]

On 2015, October 27th, the US Food and Drug Administration (FDA) has officially approved talimogene laherparepvec (T-VEC, also known as OncoVEXGM-CSF) for use in melanoma patients with injectable but non-resectable lesions in the skin and lymph nodes. T-VEC (which is commercialized by Amgen, Inc. under the name of Imlygic®) becomes therefore the first oncolytic virus approved for cancer therapy in the US. [ABSTRACT FROM PUBLISHER]

The article discusses the approval received from the US Food and Drug Administration for treating patients with unresectable melanoma with wild-type genes BRAFV600 using a combination of the drugs nivolumab (Opdivo) and ipilimumab (Yervoy). The overall response rate of Cytotoxic T Lymphocyte-associated molecule-4(CTLA-4) was low in standalone blockade. This combination drug is engineered to improved progression-free survival and an overall improved response rate and exhibits a safe profile.

Results from recent clinical trials demonstrate that a combinatorial immunotherapeutic regimen based on 2 distinct checkpoint blockers, namely, the CTLA4-targeting agent ipilimumab and the PD-1-specific molecule nivolumab, causes objective responses in a majority of subjects with advanced melanoma. These findings revolutionize the treatment of a neoplasm that was considered incurable until recently. Nonetheless, announcing the defeat of melanoma appears premature. Indeed, a sizeable fraction of patients does not respond to ipilimumab plus nivolumab, and the long-term efficacy of this immunotherapeutic regimen has not yet been investigated. Moreover, many patients experience severe side effects, calling for the development of strategies that uncouple the efficacy of ipilimumab plus nivolumab from their toxicity. [ABSTRACT FROM PUBLISHER]

The first study demonstrating that human colorectal carcinoma (CRC) is under robust immunosurveillance was published a decade ago. Today, it is clear that CRC patients with Stage III lesions abundantly infiltrated by effector memory T cells have a better prognosis than subjects with Stage I neoplasms exhibiting no or poor immune infiltration. Thus, immunological parameters have a superior prognostic value for CRC patients than TNM staging or the Dukes classification. In spite of the fact that CRC is the first neoplasia found to be under immunological control, most attempts made so far to cure this malignancy with immunotherapy have failed. With the exception of a minority of lesions characterized by microsatellite instability (MSI), CRC seems to be insensitive to the blockade of immunological checkpoints with monoclonal antibodies (mAbs) specific for cytotoxic T lymphocyte-associated protein 4 (CTLA4), programmed cell death 1 (PDCD1, best known as PD-1) and the PD-1 ligand CD274 (best known as PD-L1). Thus, CRC stands in contrast with an increasing number of malignancies that respond to checkpoint blockers. Efforts should therefore be dedicated to the development of strategies to (re)instate immunosurveillance in patients with MSI-CRC, perhaps based on the identification of novel, locally relevant immunological checkpoints. [ABSTRACT FROM PUBLISHER]

The blockade of immunological checkpoints has been successfully employed for the treatment of various solid neoplasms including melanoma, mesothelioma, non-small cell lung carcinoma, and renal cell carcinoma. A recent study indicates that the vast majority of patients with advanced, heavily pretreated Hodgkin's lymphoma (HL) also respond to a monoclonal antibody targeting programmed cell death 1 (PDCD1, best known as PD-1). Thus, checkpoint blockers may soon become part of our therapeutic armamentarium against hematological tumors. This would be particularly important as it would spare (at least some) patients the deleterious toxic effects of combinatorial chemotherapies and bone marrow transplantation. We anticipate that the realm of immunotherapy will eventually conquer vast portions of the territory that now belongs to hematological malignancies. [ABSTRACT FROM AUTHOR]

The author reflects on the approval of the U.S. Food and Drug Administration (FDA) on pembrolizumab, a monoclonal antibody that targets programmed cell death 1 (PDCD1). The author states that the antibody was granted upon disclosure of safety and efficacy results from clinical trial conducted on 173 participants with advanced melanoma. The author mentions that the pembrolizumab adds to therapeutic options for patients with melanoma who failed to respond to other medications.

The article discusses a study which focuses on the action mechanism of lenalidomide, a derivative of thalidomide, and other immunomodulatory drugs (IMiDs). Topics include the development of lenalidomide for the improvement of thalidomide's safety, the approval of pomalidomide by the U.S. Food and Drug Administration (FDA) for the treatment of multiple myeloma (MM), and the interaction between thalidomide and the E3 ubiquitin ligase cereblon (CRBN).

BCL2 robustly preserves mitochondrial integrity, hence inhibiting innate immune signaling and apoptotic cell death in several cell types. Here, we comment on our recent data demonstrating that BCL2 also limits the ability of dendritic cells to elicit adaptive immune responses, lending support to a universal immunosuppressive function for the mitochondrial immune checkpoint. [ABSTRACT FROM AUTHOR]

The anticancer immune response is shaped by immunogenic cell stress and death pathways. Thus, cancer cells can release danger-associated molecular patterns that act on pattern recognition receptors expressed by dendritic cells and their precursors to elicit an antitumor immune response. Here, we investigated the impact of single nucleotide polymorphisms (SNPs) in genes affecting this cancer-immunity dialogue in the context of head and neck squamous cell carcinoma (HNSCC). We observed that homozygosity for a loss-of-function SNP (rs2241880, leading to the substitution of a threonine residue in position 300 by an alanine) affecting autophagy related 16 like 1 (ATG16L1) is coupled to poor progression-free survival in platinum-treated HNSCC patients. This result was obtained on a cohort of patients enrolled at the Gustave Roussy Cancer Campus and was validated on an independent cohort of The Cancer Genome Atlas (TCGA). Homozygosity in rs2241880 is well known to predispose to Crohn's disease, and epidemiological associations between Crohn's disease and HNSCC have been reported at the levels of cancer incidence and prognosis. We speculate that rs2241880 might be partially responsible for this association. [ABSTRACT FROM AUTHOR]

Accumulating evidence indicates that immune checkpoint inhibitors (ICIs) can restore CD8+ cytotoxic T lymphocyte (CTL) functions in preclinical models of acute myeloid leukemia (AML). However, ICIs targeting programmed cell death 1 (PDCD1, best known as PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA4) have limited clinical efficacy in patients with AML. Natural killer (NK) cells are central players in AML-targeting immune responses. However, little is known on the relationship between co-inhibitory receptors expressed by NK cells and the ability of the latter to control AML. Here, we show that hepatitis A virus cellular receptor 2 (HAVCR2, best known as TIM-3) is highly expressed by NK cells from AML patients, correlating with improved functional licensing and superior effector functions. Altogether, our data indicate that NK cell frequency as well as TIM-3 expression levels constitute prognostically relevant biomarkers of active immunity against AML. [ABSTRACT FROM AUTHOR]

LTX-315 is a nonameric oncolytic peptide in early clinical development for the treatment of solid malignancies. Preclinical and clinical evidence indicates that the anticancer properties of LTX-315 originate not only from its ability to selectively kill cancer cells, but also from its capacity to promote tumor-targeting immune responses. Here, we investigated the therapeutic activity and immunological correlates of intratumoral LTX-315 administration in three syngeneic mouse models of breast carcinoma, with a focus on the identification of possible combinatorial partners. We found that breast cancer control by LTX-315 is accompanied by a reconfiguration of the immunological tumor microenvironment that supports the activation of anticancer immunity and can be boosted by radiation therapy. Mechanistically, depletion of natural killer (NK) cells compromised the capacity of LTX-315 to limit local and systemic disease progression in a mouse model of triple-negative breast cancer, and to extend the survival of mice bearing hormone-accelerated, carcinogen-driven endogenous mammary carcinomas. Altogether, our data suggest that LTX-315 controls breast cancer progression by engaging NK cell-dependent immunity. [ABSTRACT FROM AUTHOR]

Antibodies targeting the co-inhibitory receptor programmed cell death 1 (PDCD1, best known as PD-1) or its main ligand CD274 (best known as PD-L1) have shown some activity in patients with metastatic triple-negative breast cancer (TNBC), especially in a recent Phase III clinical trial combining PD-L1 blockade with taxane-based chemotherapy. Despite these encouraging findings, however, most patients with TNBC fail to derive significant benefits from PD-L1 blockade, calling for the identification of novel therapeutic approaches. Here, we used the 4T1 murine mammary cancer model of metastatic and immune-resistant TNBC to test whether focal radiation therapy (RT), a powerful inducer of immunogenic cell death, in combination with various immunotherapeutic strategies can overcome resistance to immune checkpoint blockade. Our results suggest that focal RT enhances the therapeutic effects of PD-1 blockade against primary 4T1 tumors and their metastases. Similarly, the efficacy of an antibody specific for V-set immunoregulatory receptor (VSIR, another co-inhibitory receptor best known as VISTA) was enhanced by focal RT. Administration of cyclophosphamide plus RT and dual PD-1/VISTA blockade had superior therapeutic effects, which were associated with activation of tumor-infiltrating CD8+ T cells and depletion of intratumoral granulocytic myeloid-derived suppressor cells (MDSCs). Overall, these results demonstrate that RT can sensitize immunorefractory tumors to VISTA or PD-1 blockade, that this effect is enhanced by the addition of cyclophosphamide and suggest that a multipronged immunotherapeutic approach may also be required to increase the incidence of durable responses in patients with TNBC. [ABSTRACT FROM AUTHOR]

Cancer immunosurveillance generally relies on adaptive immune programs executed by CD8+ T cells. Our findings demonstrate that CD8+ T cells fail to control early oncogenesis in a mouse model of luminal B breast cancer and suggest that natural killer (NK) cells may instead play a predominant role in this setting. [ABSTRACT FROM AUTHOR]

Resiquimod (R848) and motolimod (VTX-2337) are second-generation experimental derivatives of imiquimod, an imidazoquinoline with immunostimulatory properties originally approved by the US Food and Drug Administration for the topical treatment of actinic keratosis and genital warts more than 20 years ago. Both resiquimod and motolimod operate as agonists of Toll-like receptor 7 (TLR7) and/or TLR8, in thus far delivering adjuvant-like signals to antigen-presenting cells (APCs). In line with such an activity, these compounds are currently investigated as immunostimulatory agents for the treatment of various malignancies, especially in combination with peptide-based, dendritic cell-based, cancer cell lysate-based, or DNA-based vaccines. Here, we summarize preclinical and clinical evidence recently collected to support the development of resiquimod and motolimod and other TLR7/TLR8 agonists as anticancer agents. [ABSTRACT FROM AUTHOR]

PT-112 is a novel platinum-pyrophosphate conjugate under clinical development for cancer therapy. PT-112 mediates cytostatic and cytotoxic effects against a variety of human and mouse cancer cell lines in vitro. The cytotoxic response to PT-112 is associated with the emission of danger signals underpinning the initiation of anticancer immunity, including calreticulin exposure on the surface of dying cells, as well as ATP and HMGB1 secretion. Consistently, mouse cancer cells succumbing to PT-112 in vitro can be used to provide syngeneic, immunocompetent mice with immunological protection against a subsequent challenge with living tumor cells of the same type. Moreover, PT-112 administration synergizes with PD-1 or PD-L1 blockade in the control of mouse cancers in immunologically competent settings, as it simultaneously recruits immune effector cells and depletes immunosuppressive cells in the tumor microenvironment. Finally, PT-112 employed intratumorally in the context of immune checkpoint inhibition initiates a robust immune response that has systemic outreach and limits the growth of untreated, distant lesions. Thus, PT-112 induces the immunogenic demise of cancer cells, and hence stands out as a promising combinatorial partner of immune checkpoint blockers, especially for the treatment of otherwise immunologically cold tumors. [ABSTRACT FROM AUTHOR]

The term 'immunogenic cell death' (ICD) denotes an immunologically unique type of regulated cell death that enables, rather than suppresses, T cell-driven immune responses that are specific for antigens derived from the dying cells. The ability of ICD to elicit adaptive immunity heavily relies on the immunogenicity of dying cells, implying that such cells must encode and present antigens not covered by central tolerance (antigenicity), and deliver immunostimulatory molecules such as damage-associated molecular patterns and cytokines (adjuvanticity). Moreover, the host immune system must be equipped to detect the antigenicity and adjuvanticity of dying cells. As cancer (but not normal) cells express several antigens not covered by central tolerance, they can be driven into ICD by some therapeutic agents, including (but not limited to) chemotherapeutics of the anthracycline family, oxaliplatin and bortezomib, as well as radiation therapy. In this Trial Watch, we describe current trends in the preclinical and clinical development of ICD-eliciting chemotherapy as partner for immunotherapy, with a focus on trials assessing efficacy in the context of immunomonitoring. [ABSTRACT FROM AUTHOR]

Dendritic- cells (DCs) have received considerable attention as potential targets for the development of anticancer vaccines. DC-based anticancer vaccination relies on patient-derived DCs pulsed with a source of tumor-associated antigens (TAAs) in the context of standardized maturation-cocktails, followed by their reinfusion. Extensive evidence has confirmed that DC-based vaccines can generate TAA-specific, cytotoxic T cells. Nonetheless, clinical efficacy of DC-based vaccines remains suboptimal, reflecting the widespread immunosuppression within tumors. Thus, clinical interest is being refocused on DC-based vaccines as combinatorial partners for T cell-targeting immunotherapies. Here, we summarize the most recent preclinical/clinical development of anticancer DC vaccination and discuss future perspectives for DC-based vaccines in immuno-oncology. [ABSTRACT FROM AUTHOR]

Caspases are known for their ability to precipitate apoptosis. Our findings indicate that accelerating the terminal inactivation of cells dying in response to radiation therapy limit their immunogenicity as a consequence of reduced type I interferon secretion. Thus, caspase inhibitors stand out as promising combinatorial partners to improve the immunogenicity of radiation therapy in the clinic. [ABSTRACT FROM AUTHOR]

Caspase 3 (CASP3) has a key role in the execution of apoptosis, and many cancer cells are believed to disable CASP3 as a mechanism of resistance to cytotoxic therapeutics. Alongside, CASP3 regulates stress-responsive immunomodulatory pathways, including secretion of type I interferon (IFN). Here, we report that mouse mammary carcinoma TSA cells lacking Casp3 or subjected to chemical caspase inhibition were as sensitive to the cytostatic and cytotoxic effects of radiation therapy (RT) in vitro as their control counterparts, yet secreted increased levels of type I IFN. This effect originated from the accrued accumulation of irradiated cells with cytosolic DNA, likely reflecting the delayed breakdown of cells experiencing mitochondrial permeabilization in the absence of CASP3. Casp3-/- TSA cells growing in immunocompetent syngeneic mice were more sensitive to RT than their CASP3-proficient counterparts, and superior at generating bona fide abscopal responses in the presence of an immune checkpoint blocker. Finally, multiple genetic signatures of apoptotic proficiency were unexpectedly found to have robust negative (rather than positive) prognostic significance in a public cohort of breast cancer patients. However, these latter findings were not consistent with genetic signatures of defective type I IFN signaling, which were rather associated with improved prognosis. Differential gene expression analysis on patient subgroups with divergent prognosis (as stratified by independent signatures of apoptotic proficiency) identified SLC7A2 as a new biomarker with independent prognostic value in breast cancer patients. With the caveats associated with the retrospective investigation of heterogeneous, public databases, our data suggest that apoptotic caspases may influence the survival of breast cancer patients (or at least some subsets thereof) via mechanisms not necessarily related to type I IFN signaling as they identify a novel independent prognostic biomarker that awaits prospective validation. [ABSTRACT FROM AUTHOR]

The article discusses a study on molecular mechanism through which human pancreatic ductal adenocarcinomas (PDAs)-infiltrating T cells suppress anticancer immunosurveillance; and discusses role of PD-L1/PD-1 axis to target monoclonal antibodies and approval by the U.S. Food and Drug Administration (FDA).

The article discusses the failure of the Phase III clinical trial to examine the efficacy of Stimuvax, an anticancer vaccine licensed by Merck & Co. Inc., in a cohort of non-small cell lung carcinoma (NSCLC) patients. It mentions that the vaccine might have been aimed in a suboptimal fashion. It states that the clinical trial's design mught have been overoptimistic as NSCLC patients have not been filtrated at enrollment based on exclusion criteria based in biomarker.

One particular paradigm of anticancer immunotherapy relies on the administration of (potentially) tumor-reactive immune effector cells. Generally, these cells are obtained from autologous peripheral blood lymphocytes (PBLs) ex vivo (in the context of appropriate expansion, activation and targeting protocols), and re-infused into lymphodepleted patients along with immunostimulatory agents. In spite of the consistent progress achieved throughout the past two decades in this field, no adoptive cell transfer (ACT)-based immunotherapeutic regimen is currently approved by regulatory agencies for use in cancer patients. Nonetheless, the interest of oncologists in ACT-based immunotherapy continues to increase. Accumulating clinical evidence indicates indeed that specific paradigms of ACT, such as the infusion of chimeric antigen receptor (CAR)-expressing autologous T cells, are associated with elevated rates of durable responses in patients affected by various neoplasms. In line with this notion, clinical trials investigating the safety and therapeutic activity of ACT in cancer patients are being initiated at an ever increasing pace. Here, we review recent preclinical and clinical advances in the development of ACTbased immunotherapy for oncological indications. [ABSTRACT FROM AUTHOR]