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Gliadin induces neutrophil migration via engagement of the formyl peptide receptor, FPR1. 12 Grommes J, Drechsler M, Soehnlein O. CCR5 and FPR1 mediate neutrophil recruitment in endotoxin-induced lung injury. 13 Cardini S, Dalli J, Fineschi S, Perretti M, Lungarella G, Lucattelli M. Genetic ablation of the fpr1 gene confers protection from smoking-induced lung emphysema in mice. [Extracted from the article]

Pattern recognition receptors allow the innate immune system to perceive the presence of microbial products and to launch the first steps of the defense response. Some pattern recognition receptors also sense endogenous ligands that are released from uninfected dying cells, thereby activating immune responses against dead-cell antigens. This applies to toll-like receptors 3 and 4 (TLR3, TLR4), which sense doublestranded RNA and high-mobility group protein B1 (HMGB1), respectively, as well as to formyl peptide receptor-1 (FPR1), which interacts with Annexin A1 (ANXA1) from dead cells. Breast cancer patients who bear loss-of-function alleles in TLR3, TLR4, and FPR1 exhibit a reduced metastasis-free and overall survival after treatment with anthracycline-based adjuvant chemotherapy. These genetic defects are epistatic with respect to each other, suggesting that they act on the same pathway, linking chemotherapy to a therapeutically relevant anticancer immune response. Loss-of-function alleles in TLR4 and FPR1 also affect the prognosis of colorectal cancer patients treated with oxaliplatin-based chemotherapy. Altogether, these results support the idea that conventional anticancer treatments rely on stimulation of anticancer immune responses to become fully efficient. [ABSTRACT FROM AUTHOR]

Antitumor immunity driven by intratumoral dendritic cells contributes to the efficacy of anthracycline-based chemotherapy in cancer.We identified a loss-of-function allele of the gene coding for formyl peptide receptor 1 (FPR1) that was associated with poor metastasis-free and overall survival in breast and colorectal cancer patients receiving adjuvant chemotherapy. The therapeutic effects of anthracyclines were abrogated in tumor-bearing Fpr1-/- mice due to impaired antitumor immunity. Fpr1-deficient dendritic cells failed to approach dying cancer cells and, as a result, could not elicit antitumor T cell immunity. Experiments performed in a microfluidic device confirmed that FPR1 and its ligand, annexin-1, promoted stable interactions between dying cancer cells and human or murine leukocytes. Altogether, these results highlight the importance of FPR1 in chemotherapy-induced anticancer immune responses. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) occupy a privileged position at the interface between innate and adaptive immunity, orchestrating a large panel of responses to both physiological and pathological cues. In particular, whereas the presentation of antigens by immature DCs generally results in the development of immunological tolerance, mature DCs are capable of priming robust, and hence therapeutically relevant, adaptive immune responses. In line with this notion, functional defects in the DC compartment have been shown to etiologically contribute to pathological conditions including (but perhaps not limited to) infectious diseases, allergic and autoimmune disorders, graft rejection and cancer. Thus, the possibility of harnessing the elevated immunological potential of DCs for anticancer therapy has attracted considerable interest from both researchers and clinicians over the last decade. Alongside, several methods have been developed not only to isolate DCs from cancer patients, expand them, load them with tumorassociated antigens and hence generate highly immunogenic clinical grade infusion products, but also to directly target DCs in vivo. This intense experimental efort has culminated in 2010 with the approval by the US FDA of a DC-based preparation (sipuleucel-T, Provenge®) for the treatment of asymptomatic or minimally symptomatic metastatic castration-refractory prostate cancer. As an update to the latest Trial watch dealing with this exciting ield of research (October 2012), here we summarize recent advances in DC-based anticancer regimens, covering both high-impact studies that have been published during the last 13 mo and clinical trials that have been launched in the same period to assess the antineoplastic potential of this variant of cellular immunotherapy. [ABSTRACT FROM AUTHOR]

Radiotherapy has extensively been employed as a curative or palliative intervention against cancer throughout the last century, with a varying degree of success. For a long time, the antineoplastic activity of X- and γ-rays was entirely ascribed to their capacity of damaging macromolecules, in particular DNA, and hence triggering the (apoptotic) demise of malignant cells. However, accumulating evidence indicates that (at least part of) the clinical potential of radiotherapy stems from cancer cell-extrinsic mechanisms, including the normalization of tumor vasculature as well as short- and long-range bystander effects. Local bystander effects involve either the direct transmission of lethal signals between cells connected by gap junctions or the production of diffusible cytotoxic mediators, including reactive oxygen species, nitric oxide and cytokines. Conversely, long-range bystander effects, also known as out-of-field or abscopal effects, presumably reflect the elicitation of tumor-specific adaptive immune responses. Ionizing rays have indeed been shown to promote the immunogenic demise of malignant cells, a process that relies on the spatiotemporally defined emanation of specific damage-associated molecular patterns (DAMPs). Thus, irradiation reportedly improves the clinical efficacy of other treatment modalities such as surgery (both in neo-adjuvant and adjuvant settings) or chemotherapy. Moreover, at least under some circumstances, radiotherapy may potentiate anticancer immune responses as elicited by various immunotherapeutic agents, including (but presumably not limited to) immunomodulatory monoclonal antibodies, cancer-specific vaccines, dendritic cell-based interventions and Toll-like receptor agonists. Here, we review the rationale of using radiotherapy, alone or combined with immunomodulatory agents, as a means to elicit or boost anticancer immune responses, and present recent clinical trials investigating the therapeutic potential of this approach in cancer patients. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) have long been known for their ability to initiate innate immune responses upon exposure to conserved microbial components such as lipopolysaccharide (LPS) and double-stranded RNA. More recently, this family of pattern recognition receptors has been attributed a critical role in the elicitation of anticancer immune responses, raising interest in the development of immunochemotherapeutic regimens based on natural or synthetic TLR agonists. In spite of such an intense wave of preclinical and clinical investigation, only three TLR agonists are currently licensed by FDA for use in cancer patients: bacillus Calmette-Guérin (BCG), an attenuated strain of Mycobacterium bovis that operates as a mixed TLR2/ TLR4 agonist; monophosphoryl lipid A (MPL), a derivative of Salmonella minnesota that functions as a potent agonist of TLR4; and imiquimod, a synthetic imidazoquinoline that activates TLR7. One year ago, in the August and September issues of OncoImmunology, we described the main biological features of TLRs and discussed the progress of clinical studies evaluating the safety and therapeutic potential of TLR agonists in cancer patients. Here, we summarize the latest developments in this exciting area of research, focusing on preclinical studies that have been published during the last 13 mo and clinical trials launched in the same period to investigate the antineoplastic activity of TLR agonists. [ABSTRACT FROM AUTHOR]

During the past two decades, the notion that cancer would merely constitute a cell-intrinsic disease has gradually been complemented by a model postulating that the immune system plays a relevant role during all stages of oncogenesis and tumor progression. Along with this conceptual shift, several strategies have been devised to stimulate tumorspeciic immune responses, including relatively unselective approaches such as the systemic administration of adjuvants or immunomodulatory cytokines. One year ago, in the July issue of OncoImmunology, we described the main biological features of this large group of proteins and discussed the progress of ongoing clinical studies evaluating their safety and therapeutic potential in cancer patients. Here, we summarize the latest developments in this area of clinical research, focusing on high impact studies that have been published during the last 13 mo and clinical trials launched in the same period to investigate which cytokines can be employed as safe and efficient immunostimulatory interventions against cancer. [ABSTRACT FROM AUTHOR]

Oncolytic virotherapy is emerging as a promising approach for the treatment of several neoplasms. The term "oncolytic viruses" is generally employed to indicate naturally occurring or genetically engineered attenuated viral particles that cause the demise of malignant cells while sparing their nontransformed counterparts. From a conceptual standpoint, oncolytic viruses differ from so-called "oncotropic viruses" in that only the former are able to kill cancer cells, even though both display a preferential tropism for malignant tissues. Of note, such a specificity can originate at several different steps of the viral cycle, including the entry of virions (transductional specificity) as well as their intracellular survival and replication (post-transcriptional and transcriptional specificity). During the past two decades, a large array of replication-competent and replication-incompetent oncolytic viruses has been developed and engineered to express gene products that would specifically promote the death of infected (cancer) cells. However, contrarily to long-standing beliefs, the antineoplastic activity of oncolytic viruses is not a mere consequence of the cytopathic effect, i.e., the lethal outcome of an intense, productive viral infection, but rather involves the elicitation of an antitumor immune response. In line with this notion, oncolytic viruses genetically modified to drive the local production of immunostimulatory cytokines exert more robust therapeutic effects than their non-engineered counterparts. Moreover, the efficacy of oncolytic virotherapy is significantly improved by some extent of initial immunosuppression (facilitating viral replication and spread) followed by the administration of immunostimulatory molecules (boosting antitumor immune responses). In this Trial Watch, we will discuss the results of recent clinical trials that have evaluated/ are evaluating the safety and antineoplastic potential of oncolytic virotherapy. [ABSTRACT FROM AUTHOR]

Adoptive cell transfer (ACT) represents a prominent form of immunotherapy against malignant diseases. ACT is conceptually distinct from dendritic cell-based approaches (which de facto constitute cellular vaccines) and allogeneic transplantation (which can be employed for the therapy of hematopoietic tumors) as it involves the isolation of autologous lymphocytes exhibiting antitumor activity, their expansion/activation ex vivo and their reintroduction into the patient. Re-infusion is most often performed in the context of lymphodepleting regimens (to minimize immunosuppression by host cells) and combined with immunostimulatory interventions, such as the administration of Toll-like receptor agonists. Autologous cells that are suitable for ACT protocols can be isolated from tumor-infiltrating lymphocytes or generated by engineering their circulating counterparts for the expression of transgenic tumor-specific T-cell receptors. Importantly, lymphocytes can be genetically modified prior to re-infusion for increasing their persistence in vivo, boosting antitumor responses and minimizing side effects. Moreover, recent data indicate that exhausted antitumor T lymphocytes may be rejuvenated in vitro by exposing them to specific cytokine cocktails, a strategy that might considerably improve the clinical success of ACT. Following up the Trial Watch that we published on this topic in the third issue of OncoImmunology (May 2012), here we summarize the latest developments in ACT-related research, covering both high-impact studies that have been published during the last 13 months and clinical trials that have been initiated in the same period to assess the antineoplastic profile of this form of cellular immunotherapy. [ABSTRACT FROM AUTHOR]

The foundation of modern vaccinology dates back to the 1790s, when the English physician Edward Jenner uncovered the tremendous medical potential of prophylactic vaccination. Jenner's work ignited a wave of nationwide vaccination campaigns abating the incidence of multiple life-threatening infectious diseases and culminating with the eradication of natural smallpox virus, which was definitively certified by the WHO in 1980. The possibility of using vaccines against cancer was first proposed at the end of the 19th century by Paul Ehrlich and William Coley. However, it was not until the 1990s that such a hypothesis began to be intensively investigated, following the realization that the immune system is not completely unresponsive to tumors and that neoplastic cells express immunogenic tumor-associated antigens (TAAs). Nowadays, anticancer vaccines are rapidly moving from the bench to the bedside, and a few prophylactic and therapeutic preparations have already been approved by FDA for use in humans. In this setting, one interesting approach is constituted by DNA vaccines, i.e., TAA-encoding circularized DNA constructs, often of bacterial origin, that are delivered to patients as such or by means of specific vectors, including (but not limited to) liposomal preparations, nanoparticles, bacteria and viruses. The administration of DNA vaccines is most often performed via the intramuscular or subcutaneous route and is expected to cause (1) the endogenous synthesis of the TAA by myocytes and/or resident antigen-presenting cells; (2) the presentation of TAA-derived peptides on the cell surface, in association with MHC Class I molecules; and (3) the activation of potentially therapeutic tumor-specific immune responses. In this Trial Watch, we will summarize the results of recent clinical trials that have evaluated/are evaluating DNA vaccines as therapeutic interventions against cancer. [ABSTRACT FROM AUTHOR]

It is now clear that the immune system plays a critical role not only during oncogenesis and tumor progression, but also as established neoplastic lesions respond to therapy. Selected cytotoxic chemicals can indeed elicit immunogenic cell death, a functionally peculiar type of apoptosis that stimulates tumorspecific cognate immune responses. Such immunogenic chemotherapeutics include cyclophosphamide, doxorubicin and oxaliplatin (which are approved by FDA for the treatment of various hematological and solid malignancies), mitoxantrone (which is currently employed both as an anticancer agent and against multiple sclerosis) and patupilone (a microtubular poison in clinical development). One year ago, in the second issue of OncoImmunology, we discussed the scientific rationale behind immunogenic chemotherapy and reviewed the status of recent clinical trials investigating the off-label use of cyclophosphamide, doxorubicin, oxaliplatin and mitoxantrone in cancer patients. Here, we summarize the latest developments in this area of clinical research, covering both high-impact studies that have been published during the last 13 months and clinical trials that have been initiated in the same period to assess the antineoplastic profile of immunogenic chemotherapeutics. [ABSTRACT FROM AUTHOR]

Cardiac glycosides (CGs) are natural compounds sharing the ability to operate as potent inhibitors of the plasma membrane Na+/K+-ATPase, hence promoting—via an indirect mechanism—the intracellular accumulation of Ca2+ ions. In cardiomyocytes, increased intracellular Ca2+ concentrations exert prominent positive inotropic effects, that is, they increase myocardial contractility. Owing to this feature, two CGs, namely digoxin and digitoxin, have extensively been used in the past for the treatment of several cardiac conditions, including distinct types of arrhythmia as well as contractility disorders. Nowadays, digoxin is approved by the FDA and indicated for the treatment of congestive heart failure, atrial fibrillation and atrial flutter with rapid ventricular response, whereas the use of digitoxin has been discontinued in several Western countries. Recently, CGs have been suggested to exert potent antineoplastic effects, notably as they appear to increase the immunogenicity of dying cancer cells. In this Trial Watch, we summarize the mechanisms that underpin the unsuspected anticancer potential of CGs and discuss the progress of clinical studies that have evaluated/are evaluating the safety and efficacy of CGs for oncological indications. [ABSTRACT FROM AUTHOR]

During the past 20 years, dozens—if not hundreds—of monoclonal antibodies have been developed and characterized for their capacity to mediate antineoplastic effects, either as they activate/enhance tumor-specific immune responses, either as they interrupt cancer cell-intrinsic signal transduction cascades, either as they specifically delivery toxins to malignant cells or as they block the tumor-stroma interaction. Such an intense research effort has lead to the approval by FDA of no less than 14 distinct molecules for use in humans affected by hematological or solid malignancies. In the inaugural issue of OncoImmunology, we briefly described the scientific rationale behind the use of monoclonal antibodies in cancer therapy and discussed recent, ongoing clinical studies investigating the safety and efficacy of this approach in patients. Here, we summarize the latest developments in this exciting area of clinical research, focusing on high impact studies that have been published during the last 15 months and clinical trials launched in the same period to investigate the therapeutic profile of promising, yet hitherto investigational, monoclonal antibodies. [ABSTRACT FROM AUTHOR]

Prophylactic vaccination constitutes one of the most prominent medical achievements of history. This concept was first demonstrated by the pioneer work of Edward Jenner, dating back to the late 1790s, after which an array of preparations that confer life-long protective immunity against several infectious agents has been developed. The ensuing implementation of nation-wide vaccination programs has de facto abated the incidence of dreadful diseases including rabies, typhoid, cholera and many others. Among all, the most impressive result of vaccination campaigns is surely represented by the eradication of natural smallpox infection, which was definitively certified by the WHO in 1980. The idea of employing vaccines as anticancer interventions was first theorized in the 1890s by Paul Ehrlich and William Coley. However, it soon became clear that while vaccination could be efficiently employed as a preventive measure against infectious agents, anticancer vaccines would have to (1) operate as therapeutic, rather than preventive, interventions (at least in the vast majority of settings), and (2) circumvent the fact that tumor cells often fail to elicit immune responses. During the past 30 y, along with the recognition that the immune system is not irresponsive to tumors (as it was initially thought) and that malignant cells express tumorassociated antigens whereby they can be discriminated from normal cells, considerable efforts have been dedicated to the development of anticancer vaccines. Some of these approaches, encompassing cell-based, DNA-based and purified component-based preparations, have already been shown to exert conspicuous anticancer effects in cohorts of patients affected by both hematological and solid malignancies. In this Trial Watch, we will summarize the results of recent clinical trials that have evaluated/are evaluating purified peptides or fulllength proteins as therapeutic interventions against cancer [ABSTRACT FROM AUTHOR]

Solid tumors are constituted of a variety of cellular components, including bona fide malignant cells as well as endothelial, structural and immune cells. On one hand, the tumor stroma exerts major pro-tumorigenic and immunosuppressive functions, reflecting the capacity of cancer cells to shape the microenvironment to satisfy their own metabolic and immunological needs. On the other hand, there is a component of tumor-infiltrating leucocytes (TILs) that has been specifically recruited in the attempt to control tumor growth. Along with the recognition of the critical role played by the immune system in oncogenesis, tumor progression and response to therapy, increasing attention has been attracted by the potential prognostic and/or predictive role of the immune infiltrate in this setting. Data from large clinical studies demonstrate indeed that a robust infiltration of neoplastic lesions by specific immune cell populations, including (but not limited to) CD8+ cytotoxic T lymphocytes, Th1 and Th17 CD4+ T cells, natural killer cells, dendritic cells, and M1 macrophages constitutes an independent prognostic indicator in several types of cancer. Conversely, high levels of intratumoral CD4+CD25+FOXP3+ regulatory T cells, Th2 CD4+ T cells, myeloid-derived suppressor cells, M2 macrophages and neutrophils have frequently been associated with dismal prognosis. So far, only a few studies have addressed the true predictive potential of TILs in cancer patients, generally comforting the notion that-at least in some clinical settings- the immune infiltrate can reliably predict if a specific patient will respond to therapy or not. In this Trial Watch, we will summarize the results of clinical trials that have evaluated/are evaluating the prognostic and predictive value of the immune infiltrate in the context of solid malignancies. [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 reflects on the dominant courses of immunochemotherapy in cancer. The author focuses on the implementation of combinatorial therapy in cancer that evolves in the clinical routine. The author mentions that the application of combinatorial agents results in synergistic antineoplastic effects that develop combinatorial immunotherapeutic interventions to combine chemotherapy and radiotherapeutic regimens with immunotherapy.

The success of chemotherapy largely depends on the anticancer immune response triggered by tumor cells that succumb to immunogenic cell death (ICD). One of the hallmarks of ICD is premortem autophagy that facilitates the release of adenosine triphosphate from dying cancer cells and acts as a chemoattractant for dendritic cell precursors. Here, we show that the immune response induced by inoculation of cancer cells undergoing ICD in response to the anthracycline mitoxantrone (MTX) can be improved by a short-term fasting regimen (48 hours of starvation) and that this effect is reversed by systemic administration of the autophagy inhibitor dimethyl α-ketoglutarate. Tumor growth reduction by MTX treatment is known to depend on autophagy induction in cancer cells as well as on an intact immune system. We compared the antitumor effects of MTX on autophagy-competent cancers implanted in wild type (WT) or partially autophagy-deficient (Becn1± or Atg4b−/-) mice. While there was no difference in the tumor growth reducing effects of MTX on tumors evolving in WT, Becn1+/- and Atg4b−/- mice, we observed an increase in the toxicity of MTX on Atg4b−/- mice. These results suggest that autophagy in cancer cells (but less so in host cells) is rate-limiting for therapeutically relevant anticancer immune responses, yet has a major role in blunting the life-threatening toxicity of chemotherapy. [ABSTRACT FROM AUTHOR]

Formyl peptide receptor 1 (FPR1) is a pattern-recognition receptor that detects bacterial as well as endogenous danger-associated molecular patterns to trigger innate immune responses by myeloid cells. A single nucleotide polymorphism, rs867228 (allelic frequency 19–20%), in the gene coding for FPR1 accelerates the manifestation of multiple carcinomas, likely due to reduced anticancer immunosurveillance secondary to a defect in antigen presentation by dendritic cells. Another polymorphism in FPR1, rs5030880 (allelic frequency 12–13%), has been involved in the resistance to plague, correlating with the fact that FPR1 is the receptor for Yersinia pestis. Driven by the reported preclinical effects of FPR1 on lung inflammation and fibrosis, we investigated whether rs867228 or rs5030880 would affect the severity of coronavirus disease-19 (COVID-19). Data obtained on patients from two different hospitals in Paris refute the hypothesis that rs867228 or rs5030880 would affect the severity of COVID-19. [ABSTRACT FROM AUTHOR]

Malignant cells succumbing to some forms of radiation therapy are particularly immunogenic and hence can initiate a therapeutically relevant adaptive immune response. This reflects the intrinsic antigenicity of malignant cells (which often synthesize a high number of potentially reactive neo-antigens) coupled with the ability of radiation therapy to boost the adjuvanticity of cell death as it stimulates the release of endogenous adjuvants from dying cells. Thus, radiation therapy has been intensively investigated for its capacity to improve the therapeutic profile of several anticancer immunotherapies, including (but not limited to) checkpoint blockers, anticancer vaccines, oncolytic viruses, Toll-like receptor (TLR) agonists, cytokines, and several small molecules with immunostimulatory effects. Here, we summarize recent preclinical and clinical advances in this field of investigation. [ABSTRACT FROM PUBLISHER]

Several pattern recognition receptors including toll-like receptors and purinergic receptors are implicated in the anticancer immune response elicited by anthracyclines or oxaliplatin. Recently, formyl peptide receptor-1 (FPR1) has been involved in this response as well. FPR1 is required for the correct positioning of dendritic cells (DC) close to dying cancer cells. A genetic defect in FPR1 abrogates cross-presentation of tumor antigens by DC, thereby compromising therapy-elicited immunosurveillance. [ABSTRACT FROM AUTHOR]

During the past decade, great efforts have been dedicated to the development of clinically relevant interventions that would trigger potent (and hence potentially curative) anticancer immune responses. Indeed, developing neoplasms normally establish local and systemic immunosuppressive networks that inhibit tumor-targeting immune effector cells, be them natural or elicited by (immuno)therapy. One possible approach to boost anticancer immunity consists in the (generally systemic) administration of recombinant immunostimulatory cytokines. In a limited number of oncological indications, immunostimulatory cytokines mediate clinical activity as standalone immunotherapeutic interventions. Most often, however, immunostimulatory cytokines are employed as immunological adjuvants,i.e., to unleash the immunogenic potential of other immunotherapeutic agents, like tumor-targeting vaccines and checkpoint blockers. Here, we discuss recent preclinical and clinical advances in the use of some cytokines as immunostimulatory agents in oncological indications. [ABSTRACT FROM AUTHOR]

Neoadjuvant radiochemotherapy of esophageal carcinomas causes a variable degree of depletion of tumor-infiltrating FOXP3+regulatory T cells (Tregs). The frequency of local Tregs in the operative specimens negatively correlates with the pathological response and overall patient survival. These results underscore the importance of immunosurveillance in determining the fate of patients with esophageal cancers treated with radiochemotherapy. [ABSTRACT FROM AUTHOR]

Anthracycline-based chemotherapies are particularly effective if they succeed in reinstating immunosurveillance by the induction of immunogenic cell death (ICD) in the tumor. Recently, we discovered that ICD is coupled to the induction of type 1 interferons (IFNs-I) that act in an autocrine fashion on cancer cells, thereby increasing their immunogenic potential. [ABSTRACT FROM PUBLISHER]

An expanding panel of monoclonal antibodies (mAbs) that specifically target malignant cells or intercept trophic factors delivered by the tumor stroma is now available for cancer therapy. These mAbs can exert direct antiproliferative/cytotoxic effects as they inhibit pro-survival signal transduction cascades or activate lethal receptors at the plasma membrane of cancer cells, they can opsonize neoplastic cells to initiate a tumor-targeting immune response, or they can be harnessed to specifically deliver toxins or radionuclides to transformed cells. As an indication of the success of this immunotherapeutic paradigm, international regulatory agencies approve new tumor-targeting mAbs for use in cancer patients every year. Moreover, the list of indications for previously licensed molecules is frequently expanded to other neoplastic disorders as the results of large, randomized clinical trials become available. Here, we discuss recent advances in the preclinical and clinical development of tumor-targeting mAbs for oncological indications. [ABSTRACT FROM PUBLISHER]

Indoleamine 2,3-dioxigenase 1 (IDO1) is the main enzyme that catalyzes the first, rate-limiting step of the so-called “kynurenine pathway”, i.e., the metabolic cascade that converts the essential amino acidL-tryptophan (Trp) intoL-kynurenine (Kyn). IDO1, which is expressed constitutively by some tissues and in an inducible manner by specific subsets of antigen-presenting cells, has been shown to play a role in the establishment and maintenance of peripheral tolerance. At least in part, this reflects the capacity of IDO1 to restrict the microenvironmental availability of Trp and to favor the accumulation of Kyn and some of its derivatives. Also, several neoplastic lesions express IDO1, providing them with a means to evade anticancer immunosurveillance. This consideration has driven the development of several IDO1 inhibitors, some of which (including 1-methyltryptophan) have nowadays entered clinical evaluation. In animal tumor models, the inhibition of IDO1 by chemical or genetic interventions is indeed associated with the (re)activation of therapeutically relevant anticancer immune responses. This said, several immunotherapeutic regimens exert robust clinical activity in spite of their ability to promote the expression of IDO1. Moreover, 1-methyltryptophan has recently been shown to exert IDO1-independent immunostimulatory effects. Here, we summarize the preclinical and clinical studies testing the antineoplastic activity of IDO1-targeting interventions. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) are an evolutionarily conserved group of enzymatically inactive, single membrane-spanning proteins that recognize a wide panel of exogenous and endogenous danger signals. Besides constituting a crucial component of the innate immune response to bacterial and viral pathogens, TLRs appear to play a major role in anticancer immunosurveillance. In line with this notion, several natural and synthetic TLR ligands have been intensively investigated for their ability to boost tumor-targeting immune responses elicited by a variety of immunotherapeutic and chemotherapeutic interventions. Three of these agents are currently approved by the US Food and Drug Administration (FDA) or equivalent regulatory agencies for use in cancer patients: the so-called bacillus Calmette-Guérin, monophosphoryl lipid A, and imiquimod. However, the number of clinical trials testing the therapeutic potential of both FDA-approved and experimental TLR agonists in cancer patients is stably decreasing, suggesting that drug developers and oncologists are refocusing their interest on alternative immunostimulatory agents. Here, we summarize recent findings on the use of TLR agonists in cancer patients and discuss how the clinical evaluation of FDA-approved and experimental TLR ligands has evolved since the publication of our first Trial Watch dealing with this topic. [ABSTRACT FROM PUBLISHER]

Tumor-targeting immune responses provide a significant contribution to (when they do not entirely account for) the clinical activity of diverse antineoplastic regimens, encompassing not only a large panel of immunotherapeutic strategies but also conventional cytotoxic molecules, targeted anticancer agents and irradiation. In line with this notion, several approaches have been devised to elicit novel or boost existing anticancer immune responses, including the administration of immunomodulatory cytokines. Such a relatively unspecific intervention suffices to mediate clinical effects in (at least a subset of) patients bearing particularly immunogenic tumors, like melanoma and renal cell carcinoma. More often, however, immunostimulatory cytokines are administered to boost the immunogenic potential of other agents, including (but not limited to) immune checkpoint-blocking antibodies, anticancer vaccines, oncolytic viruses and immunogenic chemotherapeutics. Here, we summarize the latest advances in the clinical development of recombinant cytokines as an immunomodulatory intervention for cancer therapy. [ABSTRACT FROM PUBLISHER]

The expression “adoptive cell transfer” (ACT) is commonly employed to indicate an immunotherapeutic regimen involving the isolation of autologous blood-borne or tumor-infiltrating lymphocytes, their selection/expansion/activation ex vivo, and their reinfusion into the patient, most often in the context of lymphodepleting pre-conditioning and in combination with immunostimulatory treatments. Optionally, the cellular material for ACT is genetically manipulated before expansion to (1) target specific tumor-associated antigens; (2) endogenously express immunostimulatory molecules; and/or (3) persist for long periods upon reinfusion. Consistent efforts have been dedicated at the amelioration of this immunotherapeutic regimen throughout the past decade, resulting in the establishment of ever more efficient and safer ACT protocols. Accordingly, the number of clinical trials testing ACT in oncological indications does not cease to increase. In this Trial Watch, we summarize recent developments in this exciting area of research, covering both high-impact studies that have been published during the last 12 months and clinical trials that have been launched in the same period to evaluate the safety and therapeutic potential of ACT in cancer patients. [ABSTRACT FROM PUBLISHER]

Accumulating evidence suggests that the clinical efficacy of selected anticancer drugs, including conventional chemotherapeutics as well as targeted anticancer agents, originates (at least in part) from their ability to elicit a novel or reinstate a pre-existing tumor-specific immune response. One of the mechanisms whereby chemotherapy can stimulate the immune system to recognize and destroy malignant cells is commonly known as immunogenic cell death (ICD). Cancer cells succumbing to ICD are de facto converted into an anticancer vaccine and as such elicit an adaptive immune response. Several common chemotherapeutics share the ability of triggering ICD, as demonstrated in vaccination experiments relying on immunocompetent mice and syngeneic cancer cells. A large number of ongoing clinical trials involve such ICD inducers, often (but not always) as they are part of the gold standard therapeutic approach against specific neoplasms. In this Trial Watch, we summarize the latest advances on the use of cyclophosphamide, doxorubicin, epirubicin, oxaliplatin, and mitoxantrone in cancer patients, discussing high-impact studies that have been published during the last 13 months as well as clinical trials that have been initiated in the same period to assess the antineoplastic profile of these immunogenic drugs as off-label therapeutic interventions. [ABSTRACT FROM PUBLISHER]

Immunostimulatory monoclonal antibodies (mAbs) exert antineoplastic effects by eliciting a novel or reinstating a pre-existing antitumor immune response. Most often, immunostimulatory mAbs activate T lymphocytes or natural killer (NK) cells by inhibiting immunosuppressive receptors, such as cytotoxic T lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1 (PDCD1, best known as PD-1), or by engaging co-stimulatory receptors, like CD40, tumor necrosis factor receptor superfamily, member 4 (TNFRSF4, best known as OX40) or TNFRSF18 (best known as GITR). The CTLA4-targeting mAb ipilimumab has been approved by the US Food and Drug Administration for use in patients with unresectable or metastatic melanoma in 2011. The therapeutic profile of ipilimumab other CTLA4-blocking mAbs, such as tremelimumab, is currently being assessed in subjects affected by a large panel of solid neoplasms. In the last few years, promising clinical results have also been obtained with nivolumab, a PD-1-targeting mAb formerly known as BMS-936558. Accordingly, the safety and efficacy of nivolumab and other PD-1-blocking molecules are being actively investigated. Finally, various clinical trials are underway to test the therapeutic potential of OX40- and GITR-activating mAbs. Here, we summarize recent findings on the therapeutic profile of immunostimulatory mAbs and discuss clinical trials that have been launched in the last 14 months to assess the therapeutic profile of these immunotherapeutic agents. [ABSTRACT FROM PUBLISHER]

In 1997, for the first time in history, a monoclonal antibody (mAb), i.e., the chimeric anti-CD20 molecule rituximab, was approved by the US Food and Drug Administration for use in cancer patients. Since then, the panel of mAbs that are approved by international regulatory agencies for the treatment of hematopoietic and solid malignancies has not stopped to expand, nowadays encompassing a stunning amount of 15 distinct molecules. This therapeutic armamentarium includes mAbs that target tumor-associated antigens, as well as molecules that interfere with tumor-stroma interactions or exert direct immunostimulatory effects. These three classes of mAbs exert antineoplastic activity via distinct mechanisms, which may or may not involve immune effectors other than the mAbs themselves. In previous issues ofOncoImmunology, we provided a brief scientific background to the use of mAbs, all types confounded, in cancer therapy, and discussed the results of recent clinical trials investigating the safety and efficacy of this approach. Here, we focus on mAbs that primarily target malignant cells or their interactions with stromal components, as opposed to mAbs that mediate antineoplastic effects by activating the immune system. In particular, we discuss relevant clinical findings that have been published during the last 13 months as well as clinical trials that have been launched in the same period to investigate the therapeutic profile of hitherto investigational tumor-targeting mAbs. [ABSTRACT FROM PUBLISHER]

Formyl peptide receptor-1 (FPR1) is a pattern recognition receptor that is mostly expressed by myeloid cells. In patients with colorectal cancer (CRC), a loss-of-function polymorphism (rs867228) in the gene coding for FPR1 has been associated with reduced responses to chemotherapy or chemoradiotherapy. Moreover, rs867228 is associated with accelerated esophageal and colorectal carcinogenesis. Here, we show that dendritic cells from Fpr1−/− mice exhibit reduced migration in response to chemotherapy-treated CRC cells. Moreover, Fpr1−/− mice are particularly susceptible to chronic ulcerative colitis and colorectal oncogenesis induced by the mutagen azoxymethane followed by oral dextran sodium sulfate, a detergent that induces colitis. These experiments were performed after initial co-housing of Fpr1−/− mice and wild-type controls, precluding major Fpr1-driven differences in the microbiota. Pharmacological inhibition of Fpr1 by cyclosporin H also tended to increase intestinal oncogenesis in mice bearing the ApcMin mutation, and this effect was reversed by the anti-inflammatory drug sulindac. We conclude that defective FPR1 signaling favors intestinal tumorigenesis through the modulation of the innate inflammatory/immune response. [ABSTRACT FROM AUTHOR]

Formyl peptide receptor-1 (FPR1) is a pathogen recognition receptor involved in the detection of bacteria, in the control of inflammation, as well as in cancer immunosurveillance. A single nucleotide polymorphism in FPR1, rs867228, provokes a loss-of-function phenotype. In a bioinformatic study performed on The Cancer Genome Atlas (TCGA), we observed that homo-or heterozygosity for rs867228 in FPR1 (which affects approximately one-third of the population across continents) accelerates age at diagnosis of specific carcinomas including luminal B breast cancer by 4.9 years. To validate this finding, we genotyped 215 patients with metastatic luminal B mammary carcinomas from the SNPs To Risk of Metastasis (SToRM) cohort. The first diagnosis of luminal B breast cancer occurred at an age of 49.2 years for individuals bearing the dysfunctional TT or TG alleles (n = 73) and 55.5 years for patients the functional GG alleles (n = 141), meaning that rs867228 accelerated the age of diagnosis by 6.3 years (p=0.0077, Mann & Whitney). These results confirm our original observation in an independent validation cohort. We speculate that it may be useful to include the detection of rs867228 in breast cancer screening campaigns for selectively increasing the frequency and stringency of examinations starting at a relatively young age. [ABSTRACT FROM AUTHOR]

Summary Caloric restriction mimetics (CRMs) mimic the biochemical effects of nutrient deprivation by reducing lysine acetylation of cellular proteins, thus triggering autophagy. Treatment with the CRM hydroxycitrate, an inhibitor of ATP citrate lyase, induced the depletion of regulatory T cells (which dampen anticancer immunity) from autophagy-competent, but not autophagy-deficient, mutant KRAS-induced lung cancers in mice, thereby improving anticancer immunosurveillance and reducing tumor mass. Short-term fasting or treatment with several chemically unrelated autophagy-inducing CRMs, including hydroxycitrate and spermidine, improved the inhibition of tumor growth by chemotherapy in vivo. This effect was only observed for autophagy-competent tumors, depended on the presence of T lymphocytes, and was accompanied by the depletion of regulatory T cells from the tumor bed. [ABSTRACT FROM AUTHOR]

Abstract: Preclinical and clinical findings suggest that tumor-specific immune responses may be responsible – at least in part – for the clinical success of therapeutic regimens that rely on immunogenic cell death (ICD) inducers, including anthracyclines and oxaliplatin. The molecular pathways whereby some, but not all, cytotoxic agents promote bona fide ICD remain to be fully elucidated. Nevertheless, a central role for the endoplasmic reticulum (ER) stress response has been revealed in all scenarios of ICD described thus far. Hence, components of the ER stress machinery may constitute clinically relevant druggable targets for the induction of ICD. In this review, we will summarize recent findings in the field of ICD research with a special focus on ER stress mechanisms and their implication for cancer therapy. [Copyright &y& Elsevier]

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]

Retrospective clinical data indicate that cardiac glycosides (CGs), notably digoxin, prolong the survival of carcinoma patients treated with conventional chemotherapy. CGs are known to influence the immune response at multiple levels. In addition, recent results suggest that CGs trigger the immunogenic demise of cancer cells, an effect that most likely contributes to their clinical anticancer activity. [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]

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]

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]

We have recently shown that chemotherapy with immunogenic cell death (ICD)-inducing agents can be advantageously combined with fasting regimens or caloric restriction mimetics (CRMs) to achieve superior tumor growth control via a T cell-dependent mechanism. Here, we show that the blockade of the CD11b-dependent extravasation of myeloid cells blocks such a combination effect as well. Based on the characterization of the myeloid and lymphoid immune infiltrates, including the expression pattern of immune checkpoint proteins (and noting a chemotherapy-induced overexpression of programmed death-ligand 1, PD-L1, on both cancer cells and leukocytes, as well as a reduced frequency of exhausted CD8+ T cells positive for programmed cell death 1 protein, PD-1), we then evaluated the possibility to combine ICD inducers, CRMs and targeting of the PD-1/PD-L1 interaction. While fasting or CRMs failed to improve tumor growth control by PD-1 blockade, ICD inducers alone achieved a partial sensitization to treatment with a PD-1-specific antibody. However, definitive cure of most of the tumor-bearing mice was only achieved by a tritherapy combining (i) ICD inducers exemplified by mitoxantrone and oxaliplatin, (ii) CRMs exemplified by hydroxycitrate and spermidine and substitutable for by fasting, and (iii) immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 interaction. Altogether, these results point to the possibility of synergistic interactions among distinct classes of anticancer agents. [ABSTRACT FROM AUTHOR]

Mouse cancers lacking the expression of annexin A1 (ANXA1) fail to respond to immunogenic chemotherapies. This has been initially explained by the requirement of extracellular ANXA1 (which is released from dying cancer cells) to engage formyl peptide receptor-1 (FPR1) on dendritic cells (DC) for the establishment of corpse/DC synapses. Here, we show that ANXA1-deficent cancer cells exhibit a defect in the exposure of calreticulin (CALR), which is an important "eat-me" signal, facilitating the phagocytic uptake of dead-cell antigens by DC. Of note, intratumoral injection of recombinant CALR protein was able to restore the therapeutic response of ANXA1-deficient cancers to anthracycline-based chemotherapy. Carcinomas developing in patients tend to downregulate ANXA1 expression as compared to their normal tissues of origin. ANXA1-low breast, colorectal, lung and kidney cancers are scarcely infiltrated by DC and cytotoxic T lymphocytes, supporting the idea that ANXA1 deficiency facilitates immune escape. We propose that such ANXA1-low cancers might be particularly suitable to local immunotherapy with CALR protein. [ABSTRACT FROM AUTHOR]

The analysis of tumor growth curves is standard practice in experimental oncology including tumor immunology. In experimental oncology, cancer cells are inoculated into rodents (mostly mice) and their growth is monitored by measuring tumor diameter, surface or volume over time as a function of distinct treatments. Then, different groups of tumors/treatments are compared among each other for their evolution and possible responses to treatment. The R package TumGrowth has been created as a software tool allowing to carry out a series of statistical comparisons across or between groups of tumor growth curves obtained in a standard laboratory, for experimenters with limited knowledge in statistics. TumGrowth is freely available online at https://kroemerlab.shinyapps.io/TumGrowth/ and can be downloaded into any computer. It offers an exhaustive panoply of tools to visualize and analyze complex data sets including longitudinal, cross-sectional and time-to-endpoint measurements. [ABSTRACT FROM AUTHOR]