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Risk factors for colorectal cancer (CRC) include proinflammatory diets, sedentary habits, and obesity, in addition to genetic syndromes that predispose individuals to this disease. Current treatment relies on surgical excision and cytotoxic chemotherapies. There has been a renewed interest in immunotherapy as a treatment option for CRC given the success in melanoma and microsatellite instable (MSI) CRC. Immunotherapy with checkpoint inhibitors only plays a role in the 4%-6% of patients with MSIhigh tumors and even within this subpopulation, response rates can vary from 30% to 50%. Most patients with CRC do not respond to this modality of treatment, even though colorectal tumors are frequently infiltrated with T cells. Tumor cells limit apoptosis and survive following intensive chemotherapy leading to drug resistance and induction of autophagy. Pharmacological or molecular inhibition of autophagy improves the efficacy of cytotoxic chemotherapy in murine models. The microbiome clearly plays an etiologic role, in some or most colon tumors, realized by elegant findings in murine models and now investigated in human clinical trials. Recent results have suggested that cancer vaccines may be beneficial, perhaps best as preventive strategies. The search for therapies that can be combined with current approaches to increase their efficacy, and new knowledge of the biology of CRC are pivotal to improve the care of patients suffering from this disease. Here, we review the basic immunobiology of CRC, current "state-of-the-art" immunotherapies and define those areas with greatest therapeutic promise for the future., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Immunotherapy is now a cornerstone for cancer treatment, and much attention has been placed on the identification of prognostic and predictive biomarkers. The success of biomarker development is dependent on accurate and timely collection of biospecimens and high-quality processing, storage and shipping. Tumors are also increasingly used as source material for the generation of therapeutic T cells. There have been few guidelines or consensus statements on how to optimally collect and manage biospecimens and source material being used for immunotherapy and related research. The Society for Immunotherapy of Cancer Surgery Committee has brought together surgical experts from multiple subspecialty disciplines to identify best practices and to provide consensus on how best to access and manage specific tissues for immuno-oncology treatments and clinical investigation. In addition, the committee recommends early integration of surgeons and other interventional physicians with expertise in biospecimen collection, especially in clinical trials, to optimize the quality of tissue and the validity of correlative clinical studies in cancer immunotherapy., Competing Interests: Competing interests: BG is a consultant for Quest Imaging and a speaker for Castle Biosciences. PKA has partner salary from Pfizer. GB has sponsored research agreements with Takeda Oncology, Olink Proteomics, and Palleon, honorarium from Novartis, and consulting for NW Biotherapeutics. SB is a consultant for BMS. LHB is a consultant for StemImmune/Calidi, NextCure, Replimmune, Western Oncolytics, Torque Therapeutics, Khloris, Pyxis, Cytomix, and Roche-Genentech. PEF is a consultant for Monteris Medical. RLF is a consultant for Aduro Biotech, Amgen, Astra-Zeneca/Medimmune, Bain Capital Life Sciences, BMS, EMD Serono, GSK, Iovance, Lilly, MacroGenics, Merck, Nanobiotx, Numab Therapeutics, Oncorus, Ono Pharmaceutcal Co., Pfizer, PPD, Regeneron, Tesaro, Torque Therapeutics, TTMS, and VentiRx Pharmaceuticals; has contracted research agreements with Astra-Zeneca/Medimmune, BMS, Merck, Tesaro, and TTMS, has partner consulting for Janssen, Lilly, Scibase, DermTech, BMS, and Pfizer, and has partner contracted research agreements with Regeneron, Janssen, BMS, Abbvie, BI, Castle Biosciences and Lilly.YF has relationships with Imagene, Merck, Eureka and Surgamo, and partner interest in Pfizer. MLim is a consultant for Tocagen, VBI and Strykes, and receives research funding from Arbor, BMS and Biohaven. MLotze receives salary from Nurix, Inc., royalty from Cellatrope, has IP rights in Intrexon, consults for Myst, Instill, Checkmate, Carisma and Surface Oncology, and has ownership interest in iRepertoire. HM has contracted research with Puma Biotechnology. RIN is a consultant for Novartis, Castle Biosciences, and Sanofi-Granzyme and has contracted research with Regeneron and Castle Biosciences. AO is a cofounder of Tactiva Therapeutics, Inc., and receives research support from AstraZeneca and Tesaro. SP is a consultant for Abbvie, Astra-Zeneca, Cue Biopharma, Fusion Biopharma, Merck, Newlink Genetics, Oncolys Biopharma, Oncosec, Replimmune and Sensei Bio, contracted research with Abbvie, Astra-Zeneca, Cue Biopharma, Sensei Bio and Tesaro, and investigator-initiated trials with ASTX Pharmaceuticals, Astra-Zeneca, Cue Biopharma, ImmuneDesign and Merck. SAR has patents held by the NCI and cooperative research agreements with Kite, Iovance and Ziopharm. CLS is a consultant for Celldex, CureVac and Castle Biosciences, and has institutional support from Celldex, Polynoma, GSK, Merck, 3M, Theraclion and Immatics. VKS is a consultant for Array, BMS, Merck, Novartis, Pfizer, Polynoma, Regeneron and Replimmune. JBS is on the advisory board of ABL Bio and is the scientific founder of Indapta Therapeutics. ST is a consultant for TVM Life Science, received honoraria from Astra-Zeneca, Celgene and Exactis Innovation, and has research grants from BMS and Iovance. CY is a consultant for Loxo, Merck and Adaptive Biotechnologies, has contracted research with Obi and Pfizer, and has ownership interest in Molpath Dx, LLC. HLK is an employee of Immuneering Coporation., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Tumor immunology has changed the landscape of cancer treatment. Yet, not all patients benefit as cancer immune responsiveness (CIR) remains a limitation in a considerable proportion of cases. The multifactorial determinants of CIR include the genetic makeup of the patient, the genomic instability central to cancer development, the evolutionary emergence of cancer phenotypes under the influence of immune editing, and external modifiers such as demographics, environment, treatment potency, co-morbidities and cancer-independent alterations including immune homeostasis and polymorphisms in the major and minor histocompatibility molecules, cytokines, and chemokines. Based on the premise that cancer is fundamentally a disorder of the genes arising within a cell biologic process, whose deviations from normality determine the rules of engagement with the host's response, the Society for Immunotherapy of Cancer (SITC) convened a task force of experts from various disciplines including, immunology, oncology, biophysics, structural biology, molecular and cellular biology, genetics, and bioinformatics to address the complexity of CIR from a holistic view. The task force was launched by a workshop held in San Francisco on May 14-15, 2018 aimed at two preeminent goals: 1) to identify the fundamental questions related to CIR and 2) to create an interactive community of experts that could guide scientific and research priorities by forming a logical progression supported by multiple perspectives to uncover mechanisms of CIR. This workshop was a first step toward a second meeting where the focus would be to address the actionability of some of the questions identified by working groups. In this event, five working groups aimed at defining a path to test hypotheses according to their relevance to human cancer and identifying experimental models closest to human biology, which include: 1) Germline-Genetic, 2) Somatic-Genetic and 3) Genomic-Transcriptional contributions to CIR, 4) Determinant(s) of Immunogenic Cell Death that modulate CIR, and 5) Experimental Models that best represent CIR and its conversion to an immune responsive state. This manuscript summarizes the contributions from each group and should be considered as a first milestone in the path toward a more contemporary understanding of CIR. We appreciate that this effort is far from comprehensive and that other relevant aspects related to CIR such as the microbiome, the individual's recombined T cell and B cell receptors, and the metabolic status of cancer and immune cells were not fully included. These and other important factors will be included in future activities of the taskforce. The taskforce will focus on prioritization and specific actionable approach to answer the identified questions and implementing the collaborations in the follow-up workshop, which will be held in Houston on September 4-5, 2019.

During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into "passive" and "active" based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor-associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches.

Endogenously produced microRNAs are predicted to regulate the translation of over two-thirds all human gene transcripts. Certain microRNAs regulate expression of genes that are critically involved in both innate and adaptive immune responses. Immune cells represent a highly attractive target for microRNA gene therapy approaches, as these cells can be isolated, treated and then reintroduced into the patient. In this short review, we discuss how recent discoveries on the roles of microRNAs in immune-regulation will advance the field of cancer immunology and immunotherapy. Targets identified already in T cells include microRNAs, miR-17-92 family, miR-155, and miR-181a. In macrophages, miR-125b, miR-146, and miR-155 act as Pathogen Associated Molecular Pattern Molecule-associated microRNAs and miR-34C and miR-214 as Damage Associated Molecular Pattern Molecules-associated miRs. We have also demonstrated that the ability of tumors to serve as targets for cytolytic effectors is regulated by miR-222 and miR-339., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Background: Type-1 T cells are critical for effective anti-tumor immune responses. The recently discovered microRNAs (miRs) are a large family of small regulatory RNAs that control diverse aspects of cell function, including immune regulation. We identified miRs differentially regulated between type-1 and type-2 T cells, and determined how the expression of such miRs is regulated., Methods: We performed miR microarray analyses on in vitro differentiated murine T helper type-1 (Th1) and T helper type-2 (Th2) cells to identify differentially expressed miRs. We used quantitative RT-PCR to confirm the differential expression levels. We also used WST-1, ELISA, and flow cytometry to evaluate the survival, function and phenotype of cells, respectively. We employed mice transgenic for the identified miRs to determine the biological impact of miR-17-92 expression in T cells., Results: Our initial miR microarray analyses revealed that the miR-17-92 cluster is one of the most significantly over-expressed miR in murine Th1 cells when compared with Th2 cells. RT-PCR confirmed that the miR-17-92 cluster expression was consistently higher in Th1 cells than Th2 cells. Disruption of the IL-4 signaling through either IL-4 neutralizing antibody or knockout of signal transducer and activator of transcription (STAT)6 reversed the miR-17-92 cluster suppression in Th2 cells. Furthermore, T cells from tumor bearing mice and glioma patients had decreased levels of miR-17-92 when compared with cells from non-tumor bearing counterparts. CD4+ T cells derived from miR-17-92 transgenic mice demonstrated superior type-1 phenotype with increased IFN-gamma production and very late antigen (VLA)-4 expression when compared with counterparts derived from wild type mice. Human Jurkat T cells ectopically expressing increased levels of miR-17-92 cluster members demonstrated increased IL-2 production and resistance to activation-induced cell death (AICD)., Conclusion: The type-2-skewing tumor microenvironment induces the down-regulation of miR-17-92 expression in T cells, thereby diminishing the persistence of tumor-specific T cells and tumor control. Genetic engineering of T cells to express miR-17-92 may represent a promising approach for cancer immunotherapy.

Renal cell carcinoma (RCC) is the eighth most common malignancy in adults in the United States. More than 50% of individuals present with metastatic disease and conventional chemotherapeutic strategies have been associated with poor response rates. Immunotherapy with Interleukin (IL)-2, however, induces durable remission, achieving >10 year recurrence free survival in 5-10% of patients with advanced RCC. First described as a T cell growth factor, IL-2 has a wide spectrum of effects in the immune system. Some of the possible mechanisms by which IL-2 carries out its anticancer effects include the augmentation of cytotoxic immune cell functions and reversal of T cell anergy, enabling delivery of immune cells and possibly serum components into tumor. IL-2 indirectly limits tumor escape mechanisms such as defective tumor cell expression of Class I or Class II molecules or expansion of regulatory T cells. Indirect effects on the tumor microenvironment are also likely and associated with rather dramatic T cell infiltration during the global delayed type hypersensitivity response that is associated with systemic IL-2 administration. The IL-2 signaling pathway, its effects on immune cells, and its role in various independent mechanisms of tumor surveillance likely play a role but little substantive data defining a clear phenotype or genotype of IL-2 responders distinguishing them from nonresponders has emerged in the last 25 years since IL-2 therapy was initiated. At best, we can only speculate that the disturbed homeostatic host/tumor interaction is reset in a small subset of patients allowing an antitumor response to recover or ensue.

The International Society for Biologic Therapy of Cancer held a mini-symposium on October 26, 2006 in Los Angeles to review current information regarding the biologic effects of both standard and targeted therapies. The purpose of the mini-symposium was to describe the existing knowledge regarding various biologic effects of current therapies, identify the most relevant issues and gaps in the knowledge base and discuss the optimal means of obtaining necessary missing information. Topics discussed included: (1) The impact of antitumor monoclonal antibody therapy on antigen presentation and adaptive immunity; (2) the effects of antiangiogenic/targeted therapy of the immune system; (3) the impact of chemotherapy on angiogenesis and immune function; (4) combination of antiangiogenic and immunotherapy at the clinical level; (5) the effects of tyrosine kinase inhibitors on TH1/TH2 response and T-regulatory cells; (6) the impact of farnesyltransferase inhibitors and other targeted agents on T-cell activation; (7) the impact of epigenetic modulators on biologic properties, and (8) the impact of the nature of cell death on the immune system. The ultimate goals of this mini-symposium were to use the above information to inform and influence basic science efforts and discussions, rationally design combination treatment regimens and optimally employ correlative studies in the context of ongoing and future clinical investigations.

The development of a tumor over many years typically leads to reciprocal alternations in the host and the tumor, enabling tumor growth paradoxically in the setting of substantial necrosis and inflammation. When evaluating a tumor, it is important to assess 3 elements: (1) the quantity and quality of tumor-associated leukocytes, (2) their state of activation, and (3) tumor microenvironment. Peripheral blood eosinophilia and tumor-associated tissue eosinophilia are frequently associated with some tumor types and also found after immunotherapy with IL-2, IL-4, granulocyte-macrophage colony-stimulating factor, and antibody to CTLA-4. Within several tumor types including gastrointestinal tumors, tumor-associated tissue eosinophilia is associated with a significantly better prognosis. The converse is true in other tumor types such as differentiated oral squamous cell carcinoma. On the basis of the emergent data, tumor-associated eosinophils have at least 2 dominant nonoverlapping activities: (1) destructive effector functions potentially limiting tumor growth as well as causing recruitment and activation of other leukocytes, (2) immunoregulative and remodeling activities which suppress immune response and promote tumor proliferation. The mechanism by which eosinophils in particular are recruited into tumor tissue is largely unknown. Candidates for causing eosinophil chemotaxis into tumor tissue are the released damage-associated molecular pattern molecules (DAMPs) including the nuclear protein high mobility group box 1. High mobility group box 1 is released upon necrotic cell death and secreted by many cells, particularly during periods of nutrient, hypoxic, or oxidant stress. This overview on eosinophil biology in the context of cancer and necrosis, introduces intriguing and novel strategies targeting eosinophils to enable more effective biologic therapy for cancer patients.

The presence of inflammatory cells within cancer has been described for quite some time by pathologists, with generally improved outcome associated with their presence in various epithelial neoplasms. Most remarkably, this has included dendritic cells and T cells but more recently NK cells as well. Coupled with the rapid evolution of molecular technology, microarray analyses of primary tumors, serum and tumor proteomics, tumor capture analyses in the peripheral blood (together with quantitative RT-PCR), and novel histochemical markers and tissue microarrays, this provides the opportunity to establish a more effective means to study and classify into subsets various forms of cancer. Much of the current controversy in cancer diagnosis and pathologic assessment of prognosis lies in the application of these techniques in concert with other molecular tools including DNA microarrays, expression of histochemically defined cytokines, proangiogenic factors, and oncogene products, and correlating this with clinical relevance. Molecular detection technologies such as reverse transcriptase polymerase chain reaction, proteomics, and microarray analyses will be validated based on their integration with conventional cancer pathology and cancer diagnostics. Further work is needed to establish which cancer biomarkers and surrogates should be routinely measured and in which settings, and determining the appropriate sample size for such assays that can be validated in retrospective and prospective clinical studies. The ability to integrate these rapidly evolving strategies will consume much of our coordinate effort in cancer and cancer therapeutics for the near future.

The role of immunity in cancer has been abundantly demonstrated in murine tumor models as well as in man. Induction of clinically effective antitumor immune responses, based on this information, in patients with cancer however, remains elusive. This is not because tumors lack recognizable antigens [in fact there is evidence that there are thousands of potential novel targets in each tumor cell] but rather due to the fact that the induction of responses is not adequate nor particularly well understood. Tumors seem to be rather effective at limiting immune responses. Many of the molecularly defined antigens that have been detected on tumor cells are derived from self-proteins and as such are subject to tolerizing mechanisms. Such tumors have also developed escape mechanisms capable of evading or suppressing immune responses. Understanding the role of dendritic cells during the effector phase of the immune response and the complex interactions of stromal, immune, and tumor cells in the tumor microenvironment represent the next challenges to be understood for tumor immunology.

This document is an editorial from the Journal of International Society of Preventive & Community Dentistry discussing the role of the journal in advancing scientific research in cancer immunotherapy. The authors emphasize the importance of interdisciplinary collaboration and the inclusion of other disciplines such as neurobiology, artificial intelligence/machine learning, and endocrinology. They highlight the need to expand therapeutic options for cancer patients and explore antigen-specific therapies. The authors call for the identification of biomarkers and the study of the tumor microenvironment and macro-environment. They promote scientific advancement and collaboration in the field of cancer immunotherapy. Additionally, the document discusses the use of bioinformatic approaches in Systems Immunology studies and the need for experimental validation. The authors stress the value of preclinical experiments and clinical trials in understanding the mechanisms of action and responses to new therapies. They encourage the submission of clinical trial reports supported by translational studies to advance the field. The authors express a commitment to rigorous research and understanding the biology of immune therapies. [Extracted from the article]

The immune system interacts with many nominal 'danger' signals, endogenous danger‐associated (DAMP), exogenous pathogen (PAMP) and allergen (AAMP)‐associated molecular patterns. The immune context under which these are received can promote or prevent immune activating or inflammatory mechanisms and may orchestrate diverse immune responses in allergy and cancer. Each can act either by favouring a respective pathology or by supporting the immune response to confer protective effects, depending on acuity or chronicity. In this Position Paper under the collective term danger signals or DAMPs, PAMPs and AAMPs, we consider their diverse roles in allergy and cancer and the connection between these in AllergoOncology. We focus on their interactions with different immune cells of the innate and adaptive immune system and how these promote immune responses with juxtaposing clinical outcomes in allergy and cancer. While danger signals present potential targets to overcome inflammatory responses in allergy, these may be reconsidered in relation to a history of allergy, chronic inflammation and autoimmunity linked to the risk of developing cancer, and with regard to clinical responses to anti‐cancer immune and targeted therapies. Cross‐disciplinary insights in AllergoOncology derived from dissecting clinical phenotypes of common danger signal pathways may improve allergy and cancer clinical outcomes. [ABSTRACT FROM AUTHOR]

The mainstay of treatment for patients with malignant pleural disease is fluid drainage and systemic therapy. A tumor-specific oncolytic virus or T-cell–activating interleukin-2 immunotherapy may provide an opportunity for local control. We previously developed a vaccinia virus–expressing interleukin-2, an oncolytic virus that mediated tumor regression in preclinical peritoneal tumor models with expansion of tumor-infiltrating lymphocytes. We evaluated the antitumor efficacy and immune modulatory effects of vaccinia virus–expressing interleukin-2 in malignant pleural disease. A murine model of malignant pleural disease was established with percutaneous intrapleural deposition of the Lewis lung carcinoma cell line and monitored with bioluminescent imaging. After intrapleural or systemic administration of vaccinia viruses (vaccinia virus yellow fluorescent protein control, vaccinia virus–expressing interleukin-2), systemic anti–programmed cell death-1 antibody, or combination therapy (vaccinia virus–expressing interleukin-2 and anti–programmed cell death-1), tumor mass, immune cell infiltration, T-cell receptor diversity, and survival were assessed. Intrapleural vaccinia virus resulted in significant tumor regression compared with phosphate-buffered saline control (P <.05). Inclusion of the interleukin-2 transgene further increased intratumoral CD8+ T cells (P <.01) and programmed cell death-1 expression on CD8+ tumor-infiltrating lymphocytes (P <.001). Intrapleural vaccinia virus–expressing interleukin-2 was superior to systemic vaccinia virus–expressing interleukin-2, with reduced tumor burden (P <.0001) and improved survival (P <.05). Intrapleural vaccinia virus–expressing interleukin-2 alone or combined treatment with systemic anti–programmed cell death-1 reduced tumor burden (P <.01), improved survival (P <.01), and increased intratumoral αβ T-cell receptor diversity (P <.05) compared with systemic anti–programmed cell death-1 monotherapy. Intrapleural vaccinia virus–expressing interleukin-2 reduced tumor burden and enhanced survival in a murine malignant pleural disease model. Increased CD8+ tumor-infiltrating lymphocytes and αβ T-cell receptor diversity are associated with enhanced response. Clinical trials will enable assessment of intrapleural vaccinia virus–expressing interleukin-2 therapy in patients with malignant pleural disease. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Resistance to chemotherapy is a major obstacle in the effective treatment of cancer patients. B7-homolog 1, also known as programmed death ligand-1 (PD-L1), is an immunoregulatory protein that is overexpressed in several human cancers. Interaction of B7-H1 with programmed death 1 (PD-1) prevents T-cell activation and proliferation, sequestering the T-cell receptor from the cell membrane, inducing T-cell apoptosis, thereby leading to cancer immunoresistance. B7-H1 upregulation contributes to chemoresistance in several types of cancer, but little is known with respect to changes associated with 5-fluorouracil (5-FU) or gastrointestinal cancers. Methods: HCT 116 p53+/+, HCT 116 p53-/- colorectal cancer (CRC) and OE33 esophageal adenocarcinoma (EAC) cells were treated with increasing doses of 5-FU (0.5 uM, 5 uM, 50 uM, 500 uM) or interferon gamma (IFN-γ, 10 ng/ mL) in culture for 24 h and B7-H1 expression was quantified using flow cytometry and western blot analysis. We also evaluated B7-H1 expression, by immunohistochemistry, in tissue collected prior to and following neoadjuvant therapy in 10 EAC patients. Results: B7-H1 expression in human HCT 116 p53+/+ and HCT 116 p53-/- CRC cells lines, while low at baseline, can be induced by treatment with 5-FU. OE33 baseline B7-H1 expression exceeded CRC cell maximal expression and could be further increased in a dose dependent manner following 5-FU treatment in the absence of immune cells. We further demonstrate tumor B7-H1 expression in esophageal adenocarcinoma patient-derived pre-treatment biopsies. While B7-H1 expression was not enhanced in post-treatment esophagectomy specimens, this may be due to the limits of immunohistochemical quantification. Conclusions: B7-H1/PD-L1 expression can be increased following treatment with 5-FU in gastrointestinal cancer cell lines, suggesting alternative mechanisms to classic immune-mediated upregulation. This suggests that combining 5-FU treatment with PD-1/B7-H1 blockade may improve treatment in patients with gastrointestinal adenocarcinoma. [ABSTRACT FROM AUTHOR]

Tumor immune responses, including some immunotherapy strategies, can fail because of a number of reasons, such as poor tumor cell immunogenicity or local suppressive cytokine release by dendritic cells (DC) at tumor sites. The retroviral transfer of T-cell receptor (TCR) genes encoding tumor-specific receptors into T cells is a fascinating approach to bypass antigen-presenting cells and allow T cells to directly recognize antigen. It also allows the generation and expansion of potent antitumor cytotoxic T lymphocytes with defined cancer antigen specificities more readily than naive T cells. However, interleukin-10 (IL-10)-exposed dendritic cells (IL-10-DC) have been labeled tolerogenic because of the suppressive effects they have on T cell responses. Whether TCR gene-transduced effector CD8+ T cells can break through suppressive functions mediated by IL-10-DC is not known. In the current study, we demonstrate the role of IL-10 in modifying the function of DC that otherwise would activate potent TCR gene-transduced T cells against tumor antigens. TCR gene-transduced T cells maintained their cytolytic activity in the presence of DC exposed to low doses of IL-10 during maturation; however, they lost this activity in an antigen-specific manner when exposed to DC matured with high doses of IL-10. ( Cancer Sci 2005; 96: 897–902) [ABSTRACT FROM AUTHOR]

Objectives Dendritic cells, the most potent of the antigen-presenting cells, have been widely studied as a promising tool for antitumor immunotherapies. However, little has been determined about the efficacy of dendritic cell-based therapy for the treatment of squamous cell carcinoma (SCC) because there are no known SCC-specific antigens. Recent reports indicate that dendritic cells can acquire antigens in the form of apoptotic cells and induce cytotoxic T-lymphocyte responses. The aim of this study was to test the feasibility of adoptive dendritic cell immunotherapy against SCC by using apoptotic tumor cells as a source of tumor antigens. Study Design A poorly immunogenic SCC line KLN 205 was used to make subcutaneous tumors on the flank of DBA2/J syngeneic mice. Bone marrow-derived dendritic cells were pulsed with ultraviolet B-irradiated (apoptotic) KLN 205 cells in vitro and transferred to the opposite flank subcutaneously. Some of the animals received simultaneous intraperitoneal injections of low-dose interleukin-2. Results When combined with interleukin-2, adoptive transfers of dendritic cells that were pulsed with apoptotic SCC significantly suppressed the tumor growth ( P <.001) without notable side effects. Splenic T cells of treated mice produced greater amounts of interferon-γ when restimulated with the relevant tumor ( P <.001) as compared with control groups, indicative of an effective T-cell-mediated systemic immune response. Conclusion Adoptive transfer of dendritic cells pulsed with apoptotic tumor cells as a source of tumor antigens, can elicit effective antitumor responses in the poorly immunogenic SCC model when combined with interleukin-2. [ABSTRACT FROM AUTHOR]

Background: Interleukin-2 (IL-2) is a cytokine produced by activated T cells, which has shown powerful immunostimulatory and antineoplastic properties. Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated cancer with abundant lymphocyte infiltration histologically. The activity of IL-2 in the treatment of NPC patients is currently unknown. A phase II study was, therefore, initiated to evaluate the efficacy, toxicity and immunological consequences of intravenous bolus IL-2 in patients with recurrent/metastatic NPC. Methods: Between November 1996 and April 1997, 14 patients with recurrent/metastatic NPC were entered into the study. Recombinant IL-2 (Proleukin, Chiron) was injected by intravenous bolus every 8 h at 72,000 IU/kg for a maximum of 15 doses. After 7 days, patients were retreated with a second identical cycle of therapy. Those patients who were stable or responding to treatment 5–6 weeks later went on to receive another course (two cycles) of therapy. All patients received prophylactic antibiotics and antipyretic medicine. Response and toxicities were evaluated. Serial plasma level of TNF-α, IL-6, soluble IL-2 receptor, IL-10 and soluble CD8 were determined. Results: Fourteen patients received a total of 34 cycles of therapy. No response was observed. Fifty percent had stable disease, 50% had progressive disease after a median of two cycles of therapy. There was one treatment-related death from acute myocardial infarction. Body weight increase (>5%) occurred in 80% of cycles, and hypotension (BP <80 mm Hg systolic) occurred in 53%. Serum creatinine increase (>2 mg%) occurred in 24% of cycles, and SGOT/SGPT increase (>3×) in 10% of cycles. Symptoms of somnolence, general malaise, nausea and vomiting, pruritus, xerostomia, desquamation were generally mild to moderate but rapidly reversible. Conclusion: The single modality of intravenous bolus IL-2 at the dose level of 72,000 IU/kg is clinically ineffective in NPC patients. Potential mechanisms of the ineffectiveness of IL-2 therapy on NPC patients are discussed. Copyright © 2001 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Examines the use of interleukin-2 in the immunotherapy of cancer patients. Insight on the biology and clinical application of interleukin-2; Discussion on the administration of interleukin-2 in vivo; Outcome of using adoptive immunotherapy with lymphokine-activated killer cells and interleukin-2 in animal models.

Recent advances in γδ T cell biology have focused on the unique attributes of these cells and their role in regulating innate and adaptive immunity, promoting tissue homeostasis, and providing resistance to various disorders. Numerous bacterial and viral pathogens, including human immunodeficiency virus-1 (HIV), greatly alter the composition of γδ T cells in vivo. Despite the effectiveness of antiretroviral therapy (ART) in controlling HIV and restoring health in those affected, γδ T cells are dramatically impacted during HIV infection and fail to reconstitute to normal levels in HIV-infected individuals during ART for reasons that are not clearly understood. Importantly, their role in controlling HIV infection, and the implications of their failure to rebound during ART are also largely unknown and understudied. Here, we review important aspects of human γδ T cell biology, the effector and immunomodulatory properties of these cells, their prevalence and function in HIV, and their immunotherapeutic potential. [ABSTRACT FROM AUTHOR]

Oncolytic viruses (OVs) are potent anti-cancer biologics with a bright future, having substantial evidence of efficacy in patients with cancer. Bi- and tri-specific antibodies targeting tumor antigens and capable of activating T cell receptor signaling have also shown great promise in cancer immunotherapy. In a cutting-edge strategy, investigators have incorporated the two independent anti-cancer modalities, transforming them into bi- or tri-specific T cell engager (BiTE or TriTE)-armed OVs for targeted immunotherapy. Since 2014, multiple research teams have studied this combinatorial strategy, and it showed substantial efficacy in various tumor models. Here, we first provide a brief overview of the current status of oncolytic virotherapy and the use of multi-specific antibodies for cancer immunotherapy. We then summarize progress on BiTE and TriTE antibodies as a novel class of cancer therapeutics in preclinical and clinical studies, followed by a discussion of BiTE- or TriTE-armed OVs for cancer therapy in translational models. In addition, T cell receptor mimics (TCRm) have been developed into BiTEs and are expected to greatly expand the application of BiTEs and BiTE-armed OVs for the effective targeting of intracellular tumor antigens. Future applications of such innovative combination strategies are emerging as precision cancer immunotherapies. [ABSTRACT FROM AUTHOR]

Malignant pleural effusions, arising from either primary mesotheliomas or secondary malignancies, heralds advanced disease and poor prognosis. Current treatments, including therapeutic thoracentesis and tube thoracostomy, are largely palliative. The immunosuppressive environment within the pleural cavity includes myeloid derived suppressor cells, T-regulatory cells, and dysfunctional T cells. The advent of effective immunotherapy with checkpoint inhibitors and adoptive cell therapies for lung cancer and other malignancies suggests a renewed examination of local and systemic therapies for this malady. Prior strategies reporting remarkable success, including instillation of the cytokine interleukin-2, perhaps coupled with checkpoint inhibitors, should be further evaluated in the modern era. [ABSTRACT FROM AUTHOR]

Abstract: Autophagy is an evolutionarily conserved pathway responsible for delivery of cytoplasmic material into the lysosomal degradation pathway to enable vesicular exocytosis. Interleukin (IL)-2 is produced by T-cells and its activity is important for immunoregulation. Fibroblasts are an immune competent cell type, playing a critical role in wound healing, chronic inflammation, and tumor development. Although autophagy plays an important role in each of these processes, whether it regulates IL-2 activity in fibroblasts is unknown. Here, we show that autophagy is required for IL-2-induced cell growth in fibroblasts. IL-2 significantly induced autophagy in mouse embryonic fibroblasts (MEFs) and primary lung fibroblasts. Autophagy inhibitors (e.g., 3-methylamphetamine and bafilomycin A1) or knockdown of ATG5 and beclin 1 blocked clinical grade IL-2-induced autophagy. Moreover, IL-2 induced HMGB1 cytoplasmic translocation in MEFs and promoted interaction between HMGB1 and beclin1, which is required for autophagy induction. Pharmacological and genetic inhibition of autophagy inhibited IL-2-induced cell proliferation and enhanced IL-2-induced apoptosis. These findings suggest that autophagy is an important pro-survival regulator for IL-2-induced cell growth in fibroblasts. [Copyright &y& Elsevier]

Administration of high-dose interleukin-2 (HDIL-2) has durable antitumor effects in 5% to 10% of patients with melanoma and renal cell carcinoma. However, treatment is often limited by side effects, including reversible, multiorgan dysfunction characterized by a cytokine-induced systemic autophagic syndrome. Here, we hypothesized that the autophagy inhibitor chloroquine would enhance IL-2 immunotherapeutic efficacy and limit toxicity. In an advanced murine metastatic liver tumor model, IL-2 inhibited tumor growth in a dose-dependent fashion. These antitumor effects were significantly enhanced upon addition of chloroquine. The combination of IL-2 with chloroquine increased long-term survival, decreased toxicity associated with vascular leakage, and enhanced immune cell proliferation and infiltration in the liver and spleen. HDIL-2 alone increased serum levels of HMGB1, IFN-g, IL-6, and IL-18 and also induced autophagy within the liver and translocation of HMGB1 from the nucleus to the cytosol in hepatocytes, effects that were inhibited by combined administration with chloroquine. In tumor cells, chloroquine increased autophagic vacuoles and LC3-II levels inhibited oxidative phosphorylation and ATP production and promoted apoptosis, which was associated with increased Annexin-V+/propidium iodide (PI)- cells, cleaved PARP, cleaved caspase-3, and cytochrome c release from mitochondria. Taken together, our findings provide a novel clinical strategy to enhance the efficacy of HDIL-2 immunotherapy for patients with cancer. [ABSTRACT FROM AUTHOR]

Abstract: A patient from the University of Pittsburgh is presented who developed autoimmunity during IL-2 based combination therapy. IL-2 was originally described as a “T cell growth factor” capable of expanding previously activated T cells, enhancing the cytotoxicity of antigen-specific cytotoxic T cells and NK cells. High dose Interleukin 2 (HDIL2) is now FDA-approved for therapy of patients with metastatic melanoma and renal cell carcinoma, based on its ability to induce durable responses in 5–10% of patients. The antitumor effect of HDIL2 is incompletely understood, but it appears that this regimen alters the balance of immigrant T effector cells in relation to T suppressor cells. It promotes a less immunosuppressive tumor microenvironment, inducing tumor regression in a subset of patients that is yet to be defined. The antitumor activity of IL-2, as for other agents that promote durable antitumor activity against melanoma such as interferon alpha and anti-CTLA4 antibody, is frequently associated with development of autoimmunity as observed in this patient. We present studies investigating the mechanisms for the therapeutic benefit of HDIL2 in melanoma. [Copyright &y& Elsevier]