Search

Lipid nanoparticles (LNPs) exhibit remarkable mRNA delivery efficiency, yet their majority accumulate in the liver or spleen after injection. Tissue‐specific mRNA delivery can be achieved through modulating LNP properties, such as tuning PEGylation or varying lipid components systematically. In this paper, a streamlined method is used for incorporating tumor‐targeting peptides into the LNPs; the programmed death ligand 1 (PD‐L1) binding peptides are conjugated to PEGylated lipids via a copper‐free click reaction, and directly incorporated into the LNP composition (Pep LNPs). Notably, Pep LNPs display robust interaction with PD‐L1 proteins, which leads to the uptake of LNPs into PD‐L1 overexpressing cancer cells both in vitro and in vivo. To evaluate anticancer immunotherapy mediated by restoring tumor suppressor, mRNA encoding phosphatase and tensin homolog (PTEN) is delivered via Pep LNPs to PTEN‐deficient triple‐negative breast cancers (TNBCs). Pep LNPs loaded with PTEN mRNA specifically promotes autophagy‐mediated immunogenic cell death in 4T1 tumors, resulting in effective anticancer immune responses. This study highlights the potential of tumor‐targeted LNPs for mRNA‐based cancer therapy. [ABSTRACT FROM AUTHOR]

Tumor immunotherapy, represented by immune checkpoint blocking and chimeric antigen receptor (CAR) T cell therapy, has achieved promising results in clinical applications. However, it faces challenges that hinder its further development, such as limited response rates and poor tumor permeability. The efficiency of tumor immunotherapy is also closely linked to the structure and function of the immune microenvironment where the tumor resides. Recently, nanoparticle‐based tumor immune microenvironment (TIME) modulation strategies have attracted a great deal of attention in cancer immunotherapy. This is primarily due to the distinctive physical characteristics of nanoparticles, which enable them to effectively infiltrate the TIME and selectively modulate its key constituents. This paper reviews recent advances in nanoparticle engineering to improve anti‐cancer immunotherapy. Emerging nanoparticle‐based approaches for modulating immune cells, tumor stroma, cytokines and immune checkpoints are discussed, aiming to overcome current challenges in the clinic. In addition, integrating immunotherapy with various treatment modalities such as chemotherapy and photodynamic therapy can be facilitated through the utilization of nanoparticles, thereby enhancing the efficacy of cancer treatment. The future challenges and opportunities of using nanomaterials to reeducate the suppressive immune microenvironment of tumors are also discussed, with the aim of anticipating further advancements in this growing field. [ABSTRACT FROM AUTHOR]

Highly accumulated hyaluronan (HA) not only provides a physiological barrier but also supports an immune-suppressive tumour microenvironment. High-molecular-weight (HMW)-HA inhibits the activation of immune cells and their access into tumour tissues, whereas, low-molecular-weight oligo-HA is known to potentially activate dendritic cells (DCs). In this paper, we investigated whether small extracellular vesicle (EVs)-PH20 hyaluronidase induces tumour HA degradation, which, in turn, activates DCs to promote anti-cancer immune responses. Informed by our previous work, we used a small EV carrying GPI-anchored PH20 hyaluronidase (Exo-PH20) that could deeply penetrate into tumour foci via HA degradation. We found that Exo-PH20-treatment successfully activates the maturation and migration of DCs in vivo, particularly CD103+ DCs leading to the activation of tumour-specific CD8+ T cells, which work together to inhibit tumour growth. Moreover, combination with anti-PD-L1 antibody provided potent tumour-specific CD8+ T cell immune responses as well as elicited prominent tumour growth inhibition both in syngenic and spontaneous breast cancer models, and this anti-tumour immunity was durable. Together, these results present new insights for HA degradation by Exo-PH20, providing a better understanding of oligo HA-triggered immune responses to cancer. [ABSTRACT FROM AUTHOR]

Many cancer patients do not benefit from PD-L1/PD-1 blockade immunotherapies. PD-1 and LAG-3 co-upregulation in T-cells is one of the major mechanisms of resistance by establishing a highly dysfunctional state in T-cells. To identify shared features associated to PD-1/LAG-3 dysfunctionality in human cancers and T-cells, multiomic expression profiles were obtained for all TCGA cancers immune infiltrates. A PD-1/LAG-3 dysfunctional signature was found which regulated immune, metabolic, genetic, and epigenetic pathways, but especially a reinforced negative regulation of the TCR signalosome. These results were validated in T-cell lines with constitutively active PD-1, LAG-3 pathways and their combination. A differential analysis of the proteome of PD-1/LAG-3 T-cells showed a specific enrichment in ubiquitin ligases participating in E3 ubiquitination pathways. PD-1/LAG-3 co-blockade inhibited CBL-B expression, while the use of a bispecific drug in clinical development also repressed C-CBL expression, which reverted T-cell dysfunctionality in lung cancer patients resistant to PD-L1/PD-1 blockade. The combination of CBL-B-specific small molecule inhibitors with anti-PD-1/anti-LAG-3 immunotherapies demonstrated notable therapeutic efficacy in models of lung cancer refractory to immunotherapies, overcoming PD-1/LAG-3 mediated resistance. Synopsis: PD-1/LAG-3 molecular mechanism of co-signaling was identified in T-cells, and combination of CBL-B inhibitors with anti-PD-1/anti-LAG-3 immunotherapies overcame PD-1/LAG-3-mediated resistance in models of lung cancer refractory to immunotherapies. PD-1/LAG-3 co-signaling regulates a highly dysfunctional signature in T-cells. CBL E3 ubiquitin ligases are key targets associated to the regulation of PD-1/LAG-3 mediated T-cell dysfunctional pathways in cell lines and primary cells from NSCLC patients. PD-1, LAG-3 and CBL-B triple blockade overcomes PD-1/LAG-3 mediated resistance and T-cell dysfunctionality in a lung cancer model refractory to immunotherapies. CD8 T cells are responsible for the PD-1, LAG-3 and CBL-B triple blockade therapeutic antitumor effect. Patients with dysfunctional T-cell immunity resistant to conventional antibody blockade immunotherapies could benefit from immunotherapy blockade combined with CBL-B inhibitors. PD-1/LAG-3 molecular mechanism of co-signaling was identified in T-cells, and combination of CBL-B inhibitors with anti-PD-1/anti-LAG-3 immunotherapies overcame PD-1/LAG-3-mediated resistance in models of lung cancer refractory to immunotherapies. [ABSTRACT FROM AUTHOR]

Despite years of intensive research, breast cancer remains the leading cause of death in women worldwide. New technologies including oncolytic virus therapies, virus, and phage display are among the most powerful and advanced methods that have emerged in recent years with potential applications in cancer prevention and treatment. Oncolytic virus therapy is an interesting strategy for cancer treatment. Presently, a number of viruses from different virus families are under laboratory and clinical investigation as oncolytic therapeutics. Oncolytic viruses (OVs) have been shown to be able to induce and initiate a systemic antitumor immune response. The possibility of application of a multimodal therapy using a combination of the OV therapy with immune checkpoint inhibitors and cancer antigen vaccination holds a great promise in the future of cancer immunotherapy. Display of immunologic peptides on bacterial viruses (bacteriophages) is also increasingly being considered as a new and strong cancer vaccine delivery strategy. In phage display immunotherapy, a peptide or protein antigen is presented by genetic fusions to the phage coat proteins, and the phage construct formulation acts as a protective or preventive vaccine against cancer. In our laboratory, we have recently tested a few peptides (E75, AE37, and GP2) derived from HER2/neu proto‐oncogene as vaccine delivery modalities for the treatment of TUBO breast cancer xenograft tumors of BALB/c mice. Here, in this paper, we discuss the latest advancements in the applications of OVs and bacterial viruses display systems as new and advanced modalities in cancer immune therapeutics. This manuscript discusses the latest findings regarding viral vectors designed for fighting breast cancer [ABSTRACT FROM AUTHOR]

In some clinical settings such as the cancer immunotherapy trials, a treatment time‐lag effect may be present and the lag duration possibly vary from subject to subject. An efficient study design and analysis procedure should not only take into account the time‐lag effect but also consider the individual heterogeneity in the lag duration. In this paper, we present a Generalized Piecewise Weighted Logrank (GPW‐Logrank) test, designed to account for the random time‐lag effect while maximizing the study power with respect to the weights. Based on the proposed test, both analytic and numeric approaches are developed for the sample size and power calculation. Asymptotic properties are derived and finite sample efficiency is evaluated in simulations. Compared with the standard practice ignoring the delayed effect, the proposed design and analysis procedures are substantially more efficient when a random lag is expected; further, compared with the existing methods by Xu et al considering the fixed time‐lag effect, the proposed approaches are significantly more robust when the lag model is misspecified. An R package (DelayedEffect.Design) is developed for implementation. [ABSTRACT FROM AUTHOR]

Abstract: Immune system can recognize self vs transformed self. That is why cancer immunotherapy achieves notable benefits in a wide variety of cancers. Recently, several papers reported that immune checkpoint blockade therapy led to upregulation of IFNγ and in turn clearance of tumor cells. In this review, we conducted an extensive literature search of recent 5‐year studies about the roles of IFNγ signaling in both tumor immune surveillance and immune evasion. In addition to well‐known functions, IFNγ signaling also induces tumor ischemia and homeostasis program, resulting in tumor clearance and tumor escape, respectively. The yin and the yang of IFNγ signaling are summarized. Thus, this review helps us to comprehensively understand the roles of IFNγ in tumor immunity, which contributes to better design and management of clinical immunotherapy approaches. [ABSTRACT FROM AUTHOR]

A cancer clinical trial with an immunotherapy often has 2 special features, which are patients being potentially cured from the cancer and the immunotherapy starting to take clinical effect after a certain delay time. Existing testing methods may be inadequate for immunotherapy clinical trials, because they do not appropriately take the 2 features into consideration at the same time, hence have low power to detect the true treatment effect. In this paper, we proposed a piece‐wise proportional hazards cure rate model with a random delay time to fit data, and a new weighted log‐rank test to detect the treatment effect of an immunotherapy over a chemotherapy control. We showed that the proposed weight was nearly optimal under mild conditions. Our simulation study showed a substantial gain of power in the proposed test over the existing tests and robustness of the test with misspecified weight. We also introduced a sample size calculation formula to design the immunotherapy clinical trials using the proposed weighted log‐rank test. [ABSTRACT FROM AUTHOR]

Immuno‐oncology has emerged as an exciting new approach to cancer treatment. Common immunotherapy approaches include cancer vaccine, effector cell therapy, and T‐cell–stimulating antibody. Checkpoint inhibitors such as cytotoxic T lymphocyte–associated antigen 4 and programmed death‐1/L1 antagonists have shown promising results in multiple indications in solid tumors and hematology. However, the mechanisms of action of these novel drugs pose unique statistical challenges in the accurate evaluation of clinical safety and efficacy, including late‐onset toxicity, dose optimization, evaluation of combination agents, pseudoprogression, and delayed and lasting clinical activity. Traditional statistical methods may not be the most accurate or efficient. It is highly desirable to develop the most suitable statistical methodologies and tools to efficiently investigate cancer immunotherapies. In this paper, we summarize these issues and discuss alternative methods to meet the challenges in the clinical development of these novel agents. For safety evaluation and dose‐finding trials, we recommend the use of a time‐to‐event model‐based design to handle late toxicities, a simple 3‐step procedure for dose optimization, and flexible rule‐based or model‐based designs for combination agents. For efficacy evaluation, we discuss alternative endpoints/designs/tests including the time‐specific probability endpoint, the restricted mean survival time, the generalized pairwise comparison method, the immune‐related response criteria, and the weighted log‐rank or weighted Kaplan‐Meier test. The benefits and limitations of these methods are discussed, and some recommendations are provided for applied researchers to implement these methods in clinical practice. [ABSTRACT FROM AUTHOR]

Cytokine-based therapeutics have been shown to mediate objective responses in certain tumor entities but suffer from insufficient selectivity, causing limiting toxicity which prevents dose escalation to therapeutically active regimens. The antibody-based delivery of cytokines significantly increases the therapeutic index of the corresponding payload but still suffers from side effects associated with peak concentrations of the product in blood upon intravenous administration. Here we devise a general strategy (named "Intra-Cork") to mask systemic cytokine activity without impacting anti-cancer efficacy. Our technology features the use of antibody-cytokine fusions, capable of selective localization at the neoplastic site, in combination with pathway-selective inhibitors of the cytokine signaling, which rapidly clear from the body. This strategy, exemplified with a tumor-targeted IL12 in combination with a JAK2 inhibitor, allowed to abrogate cytokine-driven toxicity without affecting therapeutic activity in a preclinical model of cancer. This approach is readily applicable in clinical practice. Synopsis: A novel strategy is presented to control adverse events related to tumor-targeted cytokine therapy. The approach features the use of antibody-cytokine fusions, localizing at the neoplastic site, in combination with selective inhibitors of the cytokine signaling, which rapidly clear from the body. This strategy, exemplified with a tumor-targeted IL12 in combination with a JAK2 inhibitor (Ruxolitinib), allowed to abrogate cytokine-driven toxicity without affecting therapeutic activity in a preclinical model of cancer. The transient inhibition of L19-mIL12 signaling helped to control systemic cytokine release, body weight loss, and hepatotoxicity. The use of suitably spaced administrations of Ruxolitinib represents a general avenue to maximize the clinical utility of antibody cytokine fusions with a long residence time at the neoplastic site. The approach devised in this work is readily applicable in clinical practice. A novel strategy is presented to control adverse events related to tumor-targeted cytokine therapy. The approach features the use of antibody-cytokine fusions, localizing at the neoplastic site, in combination with selective inhibitors of the cytokine signaling, which rapidly clear from the body. [ABSTRACT FROM AUTHOR]

Background: One‐carbon (1C) metabolism is a metabolic network that plays essential roles in biological reactions. In 1C metabolism, a series of nutrients are used to fuel metabolic pathways, including nucleotide metabolism, amino acid metabolism, cellular redox defence and epigenetic maintenance. At present, 1C metabolism is considered the hallmark of cancer. The 1C units obtained from the metabolic pathways increase the proliferation rate of cancer cells. In addition, anticancer drugs, such as methotrexate, which target 1C metabolism, have long been used in the clinic. In terms of immunotherapy, 1C metabolism has been used to explore biomarkers connected with immunotherapy response and immune‐related adverse events in patients. Methods: We collected numerous literatures to explain the roles of one‐carbon metabolism in cancer immunotherapy. Results: In this review, we focus on the important pathways in 1C metabolism and the function of 1C metabolism enzymes in cancer immunotherapy. Then, we summarise the inhibitors acting on 1C metabolism and their potential application on cancer immunotherapy. Finally, we provide a viewpoint and conclusion regarding the opportunities and challenges of targeting 1C metabolism for cancer immunotherapy in clinical practicability in the future. Conclusion: Targeting one‐carbon metabolism is useful for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Natural killer cell‐derived extracellular vesicles (NK‐EVs) have shown promising potential as biotherapeutics for cancer due to their unique attributes as cytotoxic nanovesicles against cancer cells and immune‐modulatory activity towards immune cells. However, a biomanufacturing workflow is needed to produce clinical‐grade NK‐EVs for pre‐clinical and clinical applications. This study established a novel biomanufacturing workflow using a closed‐loop hollow‐fibre bioreactor to continuously produce NK‐EVs from the clinically relevant NK92‐MI cell line under serum‐free, Xeno‐free and feeder‐free conditions following GMP‐compliant conditions. The NK92 cells grown in the bioreactor for three continuous production lots resulted in large quantities of both NK cell and NK‐EV biotherapeutics at the end of each production lot (over 109 viable cells and 1013 EVs), while retaining their cytotoxic payload (granzyme B and perforin), pro‐inflammatory cytokine (interferon‐gamma) content and cytotoxicity against the human leukemic cell line K562 with limited off‐target toxicity against healthy human fibroblast cells. This scalable biomanufacturing workflow has the potential to facilitate the clinical translation of adoptive NK cell‐based and NK‐EV‐based immunotherapies for cancer with GMP considerations. [ABSTRACT FROM AUTHOR]

Currently, checkpoint inhibitor‐based immunotherapy has emerged as prevailing treatment modality for diverse cancers. However, immunotherapy as a first‐line therapy has not consistently yielded durable responses. Moreover, the risk of immune‐related adverse events increases with combination regimens. Thus, the development of predictive biomarkers is needed to optimize individuals benefit, minimize risk of toxicities, and guide combination approaches. The greatest focus has been on tumor programmed cell death‐ligand 1 (PD‐L1), microsatellite instability (MSI), and tumor mutational burden (TMB). However, there remains a subject of debate due to thresholds variability and significant heterogeneity. Major unmet challenges in immunotherapy are the discovery and validation of predictive biomarkers. Here, we show the status of tumor PD‐L1, MSI, TMB, and emerging data on novel biomarker strategies with oncogenic signaling and epigenetic regulation. Considering the exploration of peripheral and intestinal immunity has served as noninvasive alternative in predicting immunotherapy, this review also summarizes current data in systemic immunity, encompassing solute PD‐L1 and TMB, circulating tumor DNA and infiltrating lymphocytes, routine emerging inflammatory markers and cytokines, as well as gut microbiota. This review provides up‐to‐date information on the evolving field of currently available biomarkers in predicting immunotherapy. Future exploration of novel biomarkers is warranted. [ABSTRACT FROM AUTHOR]

Since it was first identified, thymosin alpha 1 (Tα1) has been characterized to have pleiotropic effects on several pathological conditions, in particular as a modulator of immune response and inflammation. Several properties exerted by Tα1 may be attributable to a direct action on lymphoid cells. Tα1 has been shown to exert an immune modulatory activity on both T cell and natural killer cell maturation and to have an effect on functions of mature lymphocytes, including stimulating cytokine production and cytotoxic T lymphocyte-mediated cytotoxic responses. In previous studies we have shown that Tα1 increases the expression of major histocompatibility complex class I surface molecules in murine and human tumor cell lines and in primary cultures of human macrophages. In the present paper, we describe preliminary data indicating that Tα1 is also capable of increasing the expression of tumor antigens in both experimental and human tumor cell lines. This effect, which is exerted at the level of the target tumor cells, represents an additional factor increasing the antitumor activity of Tα1. [ABSTRACT FROM AUTHOR]

Abstract: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. Active immunotherapies and molecules targeting tyrosine kinase receptors both offer new avenues for the treatment of NSCLC. Furthermore, their combinations or their administration along with standard treatments enlarges the potential for clinical benefit. Moreover, the discovery of biomarkers predicting the response to these new therapies should allow a better selection of patients susceptible to optimally benefit from these treatments. In this paper, we review the most promising active immunotherapies, antibodies and small molecules in the context of NSCLC management, focusing on compounds in phase III clinical development. [Copyright &y& Elsevier]

Combinational immunotherapy of dendritic cell (DC) vaccines and anti‐programmed cell death protein 1 antibodies (aPD1) has been regarded as a promising strategy for cancer treatment because it not only induces tumor‐specific T cell immune responses, but also prevents failure of T cell functions by the immune suppressive milieu of tumors. Microneedles have emerged as an innovative platform for efficient transdermal immunotherapies. However, co‐delivery of DC vaccines and aPD1 via microneedles has not been studied since conventional microneedle platforms are unsuitable for fragile therapeutics like living cells and antibodies. This study employs our newly invented cryomicroneedles (cryoMNs) to co‐deliver DC vaccines and aPD1 for the combinational immunotherapy. CryoMNs are fabricated by stepwise cryogenic micromoulding of cryogenic medium with pre‐suspended DCs and aPD1, which are further integrated with a homemade handle for convenient application. The viability of DCs in cryoMNs remains above 85%. CryoMNs are mechanically strong enough to insert into porcine and mouse skin, successfully releasing DCs and aPD1 inside skin tissue after melting. Co‐delivery of ovalbumin (OVA)‐pulsed DCs (OVA‐DCs) and aPD1 via cryoMNs induced higher antigen‐specific cellular immune responses compared with the mono‐delivery of OVA‐DCs or aPD1. Finally, administration with cryoMNs co‐encapsulated with OVA‐DCs and aPD1 increases the infiltration of effector T cells in the tumor, resulting in stronger anti‐tumor therapeutic efficacy in both prophylactic and therapeutic melanoma models compared with administration with cryoMNs loaded with OVA‐DCs or aPD1. This study demonstrates the great potential of cryoMNs as a co‐delivery system of therapeutic cells and biomacromolecules for combinational therapies. [ABSTRACT FROM AUTHOR]

Induction of potent immune responses toward tumors remains challenging in cancer immunotherapy, in which it only showed benefits in a minority of patients with "hot" tumors, which possess pre‐existing effector immune cells within the tumor. In this study, we proposed a nanoparticle‐based strategy to fire up the "cold" tumor by upregulating the components associated with T and NK cell recruitment and activation and suppressing TGF‐β1 secretion by tumor cells. Specifically, LTX‐315, a first‐in‐class oncolytic cationic peptide, and TGF‐β1 siRNA were co‐entrapped in a polymer‐lipid hybrid nanoparticle comprising PLGA, DSPE‐mPEG, and DSPE‐PEG‐conjugated with cRGD peptide (LTX/siR‐NPs). The LTX/siR‐NPs showed significant inhibition of TGF‐β1 expression, induction of type I interferon release, and triggering immunogenic cell death (ICD) in treated tumor cells, indicated via the increased levels of danger molecules, an in vitro setting. The in vivo data showed that the LTX/siR‐NPs could effectively protect the LTX‐315 peptide from degradation in serum, which highly accumulated in tumor tissue. Consequently, the LTX/siR‐NPs robustly suppressed TGF‐β1 production by tumor cells and created an immunologically active tumor with high infiltration of antitumor effector immune cells. As a result, the combination of LTX/siR‐NP treatment with NKG2A checkpoint inhibitor therapy remarkably increased numbers of CD8+NKG2D+ and NK1.1+NKG2D+ within tumor masses, and importantly, inhibited the tumor growth and prolonged survival rate of treated mice. Taken together, this study suggests the potential of the LTX/siR‐NPs for inflaming the "cold" tumor for potentiating the efficacy of cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Immunotherapy holds great promise for the treatment of malignant cancer. However, the lack of sufficient tumor neoantigens and incomplete dendritic cell (DC) maturation compromise the efficacy of immunotherapy. Here, a modular hydrogel‐based vaccine capable of eliciting a powerful and sustained immune response is developed. Briefly, CCL21a and ExoGM‐CSF+Ce6 (tumor cell‐derived exosomes with granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) mRNA encapsulated inside and sonosensitizer chlorin e6 (Ce6) incorporated in the surface) are mixed with nanoclay and gelatin methacryloyl, forming the hydrogel designated as CCL21a/ExoGM‐CSF+Ce6@nanoGel. The engineered hydrogel releases CCL21a and GM‐CSF with a time gap. The earlier released CCL21a diverts the tumor‐draining lymph node (TdLN) metastatic tumor cells to the hydrogel. Consequently, the trapped tumor cells in the hydrogel, in turn, engulf the Ce6‐containing exosomes and thus are eradicated by sonodynamic therapy (SDT), serving as the antigen source. Later, together with the remnant CCL21a, GM‐CSF produced by cells engulfing ExoGM‐CSF+Ce6 continuously recruits and provokes DCs. With the two programmed modules, the engineered modular hydrogel vaccine efficiently inhibits tumor growth and metastasis via diverting TdLN metastatic cancer to hydrogel, killing the trapped tumor cells, and eliciting prolonged and powerful immunotherapy in an orchestrated manner. The strategy would open an avenue for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Adoptive cell therapy (ACT) is a rapidly growing anti-cancer strategy that has shown promise in treating various cancer types. The concept of ACT involves activating patients' own immune cells ex vivo and then transferring them back to the patients to recognize and eliminate cancer cells. Currently, the commonly used ACT includes tumor-infiltrating lymphocytes (TILs), genetically engineered immune cells, and dendritic cells (DCs) vaccines.With the advancement of cell culture and genetic engineering techniques, ACT has been used in clinics to treat malignant hematological diseases and many new ACT-based regimens are in different stages of clinical trials. Here, representative ACT approaches are introduced and the opportunities and challenges for clinical translation of ACT are discussed. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) are currently one of the most popular treatment methods for cancers. Several ICIs have been approved in China and the United States. We created a database of approved ICIs by extracting the information of interest from the drug labels and reviewing documents disclosed on the official websites of the US Food and Drug Administration (FDA) and the Center for Drug Evaluation (CDE) of the China National Medical Products Administration (NMPA) and compared the difference between the marketed ICIs in China and the United States regarding the number of indications, tumor types, review time, treatment setting, and so forth. Until June 30, 2022, 9 and 15 ICIs had been approved for 86 and 58 indications in the United States and China, involving 20 and 14 types of tumors, respectively. The correlation between indications and disease incidence was higher in China (r = 0.64) than in the United States (r = 0.45). About half of the indications were approved as first‐line therapies in combination with chemotherapy, target therapy, or immunotherapy. Over 30% of indications were approved under accelerated or conditional approval in the two countries. A shorter regulatory review time was required by the FDA (median:181 days) compared to the NMPA (median: 279 days) for the new indication approval. Five ICIs marketed in China were approved by the FDA before the NMPA, with the median launch delay for the same indication of 344 days in China. A differentiated clinical development program that focuses on meeting unmet needs may bring new success for subsequent ICI products. [ABSTRACT FROM AUTHOR]

Recent studies have shown that activation of the cGAS‐STING pathway is a key process in antitumor immune responses and various kinds of STING agonists have been developed for cancer immunotherapy. Despite promising preclinical studies, preliminary clinical results have shown only a modest effect of STING agonists. There is therefore a need to develop more effective treatment strategies. Based on previous observations that COX‐2 is frequently overexpressed not only in a variety of cancers but also in tumor myeloid cells and that it suppresses antitumor immunity and promotes tumor survival by producing PGE2, we investigated the antitumor effects of combination therapy with a STING agonist cGAMP and the selective COX‐2 inhibitor celecoxib in mouse models. Combination treatment with cGAMP and celecoxib inhibited tumor growth compared with either monotherapy, and the combination therapy induced both local and systemic antitumor immunity. cGAMP treatment decreased PD‐1 expression on tumor‐infiltrating T‐cells and enhanced T‐cell activation in tumor‐draining lymph nodes regardless of the presence of celecoxib. Meanwhile, although celecoxib treatment did not alter the frequency of CD4+CD25+Foxp3+ regulatory T‐cells, it enhanced the expression of costimulatory molecules and glycolysis‐associated genes in tumor‐infiltrating CD11b+Ly6G+ cells. Moreover, we also found that celecoxib decreased lactate efflux and increased the frequency of IFN‐γ‐ and TNF‐α‐producing CD8+ T‐cells in the tumor microenvironment. Taken together, our findings suggest that combined treatment with celecoxib may be an effective strategy to improve the antitumor efficacy of STING agonists. [ABSTRACT FROM AUTHOR]

Arming the immune system against cancer has emerged as a powerful tool in oncology during recent years. Instead of poisoning a tumor or destroying it with radiation, therapeutic cancer vaccine, a type of cancer immunotherapy, unleashes the immune system to combat cancer. This indirect mechanism-of-action of vaccines poses the possibility of a delayed onset of clinical effect, which results in a delayed separation of survival curves between the experimental and control groups in therapeutic cancer vaccine trials with time-to-event endpoints. This violates the proportional hazard assumption. As a result, the conventional study design based on the regular log-rank test ignoring the delayed effect would lead to a loss of power. In this paper, we propose two innovative approaches for sample size and power calculation using the piecewise weighted log-rank test to properly and efficiently incorporate the delayed effect into the study design. Both theoretical derivations and empirical studies demonstrate that the proposed methods, accounting for the delayed effect, can reduce sample size dramatically while achieving the target power relative to a standard practice. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background and Purpose: Immune checkpoint inhibitors (ICI), such as anti‐PD‐1 monoclonal antibodies, have revolutionized cancer therapy by enhancing the cytotoxic effects of T‐cells against tumours. However, enhanced T‐cell activity also may cause myocarditis and cardiotoxicity. Our understanding of the mechanisms of ICI‐induced cardiotoxicity is limited. Here, we aimed to investigate the effect of PD‐1 inhibition on cardiac function and explore the molecular mechanisms of ICI‐induced cardiotoxicity. Experimental Approach: C57BL6/J and BALB/c mice were treated with isotype control or anti‐PD‐1 antibody. Echocardiography was used to assess cardiac function. Cardiac transcriptomic changes were investigated by bulk RNA sequencing. Inflammatory changes were assessed by qRT‐PCR and immunohistochemistry in heart, thymus, and spleen of the animals. In follow‐up experiments, anti‐CD4 and anti‐IL‐17A antibodies were used along with PD‐1 blockade in C57BL/6J mice. Key Results: Anti‐PD‐1 treatment led to cardiac dysfunction and left ventricular dilation in C57BL/6J mice, with increased nitrosative stress. Only mild inflammation was observed in the heart. However, PD‐1 inhibition resulted in enhanced thymic inflammatory signalling, where Il17a increased most prominently. In BALB/c mice, cardiac dysfunction was not evident, and thymic inflammatory activation was more balanced. Inhibition of IL‐17A prevented anti‐PD‐1‐induced cardiac dysfunction in C57BL6/J mice. Comparing myocardial transcriptomic changes in C57BL/6J and BALB/c mice, differentially regulated genes (Dmd, Ass1, Chrm2, Nfkbia, Stat3, Gsk3b, Cxcl9, Fxyd2, and Ldb3) were revealed, related to cardiac structure, signalling, and inflammation. Conclusions: PD‐1 blockade induces cardiac dysfunction in mice with increased IL‐17 signalling in the thymus. Pharmacological inhibition of IL‐17A treatment prevents ICI‐induced cardiac dysfunction. [ABSTRACT FROM AUTHOR]

Preclinical and clinical studies demonstrate that T cell‐dependent bispecific antibodies (TDBs) induce systemic changes in addition to tumor killing, leading to adverse events. Here, we report an in‐depth characterization of acute responses to TDBs in tumor‐bearing mice. Contrary to modest changes in tumors, rapid and substantial lymphocyte accumulation and endothelial cell (EC) activation occur around large blood vessels in normal organs including the liver. We hypothesize that organ‐specific ECs may account for the differential responses in normal tissues and tumors, and we identify a list of genes selectively upregulated by TDB in large liver vessels. Using one of the genes as an example, we demonstrate that CD9 facilitates ICAM‐1 to support T cell–EC interaction in response to soluble factors released from a TDB‐mediated cytotoxic reaction. Our results suggest that multiple factors may cooperatively promote T cell infiltration into normal organs as a secondary response to TDB‐mediated tumor killing. These data shed light on how different vascular beds respond to cancer immunotherapy and may help improve their safety and efficacy. Synopsis: T cell‐dependent bispecific antibodies induce adverse systemic changes in addition to tumor killing. This study shows how different vascular beds respond to cancer immunotherapy, suggesting that reducing leukocyte‐endothelial interactions may limit the accumulation of T cells, thereby alleviating off‐tumor adverse responses. An in‐depth characterization of acute systemic responses to T cell‐dependent bispecific antibodies is presented.Immunological and vascular responses in the liver are observed that are more striking than the tumor responses.Liver response shows a vascular‐subtype‐dependent pattern.Transcriptional programs and candidate factors are uncovered that could account for the undesirable response. [ABSTRACT FROM AUTHOR]

Hypoxia is a persistent physiological feature of many different solid tumors and a key driver of malignancy, and in recent years, it has been recognized as an important target for cancer therapy. Hypoxia occurs in the majority of solid tumors due to a poor vascular oxygen supply that is not sufficient to meet the needs of rapidly proliferating cancer cells. A hypoxic tumor microenvironment (TME) can reduce the effectiveness of other tumor therapies, such as radiotherapy, chemotherapy, and immunotherapy. In this review, we discuss the critical role of hypoxia in tumor development, including tumor metabolism, tumor immunity, and tumor angiogenesis. The treatment methods for hypoxic TME are summarized, including hypoxia‐targeted therapy and improving oxygenation by alleviating tumor hypoxia itself. Hyperoxia therapy can be used to improve tissue oxygen partial pressure and relieve tumor hypoxia. We focus on the underlying mechanisms of hyperoxia and their impact on current cancer therapies and discuss the prospects of hyperoxia therapy in cancer treatment. [ABSTRACT FROM AUTHOR]

Homeobox B7 (HOXB7) is a master regulatory gene that regulates cell proliferation and activates oncogenic pathways. Overexpression of HOXB7 correlates with aggressive behavior and poor prognosis in patients with cancer. However, the expression and role of HOXB7 in head and neck squamous cell carcinoma (HNSCC) remain unclear. In this study, we observed that most samples from patients with oropharyngeal cancer and HNSCC expressed HOXB7. As no direct inhibitor has been reported, we identified a potent peptide epitope to target HOXB7‐expressing tumors through immune cells. A novel HOXB7‐derived peptide epitope (HOXB78–25) elicited antigen‐specific and tumor‐reactive promiscuous CD4+ T cell responses. These CD4+ T cells produced γ‐interferon (IFN‐γ) and had the direct ability to kill tumors through granzyme B. Notably, downregulation of HOXB7 using siRNA enhanced human leukocyte antigen class II expression on tumor cells by decreasing the phosphorylation of MAPK. Mitogen‐activated protein kinase inhibition augmented IFN‐γ production by HOXB7‐reactive CD4+ T cell responses without decreasing the expression of HOXB7. These results suggest that combining HOXB7 peptide‐based vaccine with MAPK inhibitors could be an effective immunological strategy for cancer treatment. [ABSTRACT FROM AUTHOR]

Immunotherapy is a powerful tool for cancer treatment, but the pleiotropic nature of cytokines and immunological agents strongly limits clinical translation and safety. To address this unmet need, we designed and characterised a systemically targeted cytokine gene delivery system through transmorphic encapsidation of human recombinant adeno‐associated virus DNA using coat proteins from a tumour‐targeted bacteriophage (phage). We show that Transmorphic Phage/AAV (TPA) particles provide superior delivery of transgenes over current phage‐derived vectors through greater diffusion across the extracellular space and improved intracellular trafficking. We used TPA to target the delivery of cytokine‐encoding transgenes for interleukin‐12 (IL12), and novel isoforms of IL15 and tumour necrosis factor alpha (TNFα) for tumour immunotherapy. Our results demonstrate selective and efficient gene delivery and immunotherapy against solid tumours in vivo, without harming healthy organs. Our transmorphic particle system provides a promising modality for safe and effective gene delivery, and cancer immunotherapies through cross‐species complementation of two commonly used viruses. Synopsis: This study describes the characterization of a new phage‐derived gene delivery particle capable of systemic targeting (TPA), demonstrating its superiority over existing phage systemic viral vectors (AAVP), and its application in targeted cytokine gene therapy of cancer. TPA particles are targeted bacteriophage capsids that carry only an expression cassette flanked by AAV‐2 inverted terminal repeat sequences (ITRs), and a phage origin of replication.Following systemic administration in tumor‐bearing mice, the tumor‐targeted RGD4C.TPA binds to αvβ3 integrin receptor in tumors, resulting in selective expression of IL15, IL12, or TNFα cytokines in the tumor microenvironment.TPA‐guided cytokine delivery results in complete tumor eradication in 50% of the treated animals.Targeted expression of IL15 results in proliferation of the immune CD8+ T, natural killer (NK), and T helper 1 (Th1) cells in tumors. [ABSTRACT FROM AUTHOR]

Inhibition of programmed cell death receptor‐1 (PD‐1) and its counterpart ligands PD‐L1 and PD‐L2 pathways by the US‐FDA's approved monoclonal antibodies pembrolizumab and nivolumab has delivered breakthrough therapies against a wide range of cancers, being an important issue for clinical research. Although many structural properties of these drugs have been unveiled, only few studies were focused on their vibrational features. To fill this gap, quantum chemistry calculations are employed to depict the binding energetic modes of these antibody drugs in order to obtain their vibrational properties through a Raman scattering spectroscopy. Detailed interpretation of their harmonic vibrational wavenumbers is also presented, mainly those in the range 2,750 to 3,750 (1,200 to 1,750) cm−1 for the oncological drug pembrolizumab (nivolumab). We believe that our theoretical/computational results may be a new viable technique for improving the cancer disease therapies. [ABSTRACT FROM AUTHOR]

Immune checkpoint blockade therapy (ICBT) has become a successful cancer treatment approach in the field of cancer immunotherapy. Blockade of programmed death 1 (PD‐1) and programmed death‐ligand 1 (PD‐L1) with monoclonal antibodies have been known as successful examples of cancer immunotherapy in recent years. Although ICBT has been shown to be beneficial in cancers, such benefits have only been seen in a portion of cancer patients. In this regard, enhancing the therapeutic effects of inhibiting PD‐1 and PD‐L1 and reducing the side effects of this approach can be considered as a potential approach in a successful ICBT. In this review, we have highlighted new viewpoints regarding improving the therapeutic effect of PD‐1 and PD‐L1 blockades in cancer therapy. Besides, their expression levels as a biomarker with prognostic value, their role in intestinal microbiota modulation, combination therapy, and immune‐related side effects (irAEs) have been discussed. [ABSTRACT FROM AUTHOR]

IL-2 is a pleiotropic cytokine that regulates immune cell homeostasis. Its immunomodulatory function has been used clinically as an active immunotherapy agent for metastatic cancers. However, severe adverse effects, including the vascular leak syndrome and the preferential stimulation of anti-immunogenic Treg rather than effector T cells, have been obstacles. We newly designed a mutein IL-2, Mutakine-6 (MK-6), with reduced IL-2Rα-binding capability. MK-6 induced comparable cell growth potential toward IL-2Rβγ-positive T cells but was far less efficient in in vitro Treg proliferation and STAT5 activation. Unlike IL-2, in vivo administration of MK-6 produced minimal adverse effects. Using CT26 and B16F10-syngeneic tumor models, we found MK-6 was highly efficacious on tumor regression. Serum albumin conjugation to MK-6 prolonged in vivo half-life and accumulated in CT26 tumors, showing enhanced antitumor effect. Tumor-infiltrating leukocytes analysis revealed that albumin-fused MK-6 increased the ratio of effector CD8+ T cells to CD4+ Treg cells. These results demonstrated that MK-6 is an efficient immunomodulator potentially used for improved immunotherapy with decreased adverse effects and attenuated Treg stimulation. [ABSTRACT FROM AUTHOR]

Research efforts towards cancer therapeutics have resulted in the development of a variety of pharmacological molecules, including small synthetic molecules and biological drugs (RNA‐based therapies and monoclonal antibodies—mAbs), intended to target tumor or immune‐related cells, or their signaling mediators. The majority of them present important biopharmaceutical problems related to their difficulties for overcoming biological barriers and reach their targets. Nanotechnology has been, for more than 60 years, trying to solve these problems. As knowledge in drug discovery, molecular biology, and biomaterials advances, there has been significant progress in the adequate design of nanodelivery strategies that may significantly contribute to the exploitation of the new therapies. This review provides a critical overview of the current potential of nanotechnology to solve problems associated with the different categories of drugs. Starting with the general concept of passive and active targeting, it presents the distinct advantages that delivery technologies have shown to date for improving the therapeutic outcome of small drugs with cytotoxic activity, RNA‐ and mAb‐based therapies. Moreover, it precisely describes the benefits of combining immunotherapies and nanotechnology. The most advanced technologies are put into perspective in relation to their translational pathway and the future avenues for nano‐oncologicals. [ABSTRACT FROM AUTHOR]

Oncolytic virotherapies are perceived as remarkable immunotherapies coming into view and represent highly promising cancer treatments, yet to figure out its specific immune responses and underlying barriers remains critical. Albeit recent studies have demonstrated that oncolytic viruses (OVs) could fine tune tumor microenvironment (TME) to elicit tumor suppression mainly due to effective T‐cell responses, the interaction between suppressive T cells and OVs is barely undetermined. Herein, we found that regulatory T cells (Treg cells) were increased in the TME following systemic administration of oncolytic virus M1 along with the higher expression of relative cytokines and chemokines in both mouse RM‐1 prostatic carcinoma model and mouse B16F10 melanoma model. Besides, Treg cells expressed high levels of CD25 post‐M1 treatment, and its suppressive effect on CD8+ T cells was also elevated. Depletion of Treg cells in M1‐treated groups significantly reinforced antitumor effect of M1. Specific targeting of Treg cells using cytotoxic T lymphocyte‐associated protein 4 (CTLA‐4) antibody (Ab) in combination with M1 treatment elicited a more profound tumor suppression and longer overall survival time than M1 alone in both tumor models. Moreover, CTLA‐4 Ab further aggrandized antitumor immune response elicited by M1, including increased infiltration of CD45+ immune cells and CD8+ or CD4+ T lymphocytes, decreased ratio of Treg cells to CD4+ T lymphocytes, the intensified lymphocytotoxicity and elevated secretion of cytotoxic cytokines like interferon‐γ, granzyme B and perforin. Therefore, our findings constituted a suggestive evidence that targeting Treg cells in M1‐based oncolytic virotherapy may achieve a highly response in clinical cancer research. [ABSTRACT FROM AUTHOR]

Macrophages are abundant immune cells, which serve as a primary cell population capable of interacting with foreign substances, including engineered nanomaterials (NMs). In addition to the phagocytic activity, macrophages also play a central role in innate immunity and contribute to the initiation of adaptive immunity. Since macrophages are a natural reservoir for NMs, nanoparticles (or nano‐enabled strategies) are commonly utilized to target this cell type and fine tune its polarization status in different disease scenarios. In this review, a high‐level description of macrophage biology is first introduced. It is followed by the discussion on the impact of therapeutic NMs on macrophages in solid tumors and how macrophages, in turn, impact the immune system and heterogeneity in the tumor microenvironment. Another major thrust is to discuss the applications of NMs in noncancer diseases with a focus on how NMs can be used to influence macrophages in the process of tissue repair, wound healing, myocardial infarction, and certain autoimmune diseases. In addition to the design of nanocarriers to impact macrophage function, whether the same response outcome can be achieved by intrinsic NM's physicochemical properties, allowing the potential usage of the active pharmaceutical ingredient‐free nanomaterials for therapeutic purposes, is also discussed. [ABSTRACT FROM AUTHOR]

Highlights the International Symposium on New Trends in Human Immunology and Cancer Immunotherapy held on January 17-19, 1980 in Montpellier, France. Topics and issues discussed; Maximum number of applicants accepted for the event; Terms of accepting the papers presented in the discussion.

Immunotherapy has shown great promise for the treatment of cancer. However, the limited efficacy of single‐agent immunotherapy hinders its widespread application, which stimulated the investigation of combination therapy with improved efficacy. Herein, a tri‐functional immunostimulatory supramolecular nanomedicine consisting of indoximod (IND, an indoleamine 2,3‐dioxygenase (IDO) inhibitor), DPPA‐1 (a D‐peptide antagonist against programmed cell death ligand‐1 (PD‐L1)), and a self‐assembling D‐tetrapeptide of GDFDFDY (a powerful adjuvant with immunostimulatory properties) is reported. The resulting IND‐GDFDFDY‐DPPA‐1 behaves as a supramolecular "trident," and its three functional parts play parallel roles to boost the effective immune responses. It is shown that the supramolecular "trident" exhibits a stronger binding ability to PD‐L1 than the DPPA‐1 peptide (>fourfold) and is able to inhibit the IDO‐1 pathway more efficiently than IND itself. The supramolecular "trident" activates and recruits the cytotoxic CD8+ T lymphocytes along with other immune effector cells in tumors, concomitant with downregulation of Foxp3+ T cells and upregulation of tumor immune‐related cytokines, thus showing a strong ability to improve the tumor microenvironment and enhance immunotherapeutic effects to prevent tumor growth and metastasis in the breast tumor model. The findings may stimulate the development of self‐assembling peptide‐based multifunctional nanomedicines for cancer therapy. [ABSTRACT FROM AUTHOR]

Cancer immunotherapy has greatly advanced in recent years, with chimeric antigen receptor (CAR) T cells emerging as an innovative technology that harnesses the immune system to fight malignant diseases. These genetically engineered T‐cells have shown encouraging results for B‐cell lymphoid malignancies and are now being explored for other cancer types. However, this novel adoptive cell therapy is associated with a new spectrum of immune‐mediated adverse events and toxicities. As CAR T cells recognize and engage tumour cells, cytokines are secreted and activate other immune cells, frequently leading to rapid development of cytokine release syndrome, which can result in acute deterioration of the patient's clinical condition. In many patients, cytokine release syndrome is mild and easy to manage, but others experience persistent fevers accompanied by hypotension and hypoxia, which require management with immune‐modulatory agents. Another deleterious effect of cytokines released by effector cells is immune effector cell–associated neurotoxicity syndrome. This syndrome, caused by a disruption of the blood–brain barrier as a consequence of the immune process, can result in rapid deterioration in cognitive function. This is often associated with subtle changes in handwriting, often progressing to loss of memory and concentration and reduced ability to name objects or follow commands. In some cases, the neurological state is further compromised by seizures and in rare instances with fulminant life‐threatening cerebral oedema. In this review, we discuss these toxicities, as well as other CAR T‐cell–related immune phenomenon, and address their clinical manifestations, grading, and management options. [ABSTRACT FROM AUTHOR]

Immunotherapy has revolutionized the treatment of cancer in recent years and achieved overall success and long‐term clinical benefit in patients with a wide variety of cancer types. However, there is still a large proportion of patients exhibiting limited or no responses to immunotherapeutic strategy, some of which were even observed with hyperprogressive disease. One major obstacle restricting the efficacy is that tumor‐reactive CD8+ T cells, which are central for tumor control, undergo exhaustion, and lose their ability to eliminate cancer cells after infiltrating into the strongly immunosuppressive tumor microenvironment. Thus, as a potential therapeutic rationale in the development of cancer immunotherapy, targeting or reinvigorating exhausted CD8+ T cells has been attracting much interest. Hitherto, both intrinsic and extrinsic mechanisms that govern CD8+ T‐cell exhaustion have been explored. Specifically, the transcriptional and epigenetic landscapes have been depicted utilizing single‐cell RNA sequencing or mass cytometry (CyTOF). In addition, cellular metabolism dictating the tumor‐infiltrating CD8+ T‐cell fate is currently under investigation. A series of clinical trials are being carried out to further establish the current strategies targeting CD8+ T‐cell exhaustion. Taken together, despite the proven benefit of immunotherapy in cancer patients, additional efforts are still needed to fully circumvent limitations of exhausted T cells in the treatment. In this review, we will focus on the current cellular and molecular understanding of metabolic changes, epigenetic remodeling, and transcriptional regulation in CD8+ T‐cell exhaustion and describe hypothetical treatment approaches based on immunotherapy aiming at reinvigorating exhausted CD8+ T cells. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) have shown great potential in drug delivery, disease diagnosis, and treatment owing to their versatile native features and functions. RNA interference (RNAi) therapeutics that block the programmed death‐1 (PD‐1) and programmed death‐ligand 1 (PD‐L1) pathway have attracted increasing interest for the treatment of various cancers. Here, immunoregulatory EVs are developed by decorating M1‐macrophage‐derived EVs (M1 EV) with vesicular stomatitis virus glycoprotein (VSV‐G), a pH‐responsive viral fusion protein, and electroporating anti‐PD‐L1 siRNA (siPD‐L1) into the EVs. After administration to CT26 tumor‐bearing mice, this virus‐mimic nucleic acid engineered EVs (siRNA@V‐M1 EV) can target tumor tissues, which is attributed to the natural tumor‐homing property of M1 EV. Then, the fusion of VSV‐G with cells facilitates the direct release of siPD‐L1 into the cytoplasm and triggers robust gene silencing, leading to the efficient block of PD‐L1/PD‐1 interaction and then the elevation of CD8+ T cell population. Meanwhile, the M1 EVs and IFN‐γ secreted by the CD8+ T cells promote the repolarization of M2 tumor‐associated macrophages to M1 macrophages. The combination of PD‐L1/PD‐1 pathway blocking, T cell recognition reconstructing, and M1 macrophage repolarization via multifunctional EVs can achieve satisfactory antitumor efficacy in this tumor model, showing potential as a new modality to fight cancers. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) induce a durable response in a wide range of tumor types, but only a minority of patients outside these 'responsive' tumor types respond, with some totally resistant. The primary predictor of intrinsic immune resistance to ICIs is the complete or near‐complete absence of lymphocytes from the tumor, so‐called immunologically cold tumors. Here, we propose two broad approaches to convert 'cold' tumors into 'hot' tumors. The first is to induce immunogenic tumor cell death, through the use of oncolytic viruses or bacteria, conventional cancer therapies (e.g. chemotherapy or radiation therapy) or small molecule drugs. The second approach is to target the tumor microenvironment, and covers diverse options such as depleting immune suppressive cells; inhibiting transforming growth factor‐beta; remodelling the tumor vasculature or hypoxic environment; strengthening the infiltration and activation of antigen‐presenting cells and/or effector T cells in the tumor microenvironment with immune modulators; and enhancing immunogenicity through personalised cancer vaccines. Strategies that successfully modify cold tumors to overcome their resistance to ICIs represent mechanistically driven approaches that will ultimately result in rational combination therapies to extend the clinical benefits of immunotherapy to a broader cancer cohort. [ABSTRACT FROM AUTHOR]

A typical challenge facing the design and analysis of immuno‐oncology (IO) trials is the prevalence of nonproportional hazards (NPH) patterns manifested in Kaplan‐Meier curves under time‐to‐event endpoints. The NPH patterns would violate the proportional hazards assumption, and yet conventional design and analysis strategies often ignore such a violation, resulting in underpowered or even falsely negative IO studies. In this article, we show, both empirically and analytically, that treating nonresponders in IO studies of inadequate size would give rise to a variety of NPH patterns; we then present a novel design and analysis strategy, P%‐responder information embedded (PRIME), to properly incorporate the dichotomized response incurred from treating nonresponders. Empirical studies demonstrate that the proposed strategy can achieve desirable power, whereas the conventional alternative leads to a severe power loss. The PRIME strategy allows us to quantify the impact of treating nonresponders on study efficiency, thereby enabling a proper design of IO trials with an adequate power. More importantly, it pinpoints a solution to enhance the study efficiency and alleviates the NPH patterns by enrolling more prospective responders. An R package (Immunotherapy.Design) is developed for implementation. [ABSTRACT FROM AUTHOR]

Immunotherapy is a class of promising anticancer treatments that has recently gained attention due to surging numbers of FDA approvals and extensive preclinical studies demonstrating efficacy. Nevertheless, further clinical implementation has been limited by high variability in patient response to different immunotherapeutic agents. These treatments currently do not have reliable predictors of efficacy and may lead to side effects. The future development of additional immunotherapy options and the prediction of patient‐specific response to treatment require advanced screening platforms associated with accurate and rapid data interpretation. Advanced engineering approaches ranging from sequencing and gene editing, to tumor organoids engineering, bioprinted tissues, and organs‐on‐a‐chip systems facilitate the screening of cancer immunotherapies by recreating the intrinsic and extrinsic features of a tumor and its microenvironment. High‐throughput platform development and progress in artificial intelligence can also improve the efficiency and accuracy of screening methods. Here, these engineering approaches in screening cancer immunotherapies are highlighted, and a discussion of the future perspectives and challenges associated with these emerging fields to further advance the clinical use of state‐of‐the‐art cancer immunotherapies are provided. [ABSTRACT FROM AUTHOR]

Personalized drug therapy aims to provide tailored treatment for individual patient. Mass spectrometry (MS) is revolutionarily involved in this area because MS is a rapid, customizable, cost‐effective, and easy to be used high‐throughput method with high sensitivity, specificity, and accuracy. It is driving the formation of a new field, MS‐based personalized drug therapy, which currently mainly includes five subfields: therapeutic drug monitoring (TDM), pharmacogenomics (PGx), pharmacomicrobiomics, pharmacoepigenomics, and immunopeptidomics. Gas chromatography‐MS (GC‐MS) and liquid chromatography‐MS (LC‐MS) are considered as the gold standard for TDM, which can be used to optimize drug dosage. Matrix‐assisted laser desorption ionization‐time of flight‐MS (MALDI‐TOF‐MS) significantly improves the capability of detecting biomacromolecule, and largely promotes the application of MS in PGx. It is becoming an indispensable tool for genotyping, which is used to discover and validate genetic biomarkers. In addition, MALDI‐TOF‐MS also plays important roles in identity of human microbiome whose diversity can explain interindividual differences of drug response. Pharmacoepigenetics is to study the role of epigenetic factors in individualized drug treatment. MS can be used to discover and validate pharmacoepigenetic markers (DNA methylation, histone modification, and noncoding RNA). For the emerging cancer immunotherapy, personalized cancer vaccine has effective immunotherapeutic activity in the clinic. MS‐based immunopeptidomics can effectively discover and screen neoantigens. This article systematically reviewed MS‐based personalized drug therapy in the above mentioned five subfields. © 2020 John Wiley & Sons Ltd. Mass Spec Rev [ABSTRACT FROM AUTHOR]

Summary: The indirect mechanism of action of immunotherapy causes a delayed treatment effect, producing delayed separation of survival curves between the treatment groups, and violates the proportional hazards assumption. Therefore using the log‐rank test in immunotherapy trial design could result in a severe loss efficiency. Although few statistical methods are available for immunotherapy trial design that incorporates a delayed treatment effect, recently, Ye and Yu proposed the use of a maximin efficiency robust test (MERT) for the trial design. The MERT is a weighted log‐rank test that puts less weight on early events and full weight after the delayed period. However, the weight function of the MERT involves an unknown function that has to be estimated from historical data. Here, for simplicity, we propose the use of an approximated maximin test, the V0 test, which is the sum of the log‐rank test for the full data set and the log‐rank test for the data beyond the lag time point. The V0 test fully uses the trial data and is more efficient than the log‐rank test when lag exits with relatively little efficiency loss when no lag exists. The sample size formula for the V0 test is derived. Simulations are conducted to compare the performance of the V0 test to the existing tests. A real trial is used to illustrate cancer immunotherapy trial design with delayed treatment effect. [ABSTRACT FROM AUTHOR]

The tumor microenvironment strongly influences clinical outcomes of immunotherapy. By transfecting genes of relevant cytokines into tumor cells, we sought to manipulate the microenvironment so as to elicit activation of T helper type 1 (Th1) responses and the maturation of dendritic cells (DCs). Using a synthetic vehicle, the efficiency of in vivo transfection of GFP‐cDNA into tumor cells was about 7.5% by intratumoral injection and about 11.5% by intravenous injection. Survival was significantly improved by both intratumoral and intravenous injection of the plasmid containing cDNA of interferon‐gamma, followed by intratumoral injection of DCs presenting the tumor antigens. Also, tumor growth was inhibited by these treatments. A more significant effect on survival and tumor growth inhibition was observed following injection of the plasmid containing cDNA of CD40 ligand, which is a potent inducer of DC‐maturation. Furthermore, the co‐injection of both IFNγ‐ and CD40 ligand‐encoding cDNA‐plasmids, followed by DC treatment, gave rise to further marked and enhancement, including 100% survival and more than 50% complete remission. This treatment regimen elicited significant increases in mature DCs and types of cells contributing to Th1 responses, and significant decreases in immune suppressor cells in the tumor. In the spleen, the treatment significantly increased activities of tumor‐specific killer and natural killer cells, but no alteration was observed in mature DCs or suppressor cells. These results indicate that transfection of these cytokine genes into tumor cells significantly alter the tumor microenvironment and improve the therapeutic results of DC‐based immunotherapy. [ABSTRACT FROM AUTHOR]

Immunotherapy, represented by immune checkpoint inhibitors (ICI), is transforming the treatment of cancer. However, only a fraction of patients show response to ICI, and there is an unmet need for biomarkers that will identify patients more likely to respond to ICI. Here we report that the ICI response prediction biomarker tumor mutational burden (TMB) shows significant sex differences. TMB's predictive power is significantly better for female than for male lung cancer patients. Receiver operating characteristic curve analysis was performed and the area under the curve (AUC) was reported to evaluate the predictive power of TMB in lung cancer ICI response. Hazard ratios (HR) of TMB‐high vs. TMB‐low patients were compared between male and female patients. Both AUC and HR differences between female and male are significant in all available independent lung cancer datasets. However, the AUC of programmed death ligand 1 (PD‐L1) expression does not show a difference between female and male, suggesting TMB, but not PD‐L1 expression has a better predictive power for female than for male lung cancer patients. Our study suggests significant sex differences in the performance of TMB in ICI response prediction. Future development of ICI biomarker should consider sex differences and special efforts should be paid to improve the performance of ICI predictive biomarkers for male lung cancer patients. What's new? Only a fraction of cancer patients show response to immune checkpoint inhibitors (ICI), and there remains an unmet need for biomarkers to select patients most likely to benefit. Inherent sex differences in immune response could potentially influence the performance of predictive biomarkers. Here, the authors report that the emerging biomarker tumor mutational burden (TMB) shows significant sex differences, with TMB's predictive power being significantly better for female than for male lung cancer patients. Future development of predictive biomarkers for ICI response should consider sex differences, and the performance of biomarkers for male lung cancer patients should also be improved. [ABSTRACT FROM AUTHOR]

Interleukin‐6 (IL‐6) is a growth factor for normal B cells and plasma cell‐derived malignancies. Here, we show that the IL‐6 signaling pathway is also active in a subset of diffuse large B‐cell lymphoma (DLBCL) patients with particularly poor prognosis. Primary DLBCL cells and DLBCL cell lines expressing IL‐6R engraft and form orthotopic lymphomas in humanized mice that ectopically produce human IL‐6, and in mice reconstituted with a human immune system. We show that a subset of DLBCL cases have evolved mechanisms that ensure constitutive activation of the IL‐6 signaling pathway, i.e., the expression of both chains of the IL‐6R, the expression of the cytokine itself, and the mutational inactivation of a negative regulator of IL‐6 signaling, SOCS1. IL‐6 signaling promotes MYC‐driven lymphomagenesis in a genetically engineered model, and treatment with the IL‐6R‐specific antibody tocilizumab reduces growth of primary DLBCL cells and of DLBCL cell lines in various therapeutic settings. The combined results uncover the IL‐6 signaling pathway as a driver and negative prognosticator in aggressive DLBCL that can be targeted with a safe and well‐tolerated biologic. Synopsis: IL‐6 is a growth factor for B cells and plasma cells, and for a subtype of diffuse large B‐cell lymphoma. The dependence of this subtype on IL‐6 can be exploited for the development of patient‐derived xenograft models, and targeted therapeutically by a monoclonal antibody approved for human use. The IL‐6 signaling pathway was active in a subset of diffuse large B cell lymphomas with a particularly poor prognosis.This subset of DLBCL expressed both chains of the IL‐6 receptor, and either cell‐intrinsically produced IL‐6 or harbored inactivating mutations in the negative regulator SOCS1.Xenotransplantation and genetically engineered mouse models revealed a critical role of IL‐6 signaling in lymphoma cell engraftment and growth.Targeting IL‐6 signaling with tocilizumab reduced DLBCL growth in cell line xenotransplantation and patient‐derived xenograft models. [ABSTRACT FROM AUTHOR]

Melanoma is the most serious type of skin cancer which develops from the occurrence of genetic mutations in the melanocytes. Based on the features of melanoma tumors such as location, genetic profile and stage, there are several therapeutic strategies including surgery, chemotherapy, and radiotherapy. However, because of the appearance resistance mechanisms, the efficiency of these treatments strategies may be reduced. It has been demonstrated that therapeutic monoclonal antibodies can improve the efficiency of melanoma therapies. Recently, several mAbs, such as nivolumab, pembrolizumab, and ipilimumab, were approved for the immunotherapy of melanoma. The antibodies inhibit immune checkpoint receptors such as CTL4 and pd‐1. Another therapeutic strategy for the treatment of melanoma is cancer vaccines, which improve clinical outcomes in patients. The combination therapy using antibodies and gene vaccine give us a new perspective in the treatment of melanoma patients. Herein, we present the recent progressions in the melanoma immunotherapy, especially dendritic cells mRNA vaccines by reviewing recent literature. [ABSTRACT FROM AUTHOR]

Up to 60% of patients treated with cancer immunotherapy develop severe or life threatening immune‐related adverse events (irAEs). Immunosuppression with high dose corticosteroids, or tumor necrosis factor (TNF) antagonists in refractory cases, is the mainstay of treatment for irAEs. It is currently unknown what impact corticosteroids and anti‐TNF have on the activity of antitumor T cells. In our study, the influence of clinically relevant doses of dexamethasone (corresponding to an oral dose of 10–125 mg prednisolone) and infliximab (anti‐TNF) on the activation and killing ability of tumor‐infiltrating lymphocytes (TILs) was tested in vitro. Overall, dexamethasone at low or intermediate/high doses impaired the activation (−46 and −62%, respectively) and tumor‐killing ability (−48 and −53%, respectively) of tumor‐specific TILs. In contrast, a standard clinical dose of infliximab only had a minor effect on T cell activation (−20%) and tumor killing (−10%). A 72‐hr resting period after withdrawal of dexamethasone was sufficient to rescue the in vitro activity of TILs, while a short withdrawal did not result in a full rescue. In conclusion, clinically relevant doses of infliximab only had a minor influence on the activity of tumor‐specific TILs in vitro, whereas even low doses of corticosteroids markedly impaired the antitumor activity of TILs. However, the activity of TILs could be restored after withdrawal of steroids. These data indirectly support steroid‐sparing strategies and early initiation of anti‐TNF therapy for the treatment of irAEs in immuno‐oncology. What's new? Corticosteroids, the most widely used drugs for the management of immune‐related adverse events (irAEs), have a significant negative impact on anti‐tumor immune responses. The impact of second‐line anti‐tumor necrosis factor (TNF) agents for steroid‐refractory irAEs is less well understood. In our study, clinically relevant doses of the anti‐TNF agent infliximab were found to have only minor impacts on tumor‐infiltrating lymphocyte (TIL) activation and killing ability, whereas the corticosteroid dexamethasone impaired TIL function. While TIL activity was restored 72 h after dexamethasone withdrawal, the findings suggest that the early application of anti‐TNF agents may be warranted, particularly for serious irAEs. [ABSTRACT FROM AUTHOR]

Highlights from the article: CTLA-4 is a member of the CD28-B7 superfamily and acts as a co-inhibitory receptor for T-cell activation. In this study, we produced the Fab fragment of ipilimumab in I Escherichia coli i , and determined its crystal structure to enable comparison with the previously reported structure of the CTLA-4 bound ipilimumab Fab, which was expressed using the CHO cell expression system for manufacturing the antibody drug. Comparison of the structures of the complementarity-determining regions (CDRs) between the apo and CTLA-4-bound ipilimumab showed little conformational difference and only minor rearrangements in the side chains interacting with CTLA-4 (Figure). In conclusion, this study demonstrates that the Fab fragment of ipilimumab, the first-in-class antibody drug targeting CTLA-4, expressed in the periplasmic space of I E. coli i is structurally very similar to that of the fragmentized Fab from the original drug, ipilimumab, expressed in mammalian expression system.