New avenues for the treatment of immunotherapy-resistant pancreatic cancer

Pancreatic cancer(PC)is characterized by its extremely aggressive nature and ranks 14th in the number of new cancer cases worldwide.However,due to its complexity,it ranks 7th in the list of the most lethal cancers worldwide.The pathogenesis of PC involves several complex processes,including familial genetic factors associated with risk factors such as obesity,diabetes mellitus,chronic pancreatitis,and smoking.Mutations in genes such as KRAS,TP53,and SMAD4 are linked to the appearance of malignant cells that generate pancreatic lesions and,consequently,cancer.In this context,some therapies are used for PC,one of which is immunotherapy,which is extremely promising in various other types of cancer but has shown little response in the treatment of PC due to various resistance mechanisms that contribute to a drop in immunotherapy efficiency.It is therefore clear that the tumor microenvironment(TME)has a huge impact on the resistance process,since cellular and non-cellular elements create an immunosuppressive environment,characterized by a dense desmoplastic stroma with cancerassociated fibroblasts,pancreatic stellate cells,extracellular matrix,and immunosuppressive cells.Linked to this are genetic mutations in TP53 and immunosuppressive factors that act on T cells,resulting in a shortage of CD8+T cells and limited expression of activation markers such as interferon-gamma.In this way,finding new strategies that make it possible to manipulate resistance mechanisms is necessary.Thus,techniques such as the use of TME modulators that block receptors and stromal molecules that generate resistance,the use of genetic manipulation in specific regions,such as microRNAs,the modulation of extrinsic and intrinsic factors associated with T cells,and,above all,therapeutic models that combine these modulation techniques constitute the promising future of PC therapy.Thus,this study aims to elucidate the main mechanisms of resistance to immunotherapy in PC and new ways of manipulating this process,resulting in a more efficient therapy for cancer patients and,consequently,a reduction in the lethality of this aggressive cancer.

Metastatic pancreatic and lung cancer patient in complete remission following immunotherapy: A case report and review of literature

BACKGROUND Metastatic pancreatic ductal adenocarcinoma(PDAC)is a lethal malignancy with dispiriting survival data.Immunotherapy is a promising approach to many cancer types,but achieves poor outcomes in advanced PDAC due to its immunosuppressive tumor microenvironment.We describe a case of metastatic PDAC effectively treated with pembrolizumab.CASE SUMMARY We report the case of a 67-year-old woman with unresectable locally advanced PDAC,treated with gemcitabine plus nab-paclitaxel followed by radiotherapy plus capecitabine.At nine months,pancreatic tumor progression was observed at the level of the hepatic hilum with the appearance of a new pulmonary nodule suggestive of a second primary,confirmed by left lung biopsy.Systemic immunotherapy was then initiated with pembrolizumab,an immune checkpoint inhibitor targeting programmed cell death protein-1 that covers the two tumor types.The patient showed a complete metabolic response that was maintained throughout the treatment.The patient continues to be disease-free at 5.6 years since the start of immunotherapy.CONCLUSION These results suggest that the administration of pembrolizumab after chemoradiotherapy has a beneficial effect in patients with metastatic PDAC.To our knowledge,this is the first reported case of a patient with metastatic PDAC and metastatic lung cancer showing such a long-lasting complete response after pembrolizumab treatment without curative surgery.Further studies are required to determine biomarkers that identify PDAC patients most likely to benefit from this immunotherapy.

Systemic treatment for advanced pancreatic cancer

Pancreatic cancer is a deadly disease with an extremely poor 5-year survival rate due to treatment resistance and late-stage detection.Despite numerous years of research and pharmaceutical development,these figures have not changed.Treatment options for advanced pancreatic cancer are still limited.This illness is typically detected at a late stage,making curative surgical resection impossible.Chemotherapy is the most commonly utilized technique for treating advanced pancreatic cancer but has poor efficacy.Targeted therapy and immunotherapy have made significant progress in many other cancer types and have been proven to have extremely promising possibilities;these therapies also hold promise for pancreatic cancer.There is an urgent need for research into targeted treatment,immunotherapy,and cancer vaccines.In this review,we emphasize the founda-tional findings that have fueled the therapeutic strategy for advanced pancreatic cancer.We also address current advancements in targeted therapy,immuno-therapy,and cancer vaccines,all of which continue to improve the clinical outcome of advanced pancreatic cancer.We believe that clinical translation of these novel treatments will improve the low survival rate of this deadly disease.

Developments and challenges in neoadjuvant therapy for locally advanced pancreatic cancer

Pancreatic ductal adenocarcinoma(PDAC)remains a significant public health challenge and is currently the fourth leading cause of cancer-related mortality in developed countries.Despite advances in cancer treatment,the 5-year survival rate for patients with PDAC remains less than 5%.In recent years,neoadjuvant therapy(NAT)has emerged as a promising treatment option for many cancer types,including locally advanced PDAC,with the potential to improve patient outcomes.To analyze the role of NAT in the setting of locally advanced PDAC over the past decade,a systematic literature search was conducted using PubMed and Web of Science.The results suggest that NAT may reduce the local mass size,promote tumor downstaging,and increase the likelihood of resection.These findings are supported by the latest evidence-based medical literature and the clinical experience of our center.Despite the potential benefits of NAT,there are still challenges that need to be addressed.One such challenge is the lack of consensus on the optimal timing and duration of NAT.Improved criteria for patient selection are needed to further identify PDAC patients likely to respond to NAT.In conclusion,NAT has emerged as a promising treatment option for locally advanced PDAC.However,further research is needed to optimize its use and to better understand the role of NAT in the management of this challenging disease.With continued advances in cancer treatment,there is hope of improving the outcomes of patients with PDAC in the future.

Cancer immunotherapy for pancreatic cancer utilizing α-gal epitope/natural anti-Gal antibody reaction

Pancreatic ductal adenocarcinoma(PDAC) has the poorest prognosis of all malignancies and is largely resistant to standard therapy. Novel treatments against PDAC are desperately needed. Anti-Gal is the most abundant natural antibody in humans,comprising about 1% of immunoglobulins and is also naturally produced in apes and Old World monkeys. The anti-Gal ligand is a carbohydrate antigen called "α-gal epitopes" with the structure Galα1-3Galβ1-4Glc NAc-R. These epitopes are expressed as major carbohydrate antigens in non-primate mammals,prosimians,and New World monkeys. Anti-Gal is exploited in cancer vaccines to increase the immunogenicity of antigen-presenting cells(APCs). Cancer cells or PDAC tumor lysates are processed to express α-gal epitopes. Vaccination with these components results in in vivo opsonization by anti-Gal Ig G in PDAC patients. The Fc portion of the vaccine-bound anti-Gal interacts with Fcγ receptors of APCs,inducing uptake of the vaccine components,transport of the vaccine tumor membranes to draining lymph nodes,and processing and presentation of tumor-associated antigens(TAAs). Cancer vaccines expressing α-gal epitopes elicit strong antibody production against multiple TAAs contained in PDAC cells and induce activation of multiple tumor-specific T cells. Here,we review new areas of clinical importance related to the α-gal epitope/anti-Gal antibody reaction and the advantages in immunotherapy against PDAC.

Immunotherapy in pancreatic cancer:Unleash its potential through novel combinations

Pancreatic cancer is the third leading cause of cancer mortality in both men and women in the United States,with poor response to current standard of care,short progression-free and overall survival.Immunotherapies that target cytotoxic T lymphocyte antigen-4,programmed cell death protein-1,and programmed death-ligand 1 checkpoints have shown remarkable activities in several cancers such as melanoma,renal cell carcinoma,and nonsmall cell lung cancer due to high numbers of somatic mutations,combined with cytotoxic T-cell responses.However,single checkpoint blockade was ineffective in pancreatic cancer,highlighting the challenges including the poor antigenicity,a dense desmoplastic stroma,and a largely immunosuppressive microenvironment.In this review,we will summarize available clinical results and ongoing efforts of combining immune checkpoint therapies with other treatment modalities such as chemotherapy,radiotherapy,and targeted therapy.These combination therapies hold promise in unleashing the potential of immunotherapy in pancreatic cancer to achieve better and more durable clinical responses by enhancing cytotoxic T-cell responses.

Understanding the immune response and the current landscape of immunotherapy in pancreatic cancer

Pancreatic ductal adenocarcinoma(PDAC)is an aggressive tumor with high lethality.Even with surgery,radiotherapy,chemotherapy,and other locoregional or systemic therapies,the survival rates for PDAC are low and have not significantly changed in the past decades.The special characteristics of the PDAC’s microenvironment and its complex immune escape mechanism need to be considered when designing novel therapeutic approaches in this disease.PDAC is characterized by chronic inflammation with a high rate of tumor-associated macrophages and myeloid-derived suppressor cells and a low rate of natural killer and effector T cells.The pancreatic microenvironment is a fibrotic,microvascularized stroma that isolates the tumor from systemic vascularization.Immunotherapy,a novel approach that has demonstrated effectiveness in certain solid tumors,has failed to show any practice-changing results in pancreatic cancer,with the exception of PDACs with mismatch repair deficiency and high tumor mutational burden,which show prolonged survival rates with immunotherapy.Currently,numerous clinical trials are attempting to assess the efficacy of immunotherapeutic strategies in PDAC,including immune checkpoint inhibitors,cancer vaccines,and adoptive cell transfer,alone or in combination with other immunotherapeutic agents,chemoradiotherapy,and other targeted therapies.A deep understanding of the immune response will help in the development of new therapeutic strategies leading to improved clinical outcomes for patients with PDAC.

Immunotherapy for pancreatic cancer

Pancreatic cancer, a highly lethal cancer, has the lowest 5-year survival rate forseveral reasons, including its tendency for the late diagnosis, a lack of serologicmarkers for screening, aggressive local invasion, its early metastaticdissemination, and its resistance to chemotherapy/radiotherapy. Pancreaticcancer evades immunologic elimination by a variety of mechanisms, includinginduction of an immunosuppressive microenvironment. Cancer-associatedfibroblasts interact with inhibitory immune cells, such as tumor-associatedmacrophages and regulatory T cells, to form an inflammatory shell-like desmoplasticstroma around tumor cells. Immunotherapy has the potential to mobilizethe immune system to eliminate cancer cells. Nevertheless, althoughimmunotherapy has shown brilliant results across a wide range of malignancies,only anti-programmed cell death 1 antibodies have been approved for use inpatients with pancreatic cancer who test positive for microsatellite instability ormismatch repair deficiency. Some patients treated with immunotherapy whoshow progression based on conventional response criteria may prove to have adurable response later. Continuation of immune-based treatment beyond diseaseprogression can be chosen if the patient is clinically stable. Immunotherapeuticapproaches for pancreatic cancer treatment deserve further exploration, given theplethora of combination trials with other immunotherapeutic agents, targetedtherapy, stroma-modulating agents, chemotherapy, and multi-way combinationtherapies.

Research progress in immunotherapy of pancreatic cancer

胰腺癌是恶性程度最高的肿瘤,并且对常规治疗无效.近年来,更多研究关注于基因工程修饰T细胞、T细胞检测点抑制剂、树突状细胞和细胞因子诱导的杀伤细胞对胰腺癌的治疗作用;胰腺原位和瘤外肿瘤冷冻免疫治疗,免疫治疗联合化疗也可增强抗肿瘤的作用;胰腺癌疫苗研究也取得一定进展.现代药理学研究也发现中草药的免疫增效作用,比如人参皂苷Rg3能够增强胰腺癌化疗病人T细胞亚群和NK细胞活性.

Viro-immune therapy:A new strategy for treatment ofpancreatic cancer

Pancreatic ductal adenocarcinoma(PDAC) is an almost uniformly lethal disease with less than 5% survival at five years. This is largely due to metastatic disease, which is already present in the majority of patients when diagnosed. Even when the primary cancer can be removed by radical surgery, local recurrence occurs within one year in 50%-80% of cases. Therefore, it is imperative to develop new approaches for the treatment of advanced cancer and the prevention of recurrence after surgery. Tumour-targeted oncolytic viruses(TOVs) have become an attractive therapeutic agent as TOVs can kill cancer cells through multiple mechanisms of action, especially via virus-induced engagement of the immune response specifically against tumour cells. To attack tumour cells effectively, tumour-specific T cells need to overcome negative regulatory signals that suppress their activation or that induce tolerance programmes such as anergy or exhaustion in the tumour microenvironment. In this regard, the recent breakthrough in immunotherapy achieved with immune checkpoint blockade agents, such as anti-cytotoxic T-lymphocyte-associate protein 4, programmed death 1(PD-1) or PD-L1 antibodies, has demonstrated the possibility of relieving immune suppression in PDAC. Therefore, the combination of oncolytic virotherapy and immune checkpoint blockade agents may synergistically function to enhance the antitumour response, lending the opportunity to be the future for treatment of pancreatic cancer.

Current developments, problems and solutions in the non-surgical treatment of pancreatic cancer

Pancreatic cancer is a common malignant neoplasm of the pancreas with an increasing incidence, a low early diagnostic rate and a fairly poor prognosis. To date, the only curative therapy for pancreatic cancer is surgical resection, but only about 20% patients have this option at the time of diagnosis and the mean 5-year survival rate after resection is only 10%-25%. Therefore, developing new treatments to improve the survival rate has practical significance for patients with this disease. This review deals with a current unmet need in medical oncology: the improvement of the treatment outcome of patients with pancreatic cancer. We summarize and discuss the latest systemic chemotherapy treatments (including adjuvant, neoadjuvant and targeted agents), radiotherapy, interventional therapy and immunotherapy. Besides discussing the current developments, we outline some of the main problems, solutions and prospects in this field.

Dendritic cell-based vaccine for pancreatic cancer in Japan

"Vaccell" is a dendritic cell(DC)-based cancer vaccine which has been established in Japan. The DCs play central roles in deciding the direction of host immune reactions as well as antigen presentation. We have demonstrated that DCs treated with a streptococcal immune adjuvant OK-432, produce interleukin-12, induce Th1-dominant state, and elicit anti-tumor effects, more powerful than those treated with the known DCmaturating factors. We therefore decided to mature DCs by the OK-432 for making an effective DC vaccine, Vaccell. The 255 patients with inoperable pancreatic cancer who received standard chemotherapy combined with DC vaccines, were analyzed retrospectively. Survival time of the patients with positive delayed type hypersensitivity(DTH) skin reaction was significantly prolonged as compared with that of the patients with negative DTH. The findings strongly suggest that there may be "Responders" for the DC vaccine in advanced pancreatic cancer patients. We next conducted a smallscale prospective clinical study. In this trial, we pulsed HLA class Ⅱ-restricted WT1 peptide(WT1-Ⅱ) in addition to HLA class Ⅰ-restricted peptide(WT1-Ⅰ) into the DCs. Survival of the patients received WT1-Ⅰ and-Ⅱ pulsed DC vaccine was significantly extended as compared to that of the patients received DCs pulsed with WT1-Ⅰ or WT1-Ⅱ alone. Furthermore, WT1-specific DTH positive patients showed significantly improved the overall survival as well as progressionfree survival as compared to the DTH negative patients. The activation of antigen-specific immune responses by DC vaccine in combination with standard chemotherapy may be associated with a good clinical outcome in advanced pancreatic cancer. We are now planning a pivotal study of the Vaccell in appropriate protocols in Japan.

Pancreatic ductal adenocarcinoma: Treatment hurdles, tumor microenvironment and immunotherapy

Pancreatic ductal adenocarcinoma(PDAC)is one of the most lethal diseases,with an average 5-year survival rate of less than 10%.Unfortunately,the majority of patients have unresectable,locally advanced,or metastatic disease at the time of diagnosis.Moreover,traditional treatments such as chemotherapy,surgery,and radiation have not been shown to significantly improve survival.Recently,there has been a swift increase in cancer treatments that incorporate immunotherapybased strategies to target all the stepwise events required for tumor initiation and progression.The results in melanoma,non-small-cell lung cancer and renal cell carcinoma are very encouraging.Unfortunately,the application of checkpoint inhibitors,including anti-CTLA4,anti-PD-1,and anti-PD-L1 antibodies,in pancreatic cancer has been disappointing.Many studies have revealed that the PDAC microenvironment supports tumor growth,promotes metastasis and consists of a physical barrier to drug delivery.Combination therapies hold great promise for enhancing immune responses to achieve a better therapeutic effect.In this review,we provide an outline of why pancreatic cancer is so lethal and of the treatment hurdles that exist.Particular emphasis is given to the role of the tumor microenvironment,and some of the latest and most promising studies on immunotherapy in PDAC are also presented.

Is metastatic pancreatic cancer an untargetable malignancy?

Metastatic pancreatic cancer(MPC) is one of the most aggressive malignancies, known to be chemo-resistant and have been recently considered resistant to some targeted therapies(TT). Erlotinib combined to gemcitabine is the only targeted therapy that showed an overall survival benefit in MPC. New targets and therapeutic approaches, based on new-TT, are actually being evaluated in MPC going from immunotherapy, epigenetics, tumor suppressor gene and oncogenes to stromal matrix regulators. We aim in this paper to present the major causes rendering MPC an untargetable malignancy and to focus on the new therapeutic modalities based on TT in MPC.

Gene therapy in pancreatic cancer

Pancreatic cancer(PC) is a highly lethal disease and notoriously difficult to treat. Only a small proportion of PC patients are eligible for surgical resection, whilst conventional chemoradiotherapy only has a modest effect with substantial toxicity. Gene therapy has become a new widely investigated therapeutic approach for PC.This article reviews the basic rationale, gene delivery methods, therapeutic targets and developments of laboratory research and clinical trials in gene therapy of PC by searching the literature published in English using the PubMed database and analyzing clinical trials registered on the Gene Therapy Clinical Trials Worldwide website(http://www. wiley.co.uk/genmed/ clinical). Viral vectors are main gene delivery tools in gene therapy of cancer, and especially, oncolytic virus shows brighter prospect due to its tumor-targeting property.Efficient therapeutic targets for gene therapy include tumor suppressor gene p53, mutant oncogene K-ras,anti-angiogenesis gene VEGFR, suicide gene HSK-TK,cytosine deaminase and cytochrome p450, multiple cytokine genes and so on. Combining different targets or combination strategies with traditional chemoradiother-apy may be a more effective approach to improve the efficacy of cancer gene therapy. Cancer gene therapy is not yet applied in clinical practice, but basic and clinical studies have demonstrated its safety and clinical benefits. Gene therapy will be a new and promising field for the treatment of PC.

Multifunctional RGD coated a single-atom iron nanozyme:A highly selective approach to inducing ferroptosis and enhancing immunotherapy for pancreatic cancer

Nanozyme is a new promising approach to cancer therapy for its ability to induce ferroptosis by activating H_(2)O_(2)via a traditional radical pathway and enhance cancer immunotherapy.However,short half-life period of hydroxyl radical(·OH)results in unsatisfied effectiveness.Herein,we synthesized a single-atom iron nanozyme(Fe-SAzyme),which can activate H_(2)O_(2)via a non-radical pathway to generate Fe-based reactive oxygen species(ROS)(O=FeO_(3)=O)for promoting the ferroptosis of pancreatic cancer cells.This Fe-SAzyme could be specifically phagocytosed by pancreatic cancer cells,increasing ROS levels and inhibiting glutathione(GSH)synthesis,which activates ferroptosis.Tumor magnetic resonance imaging(MRI)showed decreased T2 signal after intravenous injection of RGD@Fe-AC(AC=activated carbon).Moreover,RGD@Fe-AC promoted dendritic cell(DC)maturation,overcame Treg-mediated immunosuppression,activated T cells to trigger adaptive immune responses,and enhanced the efficacy ofα-PD-L1 immunotherapy.Our research demonstrated that RGD@Fe-AC provided a straightforward,easily implemented,and selective approach for pancreatic cancer treatment and immunotherapy.

Progress of tumor-associated macrophages in pancreatic cancer

Pancreatic cancer is a kind of highly aggressive malignant tumor of the digestive system.The treatment of local tumors is mainly surgical resection,but the indications are too harsh.For advanced pancreatic cancer,chemotherapy is the standard treatment,but patients have severe side effects and develop drug resistance.Tumor-associated macrophages in the tumor microenvironment of pancreatic cancer are the most abundant immune cells and play a very important role in tumor development and chemoresistance.Antitumor-associated macrophage therapy has shown some therapeutic potential.Therefore,this article reviews the mechanism of tumor-associated macrophages in pancreatic cancer and the progress of tumor-associated macrophage targeted therapy.

Immunotherapy for pancreatic ductal adenocarcinoma: an overview of clinical trials

Pancreatic ductal adenocarcinoma（PDAC） is the fourth leading cause of cancer-related death and current therapeutic strategies are often unsatisfactory. Identification and development of more efficacious therapies is urgently needed. Immunotherapy offered encouraging results in preclinical models during the last decades, and several clinical trials have explored its therapeutic application in PDAC. The aim of this review is to summarize the results of clinical trials conducted to evaluate the future perspective of immunotherapy in the treatment of PDAC.

Pancreatic cancer-improved care achievable

Pancreatic adenocarcinoma is one of the most aggressive cancers,and the decline in mortality observed in most other cancer diseases,has so far not taken place in pancreatic cancer.Complete tumor resection is a requirement for potential cure,and the reorganization of care in the direction of high patient-volume centers,offering multimodal treatment,has improved survival and Quality of Life.Also the rates and severity grade of complications are improving in high-volume pancreatic centers.One of the major problems worldwide is underutilization of surgery in resectable pancreatic cancer.Suboptimal investigation,follow up and oncological treatment outside specialized centers are additional key problems.New chemotherapeutic regimens like FOLFIRINOX have improved survival in patients with metastatic disease,and different adjuvant treatment options result in well documented survival benefit.Neoadjuvant treatment is highly relevant,but needs further evaluation.Also adjuvant immunotherapy,in the form of vaccination with synthetic K-Ras-peptides,has been shown to produce long term immunological memory in cytotoxic T-cells in long term survivors.Improvement in clinical outcome is already achievable and further progress is expected in the near future for patients treated with curative as well as palliative intention.

Therapeutic resistance in pancreatic ductal adenocarcinoma: Current challenges and future opportunities

Pancreatic ductal adenocarcinoma(PDAC)is the third leading cause of cancerrelated deaths in the United States.Although chemotherapeutic regimens such as gemcitabine+nab-paclitaxel and FOLFIRINOX(FOLinic acid,5-Fluroruracil,IRINotecan,and Oxaliplatin)significantly improve patient survival,the prevalence of therapy resistance remains a major roadblock in the success of these agents.This review discusses the molecular mechanisms that play a crucial role in PDAC therapy resistance and how a better understanding of these mechanisms has shaped clinical trials for pancreatic cancer chemotherapy.Specifically,we have discussed the metabolic alterations and DNA repair mechanisms observed in PDAC and current approaches in targeting these mechanisms.Our discussion also includes the lessons learned following the failure of immunotherapy in PDAC and current approaches underway to improve tumor’s immunological response.