Production of dendritic cell vaccines using different methods with equivalent results: Implications for emerging centers

Introduction Dendritic cell (DC) vaccines have demonstrated good efficacy in preventing relapse and in increasing survival of patients affected by a variety of both solid and hematological tumors. Most protocols used to generate these cells involve the automated separation of peripheral blood monocytes from patients. This approach requires specialized equipment, which elevates the cost of this type of therapy, potentially limiting the widespread access to patients. Method: In this study, we compare the yield and quality of dendritic cells generated from monocytes and isolated by an automated method or by manual methods using gradient centrifugation. Results The results demonstrate the equivalence of the 3 methods in relation to the yield and final quality of the product, however with considerable differences between the costs of these procedures. In addition, this study also demonstrates the feasibility of the antigenic pulse with autologous tumor cell lysates, constituting a source of antigens, not only easily obtained and manipulated, but also specific to the patient's tumor. Conclusion These findings may have important implications for emerging centers interested in using this medical approach and potentially increase the access of a greater number of patients to this therapeutic option.

Novelty in improvement of CAR T cell-based immunotherapy with the aid of CRISPR system

Abstract Introduction Chimeric Antigen Receptor (CAR) T cells have tremendous potentials for cancer treatment; however, various challenges impede their universal use. These restrictions include the poor function of T cells in tumor microenvironments, the shortage of tumor-specific antigens and, finally, the high cost and time-consuming process, as well as the poor scalability of the method. Creative gene-editing tools have addressed each of these limitations and introduced next generation products for cell therapy. The clustered regularly interspaced short palindromic repeats-associated endonuclease 9 (CRISPR/Cas9) system has triggered a revolution in biology fields, as it has a great capacity for genetic manipulation. Method In this review, we considered the latest development of CRISPR/Cas9 methods for the chimeric antigen receptor T cell (CAR T)-based immunotherapy. Results The ability of the CRISPR/Cas9 system to generate the universal CAR T cells and also potent T cells that are persistent against exhaustion and inhibition was explored. Conclusion: We explained CRISPR delivery methods, as well as addressing safety concerns related to the use of the CRISPR/Cas9 system and their potential solutions.

Radionecrosis cerebral en un adulto

Se presenta el caso clínico de un paciente de 37 años de edad con el antecedente de haber recibido radioterapia por una lesión tumoral en la región frontal derecha, el cual acudió a consulta en el Instituto de Neurología y Neurocirugía de Cuba por presentar cefalea intensa y hemiparesia izquierda. Luego de realizados los exámenes necesarios, se estableció el diagnóstico clínico-imagenológico de lesión por radionecrosis en el hemisferio contralateral, que fue corroborado en el estudio anatomopatológico una vez que se extirpó el tumor; seguidamente, se indicó inmunoterapia. La evolución del paciente fue satisfactoria, pues se logró el control de la enfermedad y la resolución de los síntomas.

The case report of a 37-year-old patient with history of having received radiotherapy due to a tumor lesion in the right frontal region is presented, who attended to the Institute of Neurology and Neurosurgery in Cuba because of intense headache and left hemiparesis. After carrying out the necessary examinations, the clinical-imaging diagnosis of a radionecrosis lesion in the contralateral hemisphere was established, which was corroborated in the pathological examination once the tumor was removed; then, immunotherapy was indicated. The patient had a favorable clinical course because the control of the disease was achieved as well as the resolution of symptoms.

Use of CAR-T cells for the treatment of relapsed and refractory multiple myeloma: a systematic review / Uso de células CAR-T no tratamento de mieloma múltiplo recidivado e refratário: uma revisão sistemática

A systematic review of published articles based on randomized clinical trials was conducted to ascertain the efficacy or perspective of using CAR-T cell therapy for refractory multiple myeloma. The PubMed database was searched with the combination of terms "multiple myeloma", "refractory multiple myeloma", "CAR T-cell", and the PRISMA criteria were followed. Of the 78 articles found, only 5 were selected. The studies used different treatment protocols and four different types of CAR-T cells. All studies obtained interesting results in terms of increased progression-free survival and negative minimal residual disease responses. Some authors detected an expansion of CAR-T cells and noted dose-dependent relationship between treatment effectiveness and serum BCMA levels. Although the results were promising, a small number of patients still relapsed a few months after CAR-T cell infusion. Therefore, this new line of therapy should be further investigated, as it significantly increases progression-free survival and improves quality of life.

Uma revisão sistemática de artigos publicados com base em ensaios clínicos randomizados foi realizada para verificar a eficácia ou perspectiva do uso da terapia com células CAR-T para mieloma múltiplo refratário. Foi pesquisada a base de dados PubMed com a combinação dos termos "multiple myeloma", "refratory multiple myeloma", "CAR T-cell" e foram seguidos os critérios PRISMA. Dos 78 artigos encontrados, apenas 5 foram selecionados. Os estudos utilizaram diferentes protocolos de tratamento e quatro tipos diferentes de células CAR-T. Todos os estudos obtiveram resultados interessantes em termos de aumento da sobrevida livre de progressão e respostas negativas à doença residual mínima. Alguns autores detectaram uma expansão das células CAR-T e observaram uma relação dose-dependente entre a eficácia do tratamento e os níveis séricos de BCMA. Embora os resultados tenham sido promissores, um pequeno número de pacientes ainda apresentou recaída alguns meses após a infusão de células CAR-T. Portanto, esta nova linha de terapia deve ser mais investigada, pois aumenta significativamente a sobrevida livre de progressão e melhora a qualidade de vida.

Drugs that act in the lymphatic system and lymphatic drug delivery: review and perspective / 药学学报

The lymphatic system, as well as pathological changes of the lymphatic system, underlies the progress of an array of diseases and conditions, including cancer, inflammation and autoimmune disorders, infectious diseases and metabolic syndrome. A variety of biological targets in the lymphatic system can be employed to modulate these high-burden diseases, and the pharmacokinetics and drug delivery strategies in the context of lymphatics are of critical importance to optimise drug exposure to lymphatic-related targets. As such, research and drug development in this field has gained increasing attention in recent years. This article aims to provide an overview of pharmaceutical research with a focus on the lymphatic system and therapeutic targets within the lymphatics, followed by lymphatic drug delivery approaches, which may be of interest for researchers in academia, pharmaceutical industry and regulatory sciences.

Treatment Strategy and Research Progress of Immune Microenvironment for Liver Metastasis of Non-small Cell Lung Cancer / 肿瘤防治研究

Liver is the common site for metastasis and spread of non-small cell lung cancer (NSCLC). Lung cancer patients with liver metastasis have poor prognosis, which may be related to liver-specific microenvironment composition. The metastasis of lung cancer to the liver is regulated by various pathophysiological factors, including the liver immune microenvironment, related cells, proteins, signaling molecules, and gene changes. These factors will affect the consistent disease process and subsequent treatment strategies. Immune checkpoint inhibitors (ICIs) have made breakthroughs in treatment of patients with advanced NSCLC. However, NSCLC patients with liver metastasis, a unique population of advanced lung cancer, are characterized by poor immunotherapeutic effect. This paper reviews the related mechanisms of the immune microenvironment in affecting the occurrence and development of liver metastases and summarizes the achievements and prospects of anti-tumor immunotherapy in liver metastases of NSCLC.

Relationship Between Peripheral Blood T Lymphocyte Subsets and Prognosis of Patients with Advanced Non-small Cell Lung Cancer Treated with Camrelizumab / 肿瘤防治研究

Objective To explore the relationship between peripheral blood T lymphocyte subsets and prognosis of patients with advanced non-small cell lung cancer (NSCLC) who received treatment with camrelizumab. Methods We retrospectively collected data from 88 patients with advanced NSCLC who underwent camrelizumab treatment. Peripheral blood lymphocyte subsets were collected from patients before and two months after treatment. Kaplan-Meier curves and Cox regression analysis were employed to investigate the relationship between peripheral blood T lymphocyte subsets and PFS and OS. Results Compared with non-responder group, the baseline peripheral blood CD4+/CD8+ ratio was higher (P=0.038), while the CD8+T lymphocyte percentage was lower (P=0.036) in the responder group. Kaplan-Meier curves showed that a high baseline CD4+/CD8+ ratio was associated with long PFS and OS (P=0.001, P=0.023). Multivariate Cox analysis revealed that the baseline CD4+/CD8+ ratio was a significant predictor for PFS and OS. Additionally, a high post-treatment CD4+/CD8+ ratio and high CD4+T lymphocyte percentage were associated with long PFS (P=0.005, P=0.015), whereas a low post-treatment CD8+T lymphocyte percentage was associated with long PFS and OS (P=0.001, P=0.016). Conclusion The peripheral blood CD4+/CD8+ ratio can serve as a predictive factor for survival of patients with NSCLC treated with camrelizumab.

Research progress of biomarkers for non-small cell lung cancer / 中国胸心血管外科临床杂志

@#Lung cancer is the leading cause of cancer-related deaths worldwide. Despite growing efforts for its early detection by screening populations at risk, the majority of lung cancer patients are still diagnosed in an advanced stage. In the last decade, the treatment of non-small cell lung cancer (NSCLC) has been improved significantly. Emerging options of targeted therapies and immunotherapies have shifted the management of lung cancer to a more personalized treatment approach, significantly influencing the clinical course and outcome of the disease. At present, molecular biomarkers are becoming a powerful tool for diagnosing cancer, predicting treatment response outcomes, and assessing prognosis. In this review, we summarized the biomarkers relevant to the diagnosis, prediction, and prognosis of NSCLC as well as promising novel predictive biomarkers in the future.

The attenuating and potentiating effects of traditional Chinese medicine in immune checkpoint therapy / 中国临床药理学与治疗学

Immunotherapy has become a global focus in cancer clinical practice and scientific research. In the past two years, PD-1\PD-L1 and CTLA-4 inhibitors, especially Nivolumab, Pembrolizumab, Atezolizumab and Lpilimumab, have been used in non-small cell lung cancer, colon cancer. Promising results have been obtained in malignancies such as melanoma and urinary tract cancer. Traditional Chinese medicine has a long history in China. Modulating immune checkpoints has certain advantages in treating malignant tumors, and it has shown good efficacy in improving its adverse events. This article reviews the role of traditional Chinese medicine in regulating immune checkpoints and improving adverse reactions and its application prospects in immunomodulatory treatment.

Progress in the application of AIT in allergic airway diseases / 中国临床药理学与治疗学

Allergen specific immunotherapy (AIT) is to identify the patient's allergen, give the patient repeated exposure to the allergen extract, and gradually increase the concentration and dose until the target maintenance dose is reached, so that the patient can develop tolerance to the allergen, which is the only treatment that can regulate the pathogenesis of allergic diseases and change its natural course. In recent years, domestic and foreign scholars have made great progress in the clinical practice and research field of AIT. This article reviewed the relevant progress of the mechanism, efficacy and drug administration of AIT.

Research progress and potential medical applications of anaplastic lymphoma kinase in treatment of non-small cell lung cancer / 中国药理学通报

During the treatment of non-small cell lung cancer ( NSCLC) , many patients have developed drug resistance due to the use of targeted EGFR inhibitors. The main reasons for drug resistance are EGFR site mutations and bypass activation. Activation of ALK pathway is one of the major types of bypass activation. A recent authoritative study indicates that ALK is closely related to immunotherapy. This article reviews the treatment of ALK in tumors from three aspects: the structure and physiological function of ALK, the small molecule inhibitor of ALK, the biological function of ALK and its related treatment methods for NSCLC, and prospects future directions for better application of ALK in the treatment of NSCLC.

Application of immunotherapy in relapsed/refractory B-cell acute lymphoblastic leukemia / 中国药房

Immunotherapy， as an emerging treatment method， has been proven to improve the prognosis of patients with relapsed/refractory B-cell acute lymphoblastic leukemia （B-ALL） and has good application prospects. Immunotherapy， including chimeric antigen receptor T cell immunotherapy （CAR-T） and monoclonal antibodies， has shown great potential for application， and has been approved for marketing. This article summarizes the application of the above two therapies in the treatment of relapsed/ refractory B-ALL， and concludes that CAR-T is a kind of personalized immunotherapy， and the selection of ideal targets is an important part of its action. Currently， the ideal targets in clinical studies include CD19， CD22 and CD19/CD22. Monoclonal antibodies， including blinatumomab and inotuzumab ozogamicin， have shown superior therapeutic efficacy for relapsed/refractory B- ALL. Immunotherapy has shown superior therapeutic effects compared to conventional chemotherapy， expanding the selection of treatment options for relapsed/refractory B-ALL.

Diagnosis and treatment pathway of neoadjuvant immunotherapy for esophageal cancer in Henan province / 中国胸心血管外科临床杂志

@#Esophageal cancer is a highly prevalent tumor species in Henan province, which brings heavy medical burden to families and society. Surgical treatment plays a dominant role in the treatment of non-advanced esophageal cancer. However, cancer cells in esophageal cancer lesions are highly invasive, postoperative recurrence and metastasis rates are pretty high. More effective systemic and comprehensive treatment is urgently needed to improve the prognosis. We invited 52 doctors in esophageal surgery, oncology, pathology, imaging, and radiation therapy of 32 hospitals at all levels in Henan province, to repeatedly negotiate and fully discuss in combination with evidence and clinical practice experience. Finally, “diagnosis and treatment pathway of neoadjuvant immunotherapy for esophageal cancer in Henan province” was formulated. In this treatment pathway, seven recommendations were proposed from seven perspectives including target population, patient evaluation, protocol selection, surgical timing, postoperative management, organ preservation, and general principles to offer reference for medical personnel related to esophageal cancer surgery.

Research Progress on Efficacy-related Biomarkers of Immunotherapy in Non-small Cell Lung Cancer / 肿瘤防治研究

Lung cancer is one of the most common cancers worldwide, and its mortality rate remains high. In addition to conventional surgery, radiotherapy, and chemotherapy, immunotherapy methods have been developed and used in recent years for the treatment of non-small cell lung cancer (NSCLC). However, only a small number of patients with NSCLC can benefit from immunotherapy strategies, and some patients even have hyperprogression after receiving immunotherapy. Therefore, precision immunotherapy requires effective biomarkers to guide it. In this paper, tissue samples, blood samples, intestinal microbiota, and other biomarkers are reviewed according to different sample sources. Blood samples, including TCR immune repertoire, Tregs cells, cytokines, lactate dehydrogenase, and other markers, are summarized and analyzed to provide reference for clinicians' diagnosis and treatment decisions.

Tumor-targeted metabolic inhibitor prodrug labelled with cyanine dyes enhances immunoprevention of lung cancer

Recent progress in targeted metabolic therapy of cancer has been limited by the considerable toxicity associated with such drugs. To address this challenge, we developed a smart theranostic prodrug system that combines a fluorophore and an anticancer drug, specifically 6-diazo-5-oxo-l-norleucine (DON), using a thioketal linkage (TK). This system enables imaging, chemotherapy, photodynamic therapy, and on-demand drug release upon radiation exposure. The optimized prodrug, DON-TK-BM3, incorporating cyanine dyes as the fluorophore, displayed potent reactive oxygen species release and efficient tumor cell killing. Unlike the parent drug DON, DON-TK-BM3 exhibited no toxicity toward normal cells. Moreover, DON-TK-BM3 demonstrated high tumor accumulation and reduced side effects, including gastrointestinal toxicity, in mice. This study provides a practical strategy for designing prodrugs of metabolic inhibitors with significant toxicity stemming from their lack of tissue selectivity.

Immunostimulatory gene therapy combined with checkpoint blockade reshapes tumor microenvironment and enhances ovarian cancer immunotherapy

Immune evasion has made ovarian cancer notorious for its refractory features, making the development of immunotherapy highly appealing to ovarian cancer treatment. The immune-stimulating cytokine IL-12 exhibits excellent antitumor activities. However, IL-12 can induce IFN-γ release and subsequently upregulate PDL-1 expression on tumor cells. Therefore, the tumor-targeting folate-modified delivery system F-DPC is constructed for concurrent delivery of IL-12 encoding gene and small molecular PDL-1 inhibitor (iPDL-1) to reduce immune escape and boost anti-tumor immunity. The physicochemical characteristics, gene transfection efficiency of the F-DPC nanoparticles in ovarian cancer cells are analyzed. The immune-modulation effects of combination therapy on different immune cells are also studied. Results show that compared with non-folate-modified vector, folate-modified F-DPC can improve the targeting of ovarian cancer and enhance the transfection efficiency of pIL-12. The underlying anti-tumor mechanisms include the regulation of T cells proliferation and activation, NK activation, macrophage polarization and DC maturation. The F-DPC/pIL-12/iPDL-1 complexes have shown outstanding antitumor effects and low toxicity in peritoneal model of ovarian cancer in mice. Taken together, our work provides new insights into ovarian cancer immunotherapy. Novel F-DPC/pIL-12/iPDL-1 complexes are revealed to exert prominent anti-tumor effect by modulating tumor immune microenvironment and preventing immune escape and might be a promising treatment option for ovarian cancer treatment.

Cancer immunotherapy with enveloped self-amplifying mRNA CARG-2020 that modulates IL-12, IL-17 and PD-L1 pathways to prevent tumor recurrence

Targeting multiple immune mechanisms may overcome therapy resistance and further improve cancer immunotherapy for humans. Here, we describe the application of virus-like vesicles (VLV) for delivery of three immunomodulators alone and in combination, as a promising approach for cancer immunotherapy. VLV vectors were designed to deliver single chain interleukin (IL)-12, short-hairpin RNA (shRNA) targeting programmed death ligand 1 (PD-L1), and a dominant-negative form of IL-17 receptor A (dn-IL17RA) as a single payload or as a combination payload. Intralesional delivery of the VLV vector expressing IL-12 alone, as well as the trivalent vector (designated CARG-2020) eradicated large established tumors. However, only CARG-2020 prevented tumor recurrence and provided long-term survival benefit to the tumor-bearing mice, indicating a benefit of the combined immunomodulation. The abscopal effects of CARG-2020 on the non-injected contralateral tumors, as well as protection from the tumor cell re-challenge, suggest immune-mediated mechanism of protection and establishment of immunological memory. Mechanistically, CARG-2020 potently activates Th1 immune mechanisms and inhibits expression of genes related to T cell exhaustion and cancer-promoting inflammation. The ability of CARG-2020 to prevent tumor recurrence and to provide survival benefit makes it a promising candidate for its development for human cancer immunotherapy.

Formation of Hyperprogression of Immunotherapy from Perspective of "Yang Deficiency and Toxin Knot" and Role of "Five Views on Differentiation and Treatment" Intervention / 中国实验方剂学杂志

Immune checkpoint inhibitors （ICIs） have shown good efficacy in tumor treatment and have changed the landscape of tumor treatment. However， some patients treated with ICIs have not only failed to achieve the desired therapeutic effect， but also developed an atypical response pattern of abnormally accelerated tumor growth， namely hyperprogressive disease （HPD）. The pathogenesis of HPD is still unclear and it is difficult to diagnose， which poses a challenge for clinical identification and treatment decisions. Exploring the underlying mechanism of HPD is important to improve the effect of immunotherapy. Based on the theory of "Yang deficiency and toxic knot"， this paper discussed the mechanism of HPD in immunotherapy from the perspective of "spleen and kidney Yang deficiency and hefty toxic pathogens". It was concluded that the inactivation of p53 oncogene and immunosuppressive microenvironment were the manifestations of the deficiency of healthy qi in the body and declined yang in the spleen and kidney， serving as an important basis for the occurrence of HPD. Adverse reactions caused by ICIs belong to the category of "drug toxicity". The occurrence and development of murine double minute 2 （MDM2）/murine double minute 4 （MDM4） activation， epidermal growth factor receptor （EGFR） mutation， and tumor inflammatory microenvironment are the manifestations of the hyperactivity of pathogenic Qi， conflict of cancer toxicity and drug toxicity， and being hefty by virtue of deficiency， which can promote the abnormal proliferation of tumor cells， and they are the core pathogenic elements of HPD and are closely related to disease prognosis. In terms of treatment， under the guidance of the theory of "five views on differentiation and treatment" （time-space view， core view， symptom view， precision view， and disease-before-onset view）， which was summarized according to the clinical practice of this research team， this paper， taking the prevention and treatment of HPD as the entry point， formulated traditional Chinese medicine （TCM） compounds to reinforce healthy Qi and warm Yang and realize the dynamic management of the whole spatiotemporal cycle， and removed toxins and resisted cancer to realize the all-round systemic intervention of the specimen. Additionally， targets were enriched in the macro-clinical manifestations and microscopic pathological changes of HPD to improve the targeting of drug selection and the precision of prevention and treatment， giving full play to the unique therapeutic advantages of TCM， and providing new ideas for the clinical application of TCM in the prevention and treatment of HPD.

Classification of bladder cancer based on immune cell infiltration and construction of a risk prediction model for prognosis / 浙江大学学报·医学版

OBJECTIVES@#To classify bladder cancer based on immune cell infiltration score and to construct a risk assessment model for prognosis of patients.@*METHODS@#The transcriptome data and data of breast cancer patients were obtained from the TCGA database. The single sample gene set enrichment analysis was used to calculate the infiltration scores of 16 immune cells. The classification of breast cancer patients was realized by unsupervised clustering, and the sensitivity of patients with different types to immunotherapy and chemotherapy was analyzed. The key modules significantly related to the infiltration of key immune cells were identified by weighted correlation network analysis (WGCNA), and the key genes in the modules were extracted. A risk scoring model and a nomogram for risk assessment of prognosis for bladder cancer patients were constructed and verified.@*RESULTS@#The immune cell infiltration scores of normal tissues and tumor tissues were calculated, and B cells, mast cells, neutrophils, T helper cells and tumor infiltrating lymphocytes were determined to be the key immune cells of bladder cancer. Breast cancer patients were clustered into two groups (Cluster 1 and Custer 2) based on immune cell infiltration scores. Compared with patients with Cluster 1, patients with Cluster 2 were more likely to benefit from immunotherapy (P<0.05), and patients with Cluster 2 were more sensitive to Enbeaten, Docetaxel, Cyclopamine, and Akadixin (P<0.05). WGCNA screened out 35 genes related to key immune cells, and 4 genes (GPR171, HOXB3, HOXB5 and HOXB6) related to the prognosis of bladder cancer were further screened by LASSO Cox regression. The areas under the ROC curve (AUC) of the bladder cancer prognosis risk scoring model based on these 4 genes to predict the 1-, 3- and 5-year survival of patients were 0.735, 0.765 and 0.799, respectively. The nomogram constructed by combining risk score and clinical parameters has high accuracy in predicting the 1-, 3-, and 5-year overall survival of bladder cancer patients.@*CONCLUSIONS@#According to the immune cell infiltration score, bladder cancer patients can be classified. And the bladder cancer prognosis risk scoring model and nomogram based on key immune cell-related genes have high accuracy in predicting the prognosis of bladder cancer patients.

Advances in molecular-targeted therapy for unresectable pancreatic cancer / 临床肝胆病杂志

Pancreatic cancer is one of the most prevalent malignant tumors of the digestive system， and its incidence and mortality rates are increasing year by year. Most patients with pancreatic cancer are unable to receive surgery due to the advanced stage. Although chemotherapy regimens based on gemcitabine and fluorouracil have prolonged the survival time of patients to some extent， some patients cannot tolerate chemotherapy and hence lose the opportunity for treatment. With the advent of the era of precision medicine， molecular-targeted therapy has exhibited an excellent therapeutic efficacy and has thus become one of the most important treatment techniques for tumors； however， due to the high heterogeneity of pancreatic cancer and its complicated tumor microenvironment， molecular-targeted therapy for pancreatic cancer has not achieved notable results. Therefore， it is imperative to seek new therapeutic targets and medications to overcome this issue. This article reviews the latest advances in the research on molecular-targeted therapy for unresectable pancreatic cancer based on common molecular targets and tumor immunity-related therapeutic targets， in order to provide new treatment strategies for patients with pancreatic cancer.