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.

Ag85B with c-di-AMP as mucosal adjuvant showed immunotherapeutic effects on persistent Mycobacterium tuberculosis infection in mice

Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains the leading cause of mortality by a single infectious agent in the world. M. tuberculosis infection could also result in clinical chronic infection, known as latent TB infection (LTBI). Compared to the current limited treatment, several subunit vaccines showed immunotherapeutic effects and were included in clinical trials. In this study, a subunit vaccine of Ag85B with a novel mucosal adjuvant c-di-AMP (Ag85B:c-di-AMP) was delivered intranasally to a persistent M. tuberculosis H37Ra infection mouse model, which also presented the asymptomatic characteristics of LTBI. Compared with Ag85B immunization, Ag85B:c-di-AMP vaccination induced stronger humoral immune responses, significantly higher CD4+ T cells recruitment, enhanced Th1/Th2/Th17 profile response in the lung, decreased pathological lesions of the lung, and reduced M. tuberculosis load in mice. Taken together, Ag85B:c-di-AMP mucosal route immunization provided an immunotherapeutic effect on persistent M. tuberculosis H37Ra infection, and c-di-AMP, as a promising potential mucosal adjuvant, could be further used in therapeutic or prophylactic vaccine strategies for persistent M. tuberculosis infection as well as LTBI.

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.

A case of severe immune liver injury caused by pembrolizumab and rechallenge / 药物流行病学杂志

An elderly female melanoma patient who experienced severe liver injury after treatment with pembrolizumab and axitinib,which improved with glucocorticoid therapy.Through medication analysis and adverse reaction scale evaluated,it was considered that severe liver injury was more closely related to the immune checkpoint inhibitor,pembrolizumab.After a comprehensive analysis of the relationship between liver injury and immunotherapy,as well as the benefits and risks of immunotherapy for patients,immunotherapy was rechallenged 40 days after discontinuation of pembrolizumab.Restarting treatment with pembrolizumab after immune-mediated hepatitis poses a risk of recurrence of hepatotoxicity.After reviewing related literature,it had been found that the incidence of severe hepatotoxicity caused by rechallenging treatment was low,and the overall safety was controllable.Pembrolizumab had brought therapeutic benefits to patients,with no further immune-mediated liver injury of 5 cycles medication.This case can provide a reference for rechallenging immunotherapy after immune-mediated hepatitis.

Immunotherapy Strategy for Advanced Non-Small Cell Lung Cancer in the Elderly / 医药导报

Immunotherapy,represented by immune checkpoint inhibitors(ICIs),has significantly changed the treat-ment strategy of non-small cell lung cancer(NSCLC)and has become an important therapy for all stages of NSCLC.However,there is an urgent need for further clarification regarding ICIs for elderly patients with advanced NSCLC.Treatment strategies for ICIs were guided by assessing survival data of elderly NSCLC patients included in clinical trials.We concluded that treatment regi-mens such as ICI monotherapy,dual immunotherapy,and ICIs combined with chemotherapy could be carried out in elderly NSCLC patients with a performance status(PS)score<2.Elderly NSCLC patients treated with ICIs could achieve similar benefits as younger patients and are generally well tolerated.However,as age increases(especially above 80 years),the efficacy decreased and the incidence of immune-related adverse events(irAEs)gradually increased.Therefore,ICIs should be carefully selected for advanced NSCLC patients at an advanced age.Compared to age,PS was a key factor causing patients to be excluded from ICIs and poorer survival outcomes.In conclusion,immunotherapy in elderly patients with advanced NSCLC is extremely challenging,and many issues still need further exploration in this field.

Progress and prospects of gastric cancer treatment in the 21st century / 中国癌症杂志

Gastric cancer,a malignant tumor with high morbidity and mortality in China,has characteristics such as high heterogeneity and poor prognosis.With the advent of the 21st century,significant progress has been made in gastric cancer diagnosis and treatment due to the rapid development of genomics,laparoscopic minimally invasive techniques,targeted therapy and immunotherapy.This article summarized the important research progress in the field of gastric cancer prevention and treatment since the 21st century,and looked forward to the future.We hope to make greater progress and breakthroughs in early screening,diagnosis and precise treatment of gastric cancer,further improve the overall survival rate of patients,and transform gastric cancer into a controllable"chronic disease".

Application and challenge of immunotherapy in perioperative therapy of gastric cancer / 中国癌症杂志

Gastric cancer is one of the common malignant tumors of digestive system in our country.The proportion of patients in advanced and late stage is large,and the choice of perioperative treatment program is always difficult in clinic.For most locally advanced gastric cancer,compared with standard radical surgery combined with postoperative adjuvant chemotherapy,perioperative treatment mode may further improve the survival of patients.However,the efficacy of conventional chemotherapy regimen has reached a plateau,while the progress of traditional molecular targeted therapy is relatively slow.In recent years,with the increasing role of immunotherapy in the treatment of advanced gastric cancer,more and more clinical studies have shown that immunotherapy can also achieve better efficacy in perioperative gastric cancer patients.This article reviewed the research progress of immunotherapy in perioperative gastric cancer in recent years.

Research progress of CCR8 in tumor immunotherapy / 中国癌症杂志

Therapies for tumors continue to develop,and tumor immunotherapy has emerged as an effective means of controlling tumor progression.Given the limitations of immunotherapy,only some specific patients can benefit from immunotherapy.Since the complex tumor microenvironment is highly influenced by individual variability,immunotherapy will be subjected to different degrees of immune suppression in different tumor microenvironments and thus cannot exert its full effect.In the tumor microenvironment,regulatory T(Treg)cell plays as an immunosuppressive role.Numerous Treg cells infiltrate in indifferent tumor types,resulting in immune escape of tumor tissues,which will have a negative impact on treatment and prognosis.CC chemokine receptor 8(CCR8)belongs to the CC chemokine receptor family.CCR8 is specifically expressed on Treg cell in the tumor microenvironment and expressed at low level in the surrounding normal tissues and peripheral blood thus it can be a specific marker for Treg cell.CCR8 is a potential therapeutic target and biomarker.This review summarized the research progress of CCR8 in different tumor types in recent years,so as to provide reference for subsequent research.

Effect of CyberKnife radiotherapy on peripheral blood lymphocytes of liver cancer / 局解手术学杂志

Objective To explore the effects of different fractionation doses,fractionation methods,and other related parameters on the peripheral blood lymphocyte count of patients with liver cancer receiving CyberKnife radiotherapy.Methods The clinical data of 90 patients with liver cancer receiving CyberKnife radiotherapy in our hospital were retrospectively analyzed.The peripheral blood lymphocyte counts of patients 1 week before CyberKnife radiotherapy and 1 week,1 month and 3 months after treatment were determined.The effects of different prescribed doses,fractionation doses and numbers of fractionations on the peripheral blood lymphocyte count were analyzed.Results The peripheral blood lymphocyte counts of patients with different prescribed doses,fractionation doses and fractionation methods after CyberKnife treatment decreased to varying degrees compared with those 1 week before treatment(P<0.05).The peripheral blood lymphocyte counts of patients in the groups with≤5 fractionations and fractionation dose>7 Gy were significantly higher than those of patients in the groups with>5 fractionations and the fractionation dose≤7 Gy,respectively(P<0.05).There was no significant difference in peripheral blood lymphocyte counts between patients with different prescribed doses before and after CyberKnife treatment(P>0.05).Conclusion CyberKnife in the treatment of liver cancer with≤5 ractionations and a fractionation dose of>7 Gy is more beneficial to alleviate the decrease of lymphocyte count caused by Cyberknife treatment.

New strategies for targeting PD-1/PD-L1:degraders,bifunctional molecules and covalent inhibitors / 中国药科大学学报

Programmed cell death protein-1(PD-1)/programmed cell death ligand-1(PD-L1)has been considered to be one of the most promising targets for tumor immunotherapy.At present,both monoclonal antibody drugs and small molecule inhibitors targeting PD-1/PD-L1 are facing bottlenecks.Numerous researchers have tried to explore different strategies to block the PD-L1/PD-L1 pathway,hoping to improve the effects of tumor immunotherapy.This review focuses on the degraders,bifunctional molecules and covalent inhibitors that target PD-L1,aiming to provide inspiring insights for the development of anti-PD-1/PD-L1 drugs.

Research progress of drugs for cancer immunotherapy based on CCL2/CCR2 signaling axis / 中国药科大学学报

C-C motif chemokine ligand 2(CCL2)and its receptor CCR2 are closely related to tumorigenesis and tumor progression.The CCL2/CCR2 signaling axis promotes tumor progression through multiple mechanisms:CCL2 binds to CCR2 on the surface of tumor cells,and thus promotes tumor growth/survival and metastasis;more importantly,CCL2 recruits a variety of immunosuppressive cells to aggregate in the tumor microenvironment,and inhibits the function and activity of immune cells,promoting tumor progression.The article reviews the CCL2/CCR2 signaling axis and its role in tumors and tumor microenvironment,with particular focus on the advances in clinical research on drugs targeting CCL2/CCR2 signaling axis,in order to gain an in-depth and overall understanding of the mechanism of action of CCL2/CCR2 axis in tumor progression and develop more effective anti-tumor immunotherapeutic agents.

Advances in treatment of immune-related adverse reactions and hyperprogressive diseases associated with antitumor immunotherapy with PD-1/PD-L1 monoclonal antibody drugs / 中国药理学与毒理学杂志

There have been breakthroughs in the development and clinical application of immuno-therapeutic agents in recent years.As the clinical targets of second-generation immune checkpoint inhibitors(ICIs),programmed death-1(PD-1)and its ligand(programmed death-ligand 1,PD-L1)have become one of the hot spots in drug discovery.The Food and Drug Administration of the USA and National Medical Products Administration in China have approved a variety of PD-1/PD-L1 monoclonal antibody drugs(such as nivolumab,pembrolizumab and atezolizumab),which are marketed for the treatment of small-cell lung cancer,rectal cancer,colon cancer,and melanoma,among other diseases.However,in the clinical application of PD-1/PD-L1 monoclonal antibody drugs,it is found that they can cause different degrees of immune-related adverse reactions in the lung,liver,kidney,gastrointestinal system,endocrine system and skin,and even the emergence of hyperprogressive disease.Effective monitoring and management of clinical applications of PD-1/PD-L1 monoclonal antibody drugs and rational use of some drugs can improve the immunotherapy process and reduce the effects of adverse reactions and hyperprogressive diseases in patients under immunotherapy.

Progress in the application of PD-(L)1 PET-targeted nuclide probes for tumor immunotherapy-related studies / 中华放射医学与防护杂志

Immunotherapy has entered the clinical treatment for various tumors, among which the blockade therapy of PD-1/PD-L1 immune checkpoint is currently the most important tumor immunotherapy method. At present, immunohistochemical method are used in clinical practice to detect PD-L1 expression in tumor patients and screen for indications. However, this method is constrained by factors such as heterogeneity, dynamic changes in PD-L1 expression, and limited sample collection. PD-(L)1 PET imaging utilizes radiolabeled molecules to non-invasively assess PD-(L)1 expression in space and time, and complementary use with IHC has theoretically incomparable advantages. This article reviews the latest progress in the PD-(L)1 probe molecular imaging principles, clinical research and existing problems.

Recent advances in the management of locally advanced head and neck squamous cell carcinoma / 中华放射肿瘤学杂志

Currently, concurrent chemoradiotherapy is the conventional treatment for locally advanced head and neck squamous cell carcinoma, but the 5-year survival rate of patients is still not high. In recent years, the development of radiotherapy technology has offered more options for patients. In addition, with the improvement of people's living standards, more and more patients begin to pursue the quality of life. There is an urgent need to explore better comprehensive treatment options to improve patient outcomes. In this article, research progress in comprehensive treatment of locally advanced head and neck squamous cell carcinoma was reviewed.

Clinical research of first-line chemotherapy and immunotherapy combined with chest radiotherapy for extensive-stage small cell lung cancer / 中华放射肿瘤学杂志

Objective:To evaluate the safety and efficacy of sequential consolidation thoracic radiotherapy after first-line chemotherapy combined with immunotherapy for extensive-stage small cell lung cancer (SCLC).Methods:A retrospective analysis of patients with extensive-stage SCLC admitted to Jiangsu Cancer Hospital from January 2019 to September 2022 was conducted. Patients who achieved effective chemotherapy combined with immunotherapy received sequential consolidation thoracic radiotherapy. The safety was evaluated according to the common terminology criteria for adverse events (CTCAE) 5.0 standard, and the overall survival (OS) and progression-free survival (PFS) were analyzed by Kaplan-Meier method.Results:A total of 33 patients were enrolled, with a median age of 66 years (range, 50-79 years). The median follow-up time was 20 months (range, 3-33 months). Fifteen patients (46%) had disease progression, and 12 patients (36%) died. The toxicities mainly included leukopenia, thrombocytopenia, radiation esophagitis, anorexia, and fatigue, etc. Six patients (18%) had grade 4 hematological toxicity, mainly leukopenia. One patient (3%) had grade 3 radiation pneumonitis, and 3 patients (9%) had grade 1-2 radiation pneumonitis. No grade 5 toxicity was observed in all patient groups. The median PFS was 12 months (95% CI=3.9-20.1). The 6-month, 1-year, and 2-year PFS rates were 78%, 49.6%, and 35.6%, respectively. The median OS was 23 months (95% CI=15.98-30.01). The 6-month, 1-year, and 2-year OS rates were 86.2%, 74.5%, and 47.2%, respectively. Conclusions:Sequential consolidation thoracic radiotherapy after first-line chemotherapy combined with immunotherapy is a safe protocol for extensive-stage SCLC. It brings survival benefits to patients by increasing PFS and OS rates.

Long-term efficacy of sequential surgery after immune combined with targeted therapy for initially unresectable hepatocellular carcinoma / 中华肝胆外科杂志

Objective:To assess the long-term outcome of sequential radical surgery after immune combined with targeted therapy for patients with initially unresectable hepatocellular carcinoma (HCC).Methods:Clinical data of 100 patients with initially unresectable HCC undergoing sequential radical surgery after immune combined with targeted therapy at the Faculty of Hepato-Pancreato-Biliary Surgery of Chinese PLA General Hospital from December 2018 to August 2023 were prospectively collected, including 87 males and 13 females, with a median age of 55 (24-73) years. The pre-treatment tumor staging was determined using the China liver cancer staging (CNLC). The efficacy of immune combined with targeted therapy was accessed using the modified response evaluation criteria in solid tumor (mRECIST). The cycles of immune combined with targeted therapy were analyzed. The tumor residual of resected tissue was analyzed through a standard pathological protocol. The prognosis was analyzed using the Kaplan-Meier method.Results:Upon initial diagnosis, there were 46 cases (46.0%) staged CNLC-Ⅲa and 40 (40.0%) staged CNLC-Ⅲb. There were also 14 cases (14.0%) staged CNLC-Ⅰb, Ⅱa, and Ⅱb who underwent immune combined with targeted therapy due to rupture of tumor or insufficient liver remnant. All patients received a median of 5 (3-28) cycles of immune combined with targeted therapy and underwent radical surgery after successful conversion. According to mRECIST, 14 (14.0%) were determined as complete remission, 63 (63.0%) as partial remission, 18 (18.0%) as stable disease, and 5 (5.0%) as disease progression. Of 24 (24.0%) were defined as pathologically complete remission by postoperative pathology. Furthermore, pathological tumor residue was less than 10% in 61 (61.0%) cases and less than 50% in 82 (82.0%) cases. The 1, 3, and 5 year-overall survival rates of patients were 98.0%, 83.1%, and 74.5%, respectively. The 1, 2 and 3 year-recurrence-free survival rates were 67.5%, 54.8%, and 49.6%, respectively.Conclusion:Sequential radical surgery after immune combined with targeted therapy benefits the long-term survival of patients with initially unresectable HCC.

Clinical analysis of the second-line treatment with lenvatinib plus camrelizumab in 12 cases of advanced intrahepatic cholangiocarcinoma / 中华肝胆外科杂志

Objective:To evaluate the efficacy and safety of lenvatinib combined with camrelizumab as the second-line treatment for advanced intrahepatic cholangiocarcinoma (ICC).Methods:The clinical data of patients with advanced ICC undergoing the second-line treatment of lenvatinib combined with camrelizumab in the Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University from June 2021 to June 2022 were screened and analyzed. A total of 12 patients were enrolled, including seven males and five females, aged (67.5±8.6) years. Response evaluation criteria in solid tumor 1.1 was used to evaluate the efficacy of treatment. The safety assessment adopts the Adverse Event Evaluation Standard 5.0. Kaplan-Meier method was conducted to plot survival curves.Results:Among the 12 patients (after 1-7 cycles of immune and targeted therapy), three achieved partial response, four achieved stable disease, and five were defined as progression disease. Adverse events of different degrees occurred in seven cases, among which three patients had adverse events of grade ≥ 3: one with hypertension, which was managed after antihypertensive and symptomatic treatment; one with elevated serum total bilirubin, which was improved after reducing the dose of lenvatinib; one with liver dysfunction, which was considered as immune-related liver toxicity and alleviated after discontinuing camrelizumab. The 1-month, 3-month, and 6-month survival rates and progression-free survival rates of the patients were 100.0%, 91.7%, 66.7%, and 83.3%, 41.7%, and 25.0%, respectively. The median overall survival of patients was 14.7 months (95% CI: 9.2-21.2) and the median time to progression was 8.0 months (95% CI: 4.1-11.9). Conclusion:Combination of lenvatinib and camrelizumab could bring survival benefits with controllable adverse events as the second-line treatment of patients with advanced ICC.

A case of recurrent renal pelvic sarcomatoid carcinoma treated with PD-1 inhibitor achieved complete remission / 中华泌尿外科杂志

Sarcomatoid carcinoma of the renal pelvis accounts for a very low percentage of malignant tumors in the renal pelvis and has a poor prognosis. This article reported a patient with sarcomatoid carcinoma of the renal pelvis. The patient presented with macroscopic hematuria as the first symptom, and CT suggested left renal occupancy, unilateral nephrectomy was performed, and pathology suggested sarcomatoid carcinoma of the renal pelvis. Three weeks after surgery, a follow-up CT showed tumor recurrence. Programmed death 1(PD-1)inhibitor was given once every 3 weeks. Repeated CT examination after 24 weeks of continuous treatment suggested that the recurrent tumor disappeared. The patients was followed-up for 42 months without tumor recurrence or metastasis.