A phase Ⅰ study of Hemay022, an irreversible dual EGFR/HER2 tyrosine kinase inhibitor in Chinese patients with HER2-positive advanced breast cancer

Objective: Hemay022 is a novel small-molecule and an irreversible tyrosine kinase inhibitor with the target of epidermal growth factor receptor(EGFR)/human epidermal growth factor receptor 2(HER2), which demonstrated anti-tumor activity in preclinical studies. This first-in-human study evaluated the safety, pharmacokinetics,tolerability and preliminary anti-tumor activity of Hemay022 in HER2-positive advanced breast cancer patients.Methods: Heavily pretreated patients with HER2-positive advanced breast cancer were assigned to eight dose cohorts in a 3+3 dose-escalation pattern at doses of 50-600 mg QD and 300 mg BID. Eligible patients were given a single dose of Hemay022 on d 1 in week 0, followed by once daily continuous doses for four weeks in 28-day cycles.Pharmacokinetic samples were obtained on d 1 and d 28. Clinical responses were assessed every eight weeks.Results: Twenty-eight patients with advanced breast cancer were treated with Hemay022. The most frequently reported drug-related adverse events were diarrhoea(85.7%), vomiting(28.6%), nausea(25.0%) and decreased appetite(17.9%). No grade 4 drug-related adverse events were reported. At 50-600 mg doses, steady state areas under the concentration-time curve and peak concentrations increased with doses. One patient achieved complete response(CR), and three achieved partial response(PR). The objective response rate(ORR) and disease control rate(DCR) were 14.3% and 46.4% in 28 patients, respectively. The median progression-free survival(PFS) was3.98 months.Conclusions: Hemay022 at the dose of 500 mg once daily was well tolerated. The pharmacokinetic properties and encouraging anti-tumor activities of Hemay022 in advanced breast cancer patients warranted further evaluation of Hemay022 for treating breast cancer patients in the current phase Ⅲ trial(No. NCT05122494).

Inetetamab combined with S-1 and oxaliplatin as first-line treatment for human epidermal growth factor receptor 2-positive gastric cancer

BACKGROUND Patients with human epidermal growth factor receptor 2(HER2)-positive advanced gastric cancer have poor outcomes.Trastuzumab combined with chemotherapy is the first-line standard treatment for HER2-positive advanced gastric cancer.Inetetamab is a novel anti-HER2 drug,and its efficacy and safety in gastric cancer have not yet been reported.AIM To evaluate the efficacy and safety of the S-1 plus oxaliplatin(SOX)regimen combined with inetetamab as a first-line treatment for HER2-positive advanced gastric cancer.METHODS Thirty-eight patients with HER2-positive advanced gastric cancer or gastroeso-phageal junction adenocarcinoma were randomly divided into two groups:One group received inetetamab combined with the SOX regimen,and the other group received trastuzumab combined with the SOX regimen.After 4-6 cycles,patients with stable disease received maintenance therapy.The primary endpoints were progression-free survival(PFS)and overall survival(OS),and the secondary endpoints were the objective response rate,disease control rate,and adverse events(AEs).RESULTS Thirty-seven patients completed the trial,with 18 patients in the inetetamab group and 19 patients in the trastuzumab group.In the inetetamab group,the median PFS was 8.5 months,whereas it was 7.3 months in the trastuzumab group(P=0.046);this difference was significant.The median OS in the inetetamab group vs the trastuzumab group was 15.4 months vs 14.3 months(P=0.33),and the objective response rate was 50%vs 42%(P=0.63),respectively;these differences were not significant.Common AEs included leukopenia,thrombocytopenia,nausea,and vomiting.The incidence rates of grade≥3 AEs were 56%in the inetetamab group and 47%in the trastuzumab group(P=0.63),with no significant difference.CONCLUSION In the first-line treatment of HER2-positive advanced gastric cancer,inetetamab and trastuzumab showed comparable efficacy.The inetetamab group showed superior PFS,and both groups had good safety.

Sequential neoadjuvant chemotherapy using pegylated liposomal doxorubicin and cyclophosphamide followed by taxanes with complete trastuzumab and pertuzumab treatment for HER2-positive breast cancer: A phase Ⅱ single-arm study

Objective: Despite cardiotoxicity overlap, the trastuzumab/pertuzumab and anthracycline combination remains crucial due to significant benefits. Pegylated liposomal doxorubicin(PLD), a less cardiotoxic anthracycline, was evaluated for efficacy and cardiac safety when combined with cyclophosphamide and followed by taxanes with trastuzumab/pertuzumab in human epidermal growth factor receptor-2(HER2)-positive early breast cancer(BC).Methods: In this multicenter, phase II study, patients with confirmed HER2-positive early BC received four cycles of PLD(30-35 mg/m^(2)) and cyclophosphamide(600 mg/m^(2)), followed by four cycles of taxanes(docetaxel,90-100 mg/m^(2) or nab-paclitaxel, 260 mg/m^(2)), concomitant with eight cycles of trastuzumab(8 mg/kg loading dose,then 6 mg/kg) and pertuzumab(840 mg loading dose, then 420 mg) every 3 weeks. The primary endpoint was total pathological complete response(tp CR, yp T0/is yp N0). Secondary endpoints included breast p CR(bp CR),objective response rate(ORR), disease control rate, rate of breast-conserving surgery(BCS), and safety(with a focus on cardiotoxicity).Results: Between May 27, 2020 and May 11, 2022, 78 patients were treated with surgery, 42(53.8%) of whom had BCS. After neoadjuvant therapy, 47 [60.3%, 95% confidence interval(95% CI), 48.5%-71.2%] patients achieved tp CR, and 49(62.8%) achieved bp CR. ORRs were 76.9%(95% CI, 66.0%-85.7%) and 93.6%(95% CI,85.7%-97.9%) after 4-cycle and 8-cycle neoadjuvant therapy, respectively. Nine(11.5%) patients experienced asymptomatic left ventricular ejection fraction(LVEF) reductions of ≥10% from baseline, all with a minimum value of >55%. No treatment-related abnormal cardiac function changes were observed in mean N-terminal pro-BNP(NT-pro BNP), troponin I, or high-sensitivity troponin.Conclusions: This dual HER2-blockade with sequential polychemotherapy showed promising activity with rapid tumor regression in HER2-positive BC. Importantly, this regimen showed an acceptable safety profile,especially a low risk of cardiac events, suggesting it as an attractive treatment approach with a favorable risk-benefit balance.

Quercetin inhibits truncated isoform of dopamine-and cAMP-regulated phosphoprotein as adjuvant treatment for trastuzumab therapy resistance in HER2-positive breast cancer

Trastuzumab resistance is one of the causes of poor prognosis in patients with human epidermal growth factor receptor 2(HER2)-positive(HER2+)breast cancer(BC).The truncated isoform of dopamine-and cAMPregulated phosphoprotein(t-DARPP)has been reported to be involved in trastuzumab therapy resistance and promoting tumor progression.To evaluate the t-DARPP expression in BC,paired tumors and surrounding normal tissues were analyzed by real-time polymerase chain reaction and confirmed higher DARPP-32 kDa family mRNA expression in HER2+BC tumor tissues.We established 2 patient-derived xenografts(PDX)mice models to test the efficacy of trastuzumab,named model 1(non-responder)and model 2(responder).t-DARPP and p95-HER2 protein-protein interactions were detected in PDX tumor tissue from non-responders using Förster resonance energy transfer assays.Instead,there is no response from the responder.Furthermore,mechanistic studies using transwell and western blot assays demonstrated that t-DARPP could upregulate epithelial-mesenchymal transition signaling proteins,enhance p95-HER2 expression and promote cell migration.We found that quercetin effectively reduced t-DARPP expression in HER2+BC cells.In t-DARPP ShRNA-suppressed cells,quercetin synergistically enhanced trastuzumab-induced apoptotic cell death and G2/M phase arrest.In conclusion,the combination of quercetin and trastuzumab treatment by targeting t-DARPP in HER2+BC patients has the potential as a biomarker for mitigating drug resistance.

Autoimmune pancreatitis with IgG4-positive plasma cell infiltration in salivary glands and biliary tract

A 62-year-old male was referred to our hospital because of liver dysfunction, diffuse pancreatic swelling, and trachelophyma. At admission, the patient was free of pain. Physical examination showed enlarged and palpable bilateral submandibular masses, but no palpable mass or organomegaly in the abdomen. Laboratory findings were as follows： total protein 90 g/L with γ-globulin of 37.3% （33 g/L）, total bilirubin 4 mg/L, aspartate aminotransferase 39 IU/L, alanine aminotransferase 67 IU/L,γ-glutamyl transpeptidase 1 647 IU/L, and amylase 135 IU/L. Autoantibodies were negative, and tumor markers were within the normal range. Serum IgG4 level was markedly elevated （18 900 rag/L）. Computed tomography （CT） showed diffuse swelling of the pancreas and dilatation of both common and intra-hepatic bile ducts. Endoscopic retrograde pancreatography （ERP） revealed diffuse irregular and narrow main pancreatic duct and stenosis of the lower common bile duct. Biopsy specimens from the pancreas, salivary gland and liver showed marked periductal IgG4-positive plasma cell infiltration with fibrosis. We considered this patient to be autoimmune pancreatitis （AIP） with fibrosclerosis of the salivary gland and biliary tract, prescribed prednisolone at an initial dose of 40 mg/d. Three months later, the laboratory data improved almost to normal. Abdominal CT reflected prominent improvement in the pancreatic lesion. Swelling of the salivary gland also improved. At present, the patient is on 10 mg/d of prednisolone without recurrence of the pancreatitis. We present here a case of AIP with fibrosclerosis of salivary gland and biliary tract.

The efficacy of tucatinib-based therapeutic approaches for HER2-positive breast cancer

Overexpression of human epidermal growth factor receptor 2 (HER2) occurs in approximately 15–20% of breast cancer cases. HER2 is a member of the epidermal growth factor receptor (EGFR) family with tyrosinase kinase activity, and its overexpression is linked to poor prognosis and shorter progression-free survival (PFS) and overall survival (OS). Among various treatment options, HER2-targeting monoclonal antibodies and tyrosine kinase inhibitors (TKIs) have mostly been applied in recent decades to treat HER2-positive (HER2^(+)) breast cancer patients. Although positive clinical outcomes were documented in both advanced disease and neoadjuvant settings, the development of resistance mechanisms to such approaches has been one of the major challenges with the continuous usage of these drugs. In addition, patients who experience disease progression after treatment with multiple HER2-targeted therapies often have limited treatment options. The Food and Drug Administration (FDA) has recently approved a new TKI (i.e., tucatinib) for use in combination with immunotherapy and/or chemotherapeutic agents for the treatment of advanced-stage/metastatic HER2^(+) breast cancer. This review highlights recent updates on the efficacy of tucatinib-based therapeutic approaches in experimental models as well as in the clinical settings of HER2^(+) breast cancer.

A multicenter study on efficacy of dual-target neoadjuvant therapy for HER2-positive breast cancer and a consistent analysis of efficacy evaluation of neoadjuvant therapy by Miller-Payne and RCB pathological evaluation systems(CSBrS-026)

Objective: The aim of this study was to investigate the factors influencing pathological complete response(pCR)rate in early breast cancer patients receiving neoadjuvant dual-target [trastuzumab(H) + pertuzumab(P)] therapy combined with chemotherapy. Additionally, the consistency of the Miller-Payne and residual cancer burden(RCB)systems in evaluating the efficacy of neoadjuvant therapy for early human epidermal growth factor receptor-2(HER2)+ breast cancer was analyzed.Methods: The clinicopathological data of female patients with early-stage HER2+ breast cancer who received dual-target neoadjuvant therapy at 26 hospitals of the Chinese Society of Breast Surgery(CSBrS) from March 2019 to December 2021 were collected. Patients were allocated to four groups: the HER2 immunohistochemistry(IHC)3+/hormone receptor(HR)-, IHC3+/HR+, IHC2+ in situ hybridization(ISH)+/HR-and IHC2+ ISH+/HR+groups. The overall pCR rate for patients, the pCR rate in each group and the factors affecting the pCR rate were analyzed. The consistency between the Miller-Payne and RCB systems in assessing the efficacy of neoadjuvant therapy was analyzed.Results: From March 1, 2019, to December 31, 2021, 77,376 female patients with early-stage breast cancer were treated at 26 hospitals;18,853(24.4%) of these patients were HER2+. After exclusion of unqualified patients, 2,395 patients who received neoadjuvant dual-target(H+P) therapy combined with chemotherapy were included in this study. The overall pCR rate was 53.0%, and the patients' HR statuses and different HER2+ statuses were significantly correlated with the pCR rate(P<0.05). The consistency of the pathological efficacy assessed by the Miller-Payne and RCB systems was 88.0%(κ=0.717, P<0.001).Conclusions: Different HER2 expression statuses and HR expression statuses are correlated with the pCR rate after dual-target neoadjuvant therapy in HER2+ breast cancer patients. There is a relatively good consistency between Miller-Payne and RCB systems in evaluating the pathologic efficacy of neoadjuvant therapy for HER2+breast cancer.

Donor-derived CD 19 CAR-T Cells versus Chemotherapy Plus Donor Lymphocyte Infusion for Treatment of Recurrent CD 19-positive B-ALL after Allogeneic Hematopoietic Stem Cell Transplantation

Objective:This study aimed to compare the efficacy of anti-CD19 chimeric antigen receptor T cells(CAR-T cells)versus chemotherapy plus donor lymphocyte infusion(chemo-DLI)for treating relapsed CD 19-positive B-cell acute lymphoblastic leukemia(B-ALL)after allogeneic hematopoietic stem cell transplantation(allo-HSCT).Methods:Clinical data of 43 patients with B-ALL who relapsed after allo-HSCT were retrospectively analyzed.Twenty-two patients were treated with CAR-T cells(CAR-T group),and 21 with chemotherapy plus DLI(chemo-DLI group).The complete remission(CR)and minimal residual disease(MRD)-negative CR rates,leukemia-free survival(LFS)rate,overall survival(OS)rate,and incidence of acute graft-versus-host disease(aGVHD),cytokine release syndrome(CRS)and immune effector cell-associated neurotoxicity syndrome(ICANS)were compared between the two groups.Results:The CR and MRD-negative CR rates in the CAR-T group(77.3%and 61.5%)were significantly higher than those in the chemo-DLI group(38.1%and 23.8%)(P=0.008 and P=0.003).The 1-and 2-year LFS rates in the CAR-T group were superior to those in the chemo-DLI group:54.5%and 50.0%vs.9.5%and 4.8%(P=0.0001 and P=0.00004).The 1-and 2-year OS rates in the CAR-T versus chemo-DLI group were 59.1%and 54.5%vs.19%and 9.5%(P=0.011 and P=0.003).Six patients(28.6%)with grade 2-4 aGVHD were identified in the chemo-DLI group.Two patients(9.1%)in the CAR-T group developed grade 1-2 aGVHD.Nineteen patients(86.4%)developed CRS in the CAR-T group,comprising grade 1-2 CRS in 13 patients(59.1%)and grade 3 CRS in 6 patients(27.3%).Two patients(9.1%)developed grade 1-2 ICANS.Conclusion:Donor-derived anti-CD19 CAR-T-cell therapy may be better,safer,and more effective than chemo-DLI for B-ALL patients who relapse after allo-HSCT.

Perianal superficial CD34-positive fibroblastic tumor: A case report

BACKGROUND Superficial CD34-positive fibroblast tumors(SCPFTs)are newly recognized fibroblast and myofibroblast tumors representing intermediate tumors.To the best of our knowledge,fewer than 50 cases have been reported.Perianal SCPFT has not been previously reported.CASE SUMMARY A 55-year-old man was hospitalized upon discovering a painless perianal lump 10 d prior.Physical examination showed a lump of approximately 3 cm×4 cm in the 7 to 8 o’clock direction in the perianal area.Perianal abscess was considered the primary diagnosis.Lump removal surgery was performed under epidural anesthesia.Postoperative pathology showed a well-circumscribed,soft tissuederived,spindle-cell tumor with strong CD34 positivity by immunohistochemistry.The final diagnosis was perianal SCPFT.There were no complications,and the patient was followed for more than 8 mo without recurrence or metastasis.CONCLUSION We report a case of perianal superficial CD34-positive fibroblast tumor.This rare mesenchymal neoplasm has distinctive histomorphology,which is important for diagnosis.Comprehensive consideration of clinical information,imaging,histology,and immunohistochemistry is important for diagnosis.

Immunohistochemical Studies of Macrophages and MHC Class Ⅱ -positive Cells in the Iris and Ciliary Body of Lewis Rats

Purpose:To investigate the density, distribution and morphology of macrophages and MHC class II -positive dendritic cells in the iris and ciliary body of lewis rats. Methods:Immunohistochemistry was performed using monoclonal antibodies specific to monocytes and macrophages (ED1,ED2) and MHC class II -positive cells (OX6) on wholemounts of the iris-ciliary body complex isolated form normal lewis rats.Results:A well developed network of macrophages was present in the iris and ciliary body of normal lewis rats. These cells, morphologically displaying dendriti-form or pleiomorphic appearance, were more densely arranged in mid-iris (950 + 189 cells/mm2) than in iris base (482 ± 78 cells/mm2) and pupil margin (595 ± 92 cells/mm2). A similar network of MHC class II -positive cells with a cell density 452 ± 78 cells/mm2 was almost uniformly distributed in the iris of normal lewis rats.Conclusions : A network of macrophages and MHC class II -positive cells was established in the iris and ciliary body of

GRAPHICAL COMPUTING METHOD OF FOUR-BAR LINKAGE(3)FIVE-POSITION GRAPHICAL SYNTHESIS

By means of programs GTMPAC based- on generalized triangle method,analy-sis and synthesis of mechanism design in accordance with absolutely graphicalmethod(absolutely germetrical method) is developed. In this paper we make a specialstudy about Five- Position graphical synthesis.

Development of a Novel Tissue-Specific Method to Detect Cytokeratin 20-Positive Circulating Tumor Cells in Metastatic Colorectal Cancer

Introduction:Although many studies have shown the vast potential of circulating tumor cells(CTCs)detection in cancer diagnosis and prognosis,our understanding of their clinical significance is still far from complete.A major obstacle arises from the lack of well-established tumor or tissue-specific markers to detect CTCs by immunocytochemical staining after immunomagnetic enrichment(IE).Methods:We have established the utility of cytokeratin 20(CK20),a gastrointestinal tract specific marker,for the specific detection and identification of colorectal cancer(CRC)CTCs.This breakthrough was successfully validated in spike-in experiments using CRC cell line models followed by a pilot study which recruited 32 metastatic CRC patients,25 benign colorectal diseases patients and 27 normal subjects.Results:CK20-positive CTCs were detected in 90%metastatic CRC patients but not in benign colorectal diseases patients and normal subjects using this refined assay.Conclusions:These impressive results have laid the foundation for further development of CK20-positive CTCs as a promising marker in diagnosis,prognostication and treatment monitoring of metastatic CRC.

Antibody-Coupled Drugs in HER2-Positive Gastric Cancer

Antibody drug conjugates (ADCs) are a new class of drugs that combine chemosynthetic drugs with antibody drugs through a linker. Antibody drug conjugates combine the targeting characteristics of traditional antibody drugs with the cytotoxic characteristics of small molecule drugs, while reducing the side effects of both drugs, making them a kind of “biological missile” and representing a relatively new and evolving class of anti-cancer drugs. Antibody-coupled drugs are currently used in many solid tumors, and this article reviews the clinical application of antibody-coupled drugs in HER2-positive gastric cancer.

Insights into the Use of CDK 4/6 Inhibitors in Patients with HR-positive Advanced or Metastatic Breast Cancer

Hormone receptor(HR)-positive breast cancer(BC)is the most common subtype of BC and some patients with such tumors experience recurrences.Endocrine-based therapy(ET)(e.g.,tamoxifen,aromatase inhibitors(AIs),and fulvestrant)that has improved outcomes in such patients represents the initial therapy for women with HR-positive/human epidermal growth factor receptor 2(HER2)-negative BC(considering no evidence of visceral crisis).However,the resistance to ET can occur in almost 50%of HR-positive BCs.In order to improve outcomes of patients with HR-positive metastatic BC,new treatment strategies are required.One such therapy is the new class of medications,cyclin-dependent kinase(CDK)4/6 inhibitors,that have improved the outcomes in such patients(both endocrine-sensitive and endocrine-resistant).This article presents evidence from the main clinical trials,which led to the approval of palbociclib,ribociclib,and abemaciclib.These three CDK 4/6 inhibitors have shown a significant improvement of the progression-free survival(PFS)in patients with HR-positive/HER2-negative metastatic BC when used in combination with selected ETs.In addition,some important patient management considerations,when choosing a particular CDK 4/6 inhibitor for an individual patient are presented.Furthermore,a need to find biomarkers for CDK 4/6 inhibitor sensitivity,efficacy,and resistance,to be able to precisely select the best patientcandidates for this treatment is highlighted.

Inetetamab combined with pyrotinib and chemotherapy in the treatment of breast cancer brain metastasis: A case report

BACKGROUND Breast cancer brain metastasis(BCBM)is an advanced breast disease that is difficult to treat and is associated with a high risk of death.Patient prognosis is usually poor,with reduced quality of life.In this context,we report the case of a patient with HER-2-positive BCBM treated with a macromolecular mAb(ine-tetamab)combined with a small molecule tyrosine kinase inhibitor(TKI).CASE SUMMARY The patient was a 58-year-old woman with a 12-year history of type 2 diabetes.She was compliant with regular insulin treatment and had good blood glucose control.The patient was diagnosed with invasive carcinoma of the right breast(T3N1M0 stage IIIa,HER2-positive type)through aspiration biopsy of the ipsilateral breast due to the discovery of a breast tumor in February 2019.Immunohistochemistry showed ER(-),PR(-),HER-2(3+),and Ki-67(55-60%+).Preoperative neoadjuvant chemotherapy,i.e.,the AC-TH regimen(epirubicin,cyclophosphamide,docetaxel-paclitaxel,and trastuzumab),was administered for 8 cycles.She underwent modified radical mastectomy of the right breast in November 2019 and received tocilizumab targeted therapy for 1 year.Brain metastasis was found 9 mo after surgery.She underwent brain metastasectomy in August 2020.Immunohistochemistry showed ER(-)and PR.(-),HER-2(3+),and Ki-67(10-20%+).In November 2020,the patient experienced headache symptoms.After an examination,tumor recurrence in the original surgical region of the brain was observed,and the patient was treated with inetetamab,pyrotinib,and capecitabine.Whole-brain radiotherapy was recommended.The patient and her family refused radiotherapy for personal reasons.In September 2021,a routine examination revealed that the brain tumor was considerably larger.The original systemic treatment was continued and combined with intensity-modulated radiation therapy for brain metastases,followed by regular hospitalization and routine examinations.The patient’s condition is generally stable,and she has a relatively high quality of life.This case report demonstrates that in patients with BCBM and resistance to trastuzumab,inetetamab combined with pyrotinib and chemotherapy can prolong survival.CONCLUSION Inetetamab combined with small molecule TKI drugs,chemotherapy and radiation may be an effective regimen for maintaining stable disease in patients with BCBM.

Disitamab vedotin combined with apatinib in gastric cancer: A case report and review of literature

BACKGROUND In patients with human epidermal growth factor receptor 2(HER2)-overex-pressing gastric cancer(GC),the combination of HER2 targeting and a standard first-line chemotherapy regimen has been demonstrated to significantly improve their prognosis.However,in a proportion of patients,cancer progresses within a short period of time,and there is currently no standard treatment after disease progression.CASE SUMMARY This study presents a case of a 51-year-old male with advanced GC who un-derwent radical resection(Billroth type II subtotal gastrectomy and gastrojejun-ostomy)and resection of liver metastases.Immunohistochemical staining revealed a HER2 score of 2+,a dMMR status,and a Ki67 proliferation index of 30%to 40%.The gene test results indicated the presence of ERBB2 amplification and a PD-L1 expression level of less than 5%.Since December 2021,the patient has experienced disease progression during both first-line(two cycles of KN026 combined with KN046)and second-line(five cycles of nivolumab combined with trastuzumab and SOX chemotherapy)treatment regimens.The patient's prognosis following the first and second lines of treatment was unfavorable,with pro-gression occurring in a relatively short time.For third-line therapy,disitamab vedotin(RC48)plus apatinib was used.At the time of this report,the patient had achieved a progression-free survival(PFS)of 25.8 months,which exceeded the median survival time for patients with advanced GC.CONCLUSION Despite the unfavorable prognosis associated with advanced GC,the imple-mentation of personalized treatment approaches may still prove beneficial for select patients.In patients with HER2-positive GC with extensive metastatic involvement,the use of the HER2-targeted combination with apatinib has demonstrated the potential to prolong both PFS and overall survival.

Xianling Lianxia formula improves the efficacy of trastuzumab by enhancing NK cell-mediated ADCC in HER2-positive BC

Trastuzumab has improved survival rates in human epidermal growth factor receptor 2(HER2)-positive breast cancer(BC),but drug resistance leads to treatment failure.Natural killer(NK)cell-mediated antibody-dependent cell cytotoxicity(ADCC)represents an essential antitumor immune mechanism of trastuzumab.Traditional Chinese medicine(TCM)has been used for centuries to treat diseases because of its capacity to improve immune responses.Xianling Lianxia formula(XLLXF),based on the principle of“strengthening body and eliminating toxin”,exhibits a synergistic effect in the trastuzumab treatment of patients with HER2-positive BC.Notably,this synergistic effect of XLLXF was executed by enhancing NK cells and ADCC,as demonstrated through in vitro co-culture of NK cells and BC cells and in vivo intervention experiments.Mechanistically,the augmented impact of XLLXF on NK cells is linked to a decrease in cytokine inducible Src homology 2(SH2)containing protein(CISH)expression,which in turn activates the Janus kinase 1(JAK1)/signal transducer and activator of transcription 5(STAT5)pathway.Collectively,these findings suggested that XLLXF holds promise for enhancing NK cell function and sensitizing patients with HER2-positive BC to trastuzumab.

Colon cancer and the immune system:The role of tumor invading T cells

Colon cancer is still one of the leading causes of cancer death worldwide. Although the host immune system has been shown to react against tumor cells, mainly through tumor infi ltrating lymphocytes and NK cells, tumor cells may utilize different ways to escape anti-tumor immune response. Tumor infi ltration of CD8+ and CD4+ (T-bet+) effector T cells has been attributed to a beneficial outcome, and the enhancement of T cell activation through T cell receptor stimulation and co-stimulatory signals provides promising strategies for immunotherapy of colon cancer. Growing evidence supports a role for the Fas/FasL system in tumor immunology, although the mechanisms and consequences of FasL activation in colon cancer are not completely understood. In animal models, depletion of regulatory T cells (CD4+ CD25+ T cells) can enhance the anti-tumor immune response under certain conditions. Taken together, recent insights in the immune reaction against colon carcinoma have provided new approaches to immunotherapy, although much remains to be learned about the exact mechanisms.

Analysis of CD8^+CD28^-T-suppressor cells in living donor liver transplant recipients

BACKGROUND:Human CD8 + CD28 - T-suppressor(Ts) cells have been considered to indicate a reduced need for immunosuppression in pediatric liver-intestine transplant recipients and recipients of deceased heart-kidney transplants.However,in adult-to-adult living donor liver transplantation(A-A LDLT)little information is available and the clinical significance is still unknown. METHODS:Flow cytometry was used to detect the population of CD8+CD28 -Ts cells present in peripheral blood in A-A LDLT recipients(n=31),patients with end- stage liver disease(n=24)and healthy controls(n=19). Meanwhile,we tested the graft function and trough levels of immunosuppression in recipients.The clinical and follow- up data of 31 transplant recipients were analyzed. RESULTS:Compared with diseased controls(P=0.007) and healthy individuals(P=0.000),a notable expansion of CD8 + CD28 - Ts cells was found in recipients of A-A LDLT.This was associated with graft function,levels of immunosuppression and rejection episodes. CONCLUSIONS:To monitor the CD8 + CD28 - Ts cells levels is important to evaluate the immune state of recipients. Meanwhile,it is also important to promote expansion of CD8+CD28 -Ts cells in recipients of A-A LDLT,not only to sustain good graft function and decrease the dosage of immunosuppressants,but also to reduce the occurrence of rejection.

HER2-Specific T Lymphocytes Kill both Trastuzumab-Resistant and Trastuzumab-Sensitive Breast Cell Lines In Vitro

Objective： Although the development of trastuzumab has improved the outlook for women with human epidermal growth factor receptor 2 （HER2）-positive breast cancer, the resistance to anti-HER2 therapy is a growing clinical dilemma. We aim to determine whether HER2-specific T cells generated from dendritic cells （DCs） modified with HER2 gene could effectively kill the HER2-positive breast cancer cells, especially the trastuzumab-resistant cells. Methods： The peripheral blood mononuclear cells （PBMCs） from healthy donors, whose HLA haplotypes were compatible with the tumor cell lines, were transfected with reconstructive human adeno-association virus （rhAAV/HER2） to obtain the specific killing activities of T cells, and were evaluated by lactate dehydrogenase （LDH） releasing assay. Results： Trastuzumab produced a significant inhibiting effect on SK-BR-3, the IC50 was 100ng/ml. MDA-MB-453 was resistant to trastuzumab even at a concentration of 10,000 ng/ml in vitro. HER2-specific T lymphocytes killed effectively SK-BR-3 [（69.86±13.41）%] and MDA-MB-453 [（78.36±10.68）%] at 40：1 （effector：target ratio, E：T）, but had no significant cytotoxicity against HER2-negative breast cancer cell lines MDA-MB-231 or MCF-7 （less than 10%）. Conclusion： The study showed that HER2-specific T lymphocytes generated from DCs modified by rhAAV/HER2 could kill HER2-positive breast cancer cell lines in a HER2-dependent manner, and result in significantly high inhibition rates on the intrinsic trastuzumab-resistant cell line MDA-MB-453 and the tastuzumab-sensitive cell line SK-BR-3. These results imply that this immunotherapy might be a potential treatment to HER2-positive breast cancer.