The immunologic abnormalities in patients with paroxysmal nocturnal hemoglobinuria are associated with disease progression.

OBJECTIVES: To suggest the presence of a hyperimmune state in patients, and indicate that immune system attack on glycosylphosphatidylinositol (+) (GPI+) cells while escaping GPI- cell immunity. METHODS: We retrospective the immune cell subtypes in peripheral blood from 25 patients visiting Tianjin Medical University General Hospital, Tianjin, China, with classical paroxysmal nocturnal hemoglobinuria (PNH) and 50 healthy controls. RESULTS: The total CD3+ and CD3+CD8+ cell levels were higher in patients with PNH. The CD3+ cells are positively, correlated with lactate dehydrogenase (LDH; r=0.5453, p=0.0040), indirect bilirubin (r=0.4260, p=0.0379) and Flear- cells in monocytes (r=0.4099, p=0.0303). However, a negative correlation was observed between CD3+ cells and hemoglobin (r= -0.4530, p=0.0105). The total CD19+ cells decreased in patients, and CD19+ cells were negatively correlated with LDH (r= -0.5640, p=0.0077) and Flear- cells in monocytes (r= -0.4432, p=0.0341). Patients showed an increased proportion of total dendritic cells (DCs), with a higher proportion of myeloid DCs (mDCs) within the DC population. Moreover, the proportion of mDC/DC was positively correlated with CD59- cells (II + III types) in red cells (r=0.7941, p=0.0004), Flear- cells in granulocytes (r=0.5357, p=0.0396), and monocytes (r=0.6445, p=0.0095). CONCLUSION: Our results demonstrated that immune abnormalities are associated with PNH development.

The role of TIM3+ NK and TIM3- NK cells in the immune pathogenesis of severe aplastic anemia.

Background: Natural killer (NK) cells play important immunoregulatory roles in the immune pathogenesis of severe aplastic anemia (SAA). Our previous research showed that SAA caused a decrease in T cell immunoglobulin mucin-3 (TIM3) expression on NK cells. Here we investigated the expression of surface receptors, and the cytotoxicity of peripheral TIM3+ NK and TIM3- NK cells in patients with SAA. Methods: The expressions of surface receptors and cytoplasmic protein of TIM3+ NK and TIM3- NK cells from peripheral blood were detected by FCM. The functions of mDCs, and apoptosis rate of K562 cells after co-culture with TIM3+ NK and TIM3- NK cells were maesured by FCM. Westren-blot was used to detect the changes of TIM3+ NK and TIM3- NK signaling pathway proteins (AKT, P-AKT) and compare the functional activity of the two groups. Results: Activating receptors NKG2D and Granzyme B were higher, while inhibiting receptors NKG2A, CD158a and CD158b were lower on TIM3- NK cells compared with TIM3+ NK cells in patients with SAA. In SAA, the expression of CD80 and CD86 on mDCs (Myeloid dendritic cells) was significantly decreased after incubation with TIM3- NK cells. The apoptosis rate (AR) of K562 cells was significantly increased after being incubated with TIM3- NK cells in SAA. The level of signal pathway protein AKT of TIM3- NK cells in SAA was similar to that of TIM3+ NK cells, and the levels of P-AKT and P-AKT/AKT ratio of TIM3- NK cells were significantly higher than those of TIM3+ NK cells. Conclusions: Therefore, TIM3 exerts its inhibitory effect on NK cells and participates in the immune pathogenesis of SAA. Low expression of TIM3 contributes to the enhancement of NK cell activity which in turn inhibits the immune activation state of SAA and improves the disease state. Our research may aid the development of new therapeutic strategies based on TIM3-NK cells infusion for the treatment of SAA.

Targeting tumor-intrinsic SLC16A3 to enhance anti-PD-1 efficacy via tumor immune microenvironment reprogramming.

Immunotherapy, especially immune checkpoint inhibitors, has revolutionized clinical practice within the last decade. However, primary and secondary resistance to immunotherapy is common in patients with diverse types of cancer. It is well-acknowledged that tumor cells can facilitate the formation of immunosuppressive microenvironments via metabolism reprogramming, and lactic acid, the metabolite of glycolysis, is a significant contributor. SLC16A3 (also named as MCT4) is a transporter mediating lactic acid efflux. In this study, we investigated the role of glycolysis in immunotherapy resistance and aimed to improve the immunotherapy effects via Slc16a3 inhibition. Bioinformatical analysis revealed that the expression of glycolysis-related genes correlated with less CD8+ T cell infiltration and increased myeloid-derived suppressor cells (MDSC) enrichment. We found that high glycolytic activity in tumor cells adversely affected the antitumor immune responses and efficacy of immunotherapy and radiotherapy. As the transporter of lactic acid, SLC16A3 is highly expressed in glycolytic B16-F10 (RRID: CVCL_0159) cells, as well as human non-small cell lung carcinoma. We validated that Slc16a3 expression in tumor cells negatively correlated with anti-PD-1 efficiency. Overexpression of Slc16a3 in tumor cells promoted lactic acid production and efflux, and reduced tumor response to anti-PD-1 inhibitors by inhibiting CD8+ T cell function. Genetic and pharmacological inhibition of Slc16a3 dramatically reduced the glycolytic activity and lactic acid production in tumor cells, and ameliorated the immunosuppressive tumor microenvironments (TMEs), leading to boosted antitumor effects via anti-PD-1 blockade. Our study therefore demonstrates that tumor cell-intrinsic SLC16A3 may be a potential target to reverse tumor resistance to immunotherapy.

Efficacy and safety of disitamab vedotin after trastuzumab for HER2 positive breast cancer: a real-world data of retrospective study.

Disitamab vedotin (RC48) is a novel cleavable antibody-drug conjugate (ADC) that has shown promising preclinical activity in HER2-positive breast cancer. However, real-world data regarding its efficacy and safety is lacking, especially in patients previously treated with trastuzumab and heavily treated patients. This retrospective study aimed to evaluate the effectiveness and safety of RC48 in HER2-positive metastatic breast cancer (MBC) in non-clinical trial settings. Eighty-one patients with metastatic HER2-positive BC who received RC48 in Shandong Cancer Hospital and Institute between September 2021 to November 2022 were included in this study. The primary endpoints were real-world progression-free survival (RWPFS) and objective response rate (ORR), and the secondary endpoints included safety and exploratory subgroup analyses. Results showed that the median RWPFS was 5.9 months, and the ORR was 29.6%, including one patient who achieved complete remission. Two-thirds of the patients had received more than one line of prior anti-HER2 treatment, and 76.6% were exposed to anti-HER2 monoclonal antibodies and tyrosine kinase inhibitors. Patients who received RC48 in ≤3 lines of treatment had significantly longer RWPFS than those who received it in ≥4 lines of treatment. The median RWPFS of RC48 in patients with trastuzumab resistance and refractoriness was 6.5 months and 5.6 months, respectively. The sequence of pyrotinib and RC48 did not influence their total efficacy. To conclude, RC48 exhibited promising efficacy in HER2-positive MBC with manageable toxicity, particularly in patients previously treated with trastuzumab and those who had undergone extensive treatment. RC48 exhibited potent activity for patients regardless of trastuzumab resistance or refractory. The sequence of pyrotinib and RC48 did not influence their total efficacy, indicating no cross-resistance.

Challenges and strategies associated with CAR-T cell therapy in blood malignancies.

Cellular immunotherapy, particularly CAR-T cells, has shown potential in the improvement of outcomes in patients with refractory and recurrent malignancies of the blood. However, achieving sustainable long-term complete remission for blood cancer remains a challenge, with resistance and relapse being expected outcomes for many patients. Although many studies have attempted to clarify the mechanisms of CAR-T cell therapy failure, the mechanism remains unclear. In this article, we discuss and describe the current state of knowledge regarding these factors, which include elements that influence the CAR-T cell, cancer cells as a whole, and the microenvironment surrounding the tumor. In addition, we propose prospective approaches to overcome these obstacles in an effort to decrease recurrence rates and extend patient survival subsequent to CAR-T cell therapy.

Targeting NKG2D/NKG2DL axis in multiple myeloma therapy.

Immune effector cells in patients with multiple myeloma (MM) are at the forefront of many immunotherapy treatments, and several methods have been developed to fully utilise the antitumour potential of immune cells. T and NK cell-derived immune lymphocytes both expressed activating NK receptor group 2 member D(NKG2D). This receptor can identify eight distinct NKG2D ligands (NKG2DL), including major histocompatibility complex class I (MHC) chain-related protein A and B (MICA and MICB). Their binding to NKG2D triggers effector roles in T and NK cells. NKG2DL is polymorphic in MM cells. The decreased expression of NKG2DL on the cell surface is explained by multiple mechanisms of tumour immune escape. In this review, we discuss the mechanisms by which the NKG2D/NKG2DL axis regulates immune effector cells and strategies for promoting NKG2DL expression and inhibiting its release in multiple myeloma and propose therapeutic strategies that increase the expression of NKG2DL in MM cells while enhancing the activation and killing function of NK cells.

Immune profiles to predict bortezomib-based treatment response for multiple myeloma patients.

BACKGROUND: To evaluate the distribution of bone marrow immune cell subsets and their correlation with treatment efficacy in patients with multiple myeloma (MM). METHODS: We analyzed the bone marrow lymphocyte subsets of 186 newly diagnosed MM patients at diagnosis and their correlation with clinical characteristics. In our study, eight-color flow cytometry, a method commonly used to detect plasma cell phenotypes, was used to analyze seven bone marrow immune cell groups by change gate-strategy. RESULTS: First, for all the 7 immune cell groups, the percentage of immature B cells was significantly lower in stage III patients than in stage I patients, while the trend was reversed in memory B cells in both the International Staging System(p = 0.004) and Revised International Staging System(p = 0.018). Second, the percentage of naïve B cells were significantly lower in patients with severe anemia, while the percentage of memory B cells had reversed trend. The percentage of immature B cells were lower in patients with Cr ≥ 2 mg/dL than in patients with Cr < 2 mg/dL. Then we followed the treatment efficacy of 152 patients who received four cycles of induction therapy (bortezomib + dexamethasone or bortezomib + lenalidomide + dexamethasone) and analyzed the relationship between bone marrow lymphocyte subsets at the initial stage and treatment response datasets. We found that both the percentage of B cells(p＜0.001) and immature B(p = 0.002) were increased in patients who achieved very good partial remission(VGPR) after four cycles of induction therapy. The ROC results indicated the combination of the multiple immune subgroups had predictive values (AUC = 0.802, p<0.001) in the treatment effect after four cycles of induction therapy. CONCLUSIONS: Overall, these results suggest that the analysis of lymphocyte subsets along with plasma cell immunophenotyping could be a potential index for determining the prognosis of MM patients.

Abnormal expression of CUX1 influences autophagy activation in paroxysmal nocturnal hemoglobinuria.

The mechanism underlying autophagy in paroxysmal nocturnal hemoglobinuria (PNH) remains largely unknown. We previously sequenced the entire genome exon of the CD59- cells from 13 patients with PNH and found genes such as CUX1 encoding Cut-like homeobox 1. Peripheral blood samples from nine patients with PNH and seven healthy controls were obtained to measure CUX1 expression. The correlation between CUX1 mRNA expression and PNH clinical indicators was analyzed. To simulate CUX1 expression in patients with PNH, we generated a panel of PNH cell lines by knocking out PIGA in K562 cell lines and transfected lentivirus with CUX1. CCK-8 and EDU assay assessed cell proliferation. Western blotting was used to detect Beclin1, LC3A, LC3B, ULK1, PI3K, AKT, p-AKT, mTOR, and p-mTOR protein levels. Autophagosomes were observed with transmission electron microscopy. Chloroquine was used to observe CUX1 expression in PNH after autophagy inhibition. Leukocytes from patients with PNH had lower levels of CUX1 mRNA expression and protein content than healthy controls. The lactose dehydrogenase level and the percentage of PNH clones were negatively correlated with CUX1 relative expression. We reduced CUX1 expression in a PIGA-knockout K562 cell line, leading to increased cell proliferation. Levels of autophagy markers Beclin1, LC3B, LC3A and ULK1 increased, and autophagosomes increased. Furthermore, PI3K/AKT/mTOR protein phosphorylation levels were lower. CUX1 expression did not change and cell proliferation decreased in CUX1 knocked down PNH cells after inhibition of autophagy by chloroquine. In brief, CUX1 loss-of-function mutation resulted in stronger autophagy in PNH.

The residual cancer burden index as a valid prognostic indicator in breast cancer after neoadjuvant chemotherapy.

PURPOSE: The residual cancer burden index (RCB) was proposed as a response evaluation criterion in breast cancer patients treated with Neoadjuvant Chemotherapy (NAC). This study evaluated the relevance of RCB with replase-free survival (RFS). METHODS: The clinical data of 254 breast cancer patients who received NAC between 2016 and 2020 were retrospectively collected. The relationship between clinicopathologic factors and RFS was evaluated using Cox proportional hazards regression models. RFS estimates were determined by Kaplan-Meier(K-M) analysis and compared using the log-rank test. Multivariate logistic regression analysis was used to evaluate the risk factors associated with RCB. Receiver operating characteristic (ROC) curves showed the potential of the RCB and MP grading systems as biomarkers for RFS. RESULTS: At a median follow-up of 52 months, 59 patients(23.23%) developed relapse. Multivariate Cox regression showed that older age (P = 0.022), high Pathologic T stage after NAC (P = 0.023) and a high RCB score(P = 0.003) were risk factors for relapse. The outcomes of the multivariate logistic analysis indicated that RCB 0 (pathologic complete response [pCR]) was associated with HER2-positive patients (P = 0.002) and triple-negative breast cancer (TNBC) patients (P = 0.013). In addition, the RCB and MP scoring systems served as prognostic markers for patients who received NAC, and their area under curves (AUCs) were 0.691 and 0.342, respectively. CONCLUSION: These data suggest that RCB can be equally applied to predict RFS in Chinese patients with NAC. The application of RCB may help guide the selection of treatment strategies.

Folic acid-coupled bovine serum albumin-modified magnetic nanocomposites from quantum-sized Fe3O4 and layered double hydroxide for actively targeted delivery of 5-fluorouracil.

The development of multifunctional magnetic nanocomposites as a drug delivery system for cancer therapy is highly desirable in current nanomedicine. Herein, folic acid-bovine serum albumin conjugate (FA-BSA) was modified on nanocomposites by combining quantum-sized Fe3O4 and layered double hydroxide (LDH) to obtain a novel FA-BSA/Fe3O4@LDH for the delivery of the anticancer drug 5-Fluorouracil (5-Fu). The prepared nanocomposites showed good dispersibility, colloidal stability, magnetic property and erythrocyte compatibility. FA-BSA/Fe3O4@LDH/5-Fu showed pH responsiveness, with both the amount and duration of release of FA-BSA/Fe3O4@LDH/5-Fu being significantly higher in pH 5.0 release medium than in pH 7.4 release medium. The cellular experiments implied that no significant cytotoxicity of FA-BSA/Fe3O4@LDH, particularly due to the presence of FA-BSA, which further enhanced the biocompatibility of the nanocomposite. Furthermore, FA-BSA/Fe3O4@LDH/5-Fu could specifically target the 2D HepG2 cells model and 3D hepatoma cell microspheres model in vitro, and efficient internalization through folate receptor-mediated endocytosis, showing excellent anti-cancer cell activity in a concentration-dependent manner. Therefore, the constructed FA-BSA/Fe3O4@LDH was able to provide a potential novel multifunctional nanocomposite for magnetic-targeting drug delivery and pH-responsive release of drugs to enhance the efficiency of cancer therapy.

Construction of a risk stratification model integrating ctDNA to predict response and survival in neoadjuvant-treated breast cancer.

BACKGROUND: The pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) of breast cancer is closely related to a better prognosis. However, there are no reliable indicators to accurately identify which patients will achieve pCR before surgery, and a model for predicting pCR to NAC is required. METHODS: A total of 269 breast cancer patients in Shandong Cancer Hospital and Liaocheng People's Hospital receiving anthracycline and taxane-based NAC were prospectively enrolled. Expression profiling using a 457 cancer-related gene sequencing panel (DNA sequencing) covering genes recurrently mutated in breast cancer was carried out on 243 formalin-fixed paraffin-embedded tumor biopsies samples before NAC from 243 patients. The unique personalized panel of nine individual somatic mutation genes from the constructed model was used to detect and analyze ctDNA on 216 blood samples. Blood samples were collected at indicated time points including before chemotherapy initiation, after the 1st NAC and before the 2nd NAC cycle, during intermediate evaluation, and prior to surgery. In this study, we characterized the value of gene profile mutation and circulating tumor DNA (ctDNA) in combination with clinical characteristics in the prediction of pCR before surgery and investigated the prognostic prediction. The median follow-up time for survival analysis was 898 days. RESULTS: Firstly, we constructed a predictive NAC response model including five single nucleotide variant (SNV) mutations (TP53, SETBP1, PIK3CA, NOTCH4 and MSH2) and four copy number variation (CNV) mutations (FOXP1-gain, EGFR-gain, IL7R-gain, and NFKB1A-gain) in the breast tumor, combined with three clinical factors (luminal A, Her2 and Ki67 status). The tumor prediction model showed good discrimination of chemotherapy sensitivity for pCR and non-pCR with an AUC of 0.871 (95% CI, 0.797-0.927) in the training set, 0.771 (95% CI, 0.649-0.883) in the test set, and 0.726 (95% CI, 0.556-0.865) in an extra test set. This tumor prediction model can also effectively predict the prognosis of disease-free survival (DFS) with an AUC of 0.749 at 1 year and 0.830 at 3 years. We further screened the genes from the tumor prediction model to establish a unique personalized panel consisting of 9 individual somatic mutation genes to detect and analyze ctDNA. It was found that ctDNA positivity decreased with the passage of time during NAC, and ctDNA status can predict NAC response and metastasis recurrence. Finally, we constructed the chemotherapy prediction model combined with the tumor prediction model and pretreatment ctDNA levels, which has a better prediction effect of pCR with the AUC value of 0.961. CONCLUSIONS: In this study, we established a chemotherapy predictive model with a non-invasive tool that is built based on genomic features, ctDNA status, as well as clinical characteristics for predicting pCR to recognize the responders and non-responders to NAC, and also predicting prognosis for DFS in breast cancer. Adding pretreatment ctDNA levels to a model containing gene profile mutation and clinical characteristics significantly improves stratification over the clinical variables alone.

Integrative proteomic and metabonomic profiling elucidates amino acid and lipid metabolism disorder in CA-MRSA-infected breast abscesses.

Objective: Bacterial culture and drug sensitivity testing have been the gold standard for confirming community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) infection in breast abscess with a long history. However, these tests may delay treatment and increase the risk of nosocomial infections. To handle and improve this critical situation, this study aimed to explore biomarkers that could facilitate the rapid diagnosis of CA-MRSA infection. Methods: This study for the first time applied label-free quantitative proteomics and non-targeted metabonomics to identify potential differentially expressed proteins (DEPs) and differentially expressed metabolites (DEMs) in breast abscess infected with CA-MRSA compared to methicillin-susceptible S. aureus (MSSA). The two omics data were integrated and analyzed using bioinformatics, and the results were validated using Parallel Reaction Monitoring (PRM). Receiver operating characteristic (ROC) curves were generated to evaluate the predictive efficiency of the identified biomarkers for diagnosing CA-MRSA infection. Results: After using the above-mentioned strategies, 109 DEPs were identified, out of which 86 were upregulated and 23 were downregulated. Additionally, a total of 61 and 26 DEMs were initially screened in the positive and negative ion modes, respectively. A conjoint analysis indicated that the amino acid metabolism, glycosphingolipid biosynthesis, and glycerophospholipid metabolism pathways were co-enriched by the upstream DEPs and downstream DEMs, which may be involved in structuring the related network of CA-MRSA infection. Furthermore, three significant DEMs, namely, indole-3-acetic acid, L-(-)-methionine, and D-sedoheptulose 7-phosphate, displayed good discriminative abilities in early identification of CA-MRSA infection in ROC analysis. Conclusion: As there is limited high-quality evidence and multiple omics research in this field, the explored candidate biomarkers and pathways may provide new insights into the early diagnosis and drug resistance mechanisms of CA-MRSA infection in Chinese women.

Immune checkpoint inhibitors for multiple myeloma immunotherapy.

Multiple myeloma (MM) is related to immune disorders, recent studys have revealed that immunotherapy can greatly benefit MM patients. Immune checkpoints can negatively modulate the immune system and are closely associated with immune escape. Immune checkpoint-related therapy has attracted much attention and research in MM. However, the efficacy of those therapies need further improvements. There need more thoughts about the immune checkpoint to translate their use in clinical work. In our review, we aggregated the currently known immune checkpoints and their corresponding ligands, further more we propose various ways of potential translation applying treatment based on immune checkpoints for MM patients.

Quality of life considerations and management in patients with myelodysplastic syndrome.

INTRODUCTION: This study aimed to identify the factors affecting the quality of life (QOL) and functional status of patients with MDS. AREAS COVERED: We reviewed the literature published in PUBMED over the past 30 years and searched for keywords such as 'quality of life' and 'myelodysplastic syndromes'. By observing the influence of their symptoms, the possibility of improving patients' QOL was considered by improving these related factors. Concurrently, the effects of related clinical treatments based on the unique disease characteristics of MDS on the patients' QOL were examined, and lifestyle factors were considered in clinical practice, providing an important path to improve the QOL and functional status of patients with MDS. EXPERT OPINION: This review summarized several areas that can improve the quality of survival of MDS patients and discusses them in depth. Although the clinical benefits may be minimal, we still hope to improve patients' daily life outcomes and enhance their quality of life at minimal cost. Also, we hope more researchers will focus on this area in the future to find more factors that may exist to supplement the limitations of these understanding and thinking, and to provide assistance in clinical work.

PR status is a more decisive factor in efficacy of adding pertuzumab into neoadjuvant therapy for HER2-positive and lymph node-positive breast cancer than ER status: a real-world retrospective study in China.

BACKGROUND: Although neoadjuvant trastuzumab and pertuzumab (HP)-based regimens are recommended for human epidermal receptor-positive (HER2 +)/lymph node-positive (N +) breast cancer (BC) patients according to NCCN guidelines, it is undeniable that many patients achieved pathological complete response (pCR) after trastuzumab (H)-based regimens without adding pertuzumab to treatment. Patients who specifically benefit from pertuzumab must be identified. The aim of this retrospective study was to evaluate progesterone receptor (PR) status as a predictor of response to the addition of pertuzumab in HER2 + /N + breast cancer. METHODS: One hundred forty-two patients who were diagnosed as HER2 + /N + BC without distant metastasis and followed by neoadjuvant HP-based or H-based therapy were retrospectively included. The endpoints were pCR and disease-free survival (DFS) times. RESULTS: In total, the pCR occurred in 25 of 87 patients (28.74%) in group H compared with 32 of 55 (58.18%) in group HP. The results revealed that hormone receptor (HR) status was significantly different on pCR in group HP. The odds of pCR for patients who have HR-positive tumors were 0.160 times (P = 0.011) that for patients with HR-negative tumors by multivariable analysis. Moreover, a similar probability of PR-positive (PR +) patients, whatever estrogen receptor (ER) status was, achieving pCR in group HP was observed. The ROC curves showed different anti-HER2 regimens provide worst predictive value in the PR + cohort (N = AUC = 0.521, 95% CI: 0.348-0.694, P = 0.813) compared with the overall cohort (AUC = 0.644, 95% CI: 0.550-0.738, P = 0.004) and ER + cohort (AUC: 0.559, 95% CI: 0.405-0.713, P = 0.451). And PR status (AUC = 0.760, 95% CI: 0.626-0.894, P = 0.001) had a greater predictive value than ER status (AUC = 0.658, 95% CI: 0.508-0.807, P = 0.048) in group HP. DFS analyses were done on 141 patients. Although ER and PR status did not show significant difference in group HP (P = 0.789 and 0.088, respectively), HP-based therapy contributed to better DFS in the ER - and PR - cohorts (P = 0.035 and 0.015, respectively). CONCLUSIONS: Compared with ER status, PR status might be a more valuable factor predicting the efficacy of adding pertuzumab into neoadjuvant therapy for HER2 + /N + BC. PR + patients benefit little from the addition of pertuzumab.

Efficacy and safety of inetetamab-containing regimens in patients with HER2-positive metastatic breast cancer: a real-world retrospective study in China.

Background: Inetetamab (cipterbin) is an innovative anti-HER2 humanized monoclonal antibody. The efficacy and safety of a combination of inetetamab and vinorelbine in the first-line treatment of human epidermal receptor positive (HER2+) metastatic breast cancer (MBC) have been confirmed. We aimed to investigate real-world data of inetetamab in complex clinical practice. Methods: We retrospectively reviewed the medical records of patients who received inetetamab as a salvage treatment at any line setting from July 2020 to June 2022. The main endpoint was progression-free survival (PFS). Results: A total of 64 patients were included in this analysis. The median progression-free survival (mPFS) was 5.6 (4.6-6.6) months. Of the patients, 62.5% received two or more lines of therapy before treatment with inetetamab. The most common chemotherapy and anti-HER2 regimens combined with inetetamab were vinorelbine (60.9%) and pyrotinib (62.5%), respectively. Patients treated with inetetamab plus pyrotinib plus vinorelbine benefited the most (p=0.048), with the mPFS of 9.3 (3.1-15.5) months and an objective response rate of 35.5%. For patients with pyrotinib pretreatment, inetetamab plus vinorelbine plus pyrotinib agents resulted in mPFS of 10.3 (5.2-15.4) months. Regimens (inetetamab plus vinorelbine plus pyrotinib vs. other therapeutic agents) and visceral metastases (yes vs. no) were independent predictors of PFS. Patients with visceral metastases treated with inetetamab plus vinorelbine plus pyrotinib had a mPFS of 6.1(5.1-7.1) months. The toxicity of inetetamab was tolerable, with the most common grade 3/4 adverse event being leukopenia (4.7%). Conclusions: HER2+ MBC patients pretreated with multiple-line therapies still respond to inetetamab-based treatment. Inetetamab combined with vinorelbine and pyrotinib may be the most effective treatment regimen, with a controllable and tolerable safety profile.

Therapeutic strategies to enhance immune response induced by multiple myeloma cells.

Multiple myeloma (MM)as a haematological malignancy is still incurable. In addition to the presence of somatic genetic mutations in myeloma patients, the presence of immunosuppressive microenvironment greatly affects the outcome of treatment. Although the discovery of immunotherapy makes it possible to break the risk of high toxicity and side effects of traditional chemotherapeutic drugs, there are still obstacles of ineffective treatment or disease recurrence. In this review, we discuss therapeutic strategies to further enhance the specific anti-tumor immune response by activating the immunogenicity of MM cells themselves. New ideas for future myeloma therapeutic approaches are provided.

Cellular immunity in the era of modern multiple myeloma therapy.

Multiple myeloma (MM) is a relapsing clonal plasma cell malignancy and incurable thus far. With the increasing understanding of myeloma, highlighting the critical importance of the immune system in the pathogenesis of MM is essential. The immune changes in MM patients after treatment are associated with prognosis. In this review, we summarize currently available MM therapies and discuss how they affect cellular immunity. We find that the modern anti-MM treatments enhance antitumour immune responses. A deeper understanding of the therapeutic activity of individual drugs offers more effective treatment approaches that enhance the beneficial immunomodulatory effects. Furthermore, we show that the immune changes after treatment in MM patients can provide useful prognostic marker. Analysing cellular immune responses offers new perspectives for evaluating clinical data and making comprehensive predictions for applying novel therapies in MM patients.

An overview of pim kinase as a target in multiple myeloma.

Multiple myeloma (MM) is the second common hematologic malignancy manifesting as a clonal proliferation of plasma cells in the bone marrow. In recent years, high expression and activity of pim kinase have been found to be associated with both the progression and prognosis of a significant proportion of malignant diseases. Therefore, pim kinase has become a potential therapeutic target in the treatment of MM and some pim kinase inhibitors have demonstrated good efficacy in clinical trials. Based on nearly the entire literature searched from PubMed in the field of pim kinase in MM, the paper concluded how pim kinase got involved in the proliferation of myeloma cells, the progression of bone disease infiltration, and even in the regulation of the immune microenvironment. Next as a very promising drug, the effectiveness of pim kinase inhibitors as single agents or in combination with other drugs in the treatment of MM was also summarized. Our analysis will guide the clinical use of pim kinase inhibitors for managing tumor load and bone disease in MM patients.

Study on the Effect of EZH2 Inhibitor Combined with TIGIT Monoclonal Antibody against Multiple Myeloma Cells.

EZH2, a member of the polycomb repressive complex 2, induces trimethylation of the downstream gene at the histone three lysine 27 (H3K27me3) position to inhibit tumor cell proliferation. Here, we showed that the apoptosis rate and apoptotic protein expression increased after EZH2 inhibition, whereas key molecules of the NF-κB signaling pathway and the downstream target genes were inhibited. Additionally, the expression of CD155, a TIGIT high-affinity ligand in multiple myeloma (MM) cells, was decreased by the mTOR signaling pathway. Furthermore, the combination of EZH2 inhibitor and TIGIT monoclonal antibody blockade enhanced the anti-tumor effect of natural killer cells. In summary, the EZH2 inhibitor not only plays an anti-tumor role as an epigenetic drug, but also enhances the anti-tumor effect of the TIGIT monoclonal antibody by affecting the TIGIT-CD155 axis between NK cells and MM cells, thus providing new ideas and theoretical basis for the treatment of MM patients.