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Malignant melanoma is a high-grade aggressive skin tumor with an increasing incidence and mortality rates worldwide. Chemotherapeutic drugs such as doxorubicin have limited efficacy against melanoma due to their poor sensitivity, severe side effects, and drug resistance. Recent studies have shown that combinations of immunotherapy and chemotherapy have a synergistic effect in enhancing the anti-tumor effect. Here, we have developed liposomes co-loaded with chlorogenic acid (CA) and doxorubicin (DOX), modified with sialic acid-octadecylamine conjugate (SA-ODA), designated CA-DOX-SAL, that facilitate drug delivery by recognizing Siglec-1 receptor on TAMs. The physicochemical studies revealed the particle size and zeta potential of CA-DOX-SAL as 128.3 ± 0.8 nm and − 4.33 ± 0.50 mV, respectively. In vitro, CA-DOX-SAL demonstrated robust cellular uptake through SA receptor-mediated tumor-associated macrophages (TAM) targeting and exerted greater cytotoxicity on tumor cells. In vivo, targeted liposomes were found to accumulate in the tumor area, leading to an improvement in anti-tumor efficacy. In addition, CA-DOX-SAL effectively inhibited B16F10 melanoma tumor growth by stimulating the transition from tumor-promoting M2-type to anti-tumor M1-type and directly killing tumor cells. Overall, the co-delivery of immunomodulatory CA and chemotherapeutic DOX presents a promising therapeutic strategy to enhance clinical outcomes in the treatment of melanoma. [ABSTRACT FROM AUTHOR]

The current standard therapy of epithelial ovarian cancer (EOC) is the combination of surgery (primary cytoreductive surgery or interval cytoreductive surgery) and platinum-based chemotherapy (mainly using paclitaxel and carboplatin either by neoadjuvant chemotherapy and/or by postoperative adjuvant chemotherapy) with/without adding targeted therapy (mainly using anti-angiogenesis agent- bevacizumab). After front-line chemotherapy, the advanced-stage EOC can be successfully controlled and three-quarters of patients can achieve a complete clinical remission. Unfortunately, nearly all patients will recur and progression-free survival (PFS) of these patients is seldom more than 3 years with a dismal median PFS of 12–18 months. With each recurrence, patients finally develop resistance to standard chemotherapy regimen, contributing to fewer than half of women who survive for more than 5 years after diagnosis with a median overall survival (OS) of 40.7 months. Due to the lower PFS and OS, particularly for those advanced-stage patients, novel therapeutic options during the front-line therapy are desperately needed to decrease the occurrence of recurrence, and the majority of them are still under investigation. It is well-known that overexpression of CA125 has been associated with attenuated cellular apoptosis, platinum chemotherapy resistance, tumor proliferation and disease progression, suggesting that anti-CA125 may play a role in the management of patients with EOC. The current review is a Part I which will focus on development of anti-CA125 monoclonal antibody, hoping that alternation of the front-line therapy by chemo-immunotherapy will be beneficial for prolonged survival of patients with EOC.

Background: Recently, several new first-line immune checkpoint inhibitors (ICIs) plus chemotherapy have been approved for patients with extensive-stage small-cell lung cancer (ES-SCLC). However, direct comparisons between first-line treatments are lacking. Therefore, we indirectly compared the efficacy and safety of specific treatment strategies to inform physicians' and patients' clinical decisions. Methods: The Pubmed, Cochrane, Embase, and Web of Science databases were searched from 1 January 2000 to 27 November 2022, for randomized clinical trials (RCTs) assessing first-line immuno-chemotherapies for ES-SCLC. A fixed-effect multivariable meta-regression model was established for frequentist network meta-analysis and hazard ratios (HRs) with 95% confidence intervals (95% CI) were computed to compare the effects of immuno-chemotherapies on patient overall survival (OS) and progression-free survival (PFS), while risk ratios with 95% CI were used for treatment- and immune-related adverse events (AEs). The p score values were then used to rank treatments based on their odds of being the best treatment option. The research protocol was registered with the PROSPERO (CRD42022383254). Results: Seven studies involving 3822 patients were eligible for analysis. Serplulimab plus chemotherapy had better OS outcomes compared to chemotherapy (HR = 0.63; 95% CI: 0.49–0.82) and ipilimumab plus chemotherapy (HR = 0.67; 95% CI: 0.50–0.90). It additionally exhibited better PFS outcomes compared to chemotherapy (HR = 0.48; 95% CI: 0.39–0.60), adebrelimab (HR = 0.72; 95% CI: 0.53–0.97), atezolizumab (HR = 0.62; 0.46–0.85), durvalumab (HR = 0.60; 95% CI: 0.45–0.80), durvalumab and tremelimumab (HR = 0.57; 95% CI: 0.43–0.76), ipilimumab (HR = 0.57; 95% CI: 0.44–0.73), and pembrolizumab (HR = 0.64; 95% CI: 0.48–0.86) plus chemotherapy. Serplulimab plus chemotherapy was linked to the greatest odds of effectively reducing the odds of death (p score = 0.87) and progression (p score = 0.99) while exhibiting a good safety profile. Conclusion: Serplulimab plus chemotherapy exhibited the best survival outcomes with manageable AEs. Thus, serplulimab plus chemotherapy may represent the optimal best first-line treatment option for ES-SCLC patients. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) is a distinct subtype of B-cell lymphoma and commonly used induction immunochemotherapies include the anti-CD20 antibody rituximab. However, efficacy data for rituximab regarding overall survival (OS) in first line MCL therapy remain conflicting. We report long-term outcomes of a pooled trials analysis comparing Cyclophosphamide, Doxorubicine, Vincristine, Prednisone (CHOP) to R-CHOP in MCL to confirm efficacy on failure free survival (FFS) and OS in relevant subgroups. Untreated, adult MCL patients of two prospective trials assigned to CHOP or R-CHOP were included. Primary endpoints were FFS and OS, secondary endpoints included duration of response (DOR), secondary malignancies and OS after relapse. Between 1996 and 2003, 385 MCL patients were assigned to CHOP (201) or R-CHOP (184). After a median follow-up of 13.4 years, the addition of Rituximab significantly improved FFS (1.36 vs. 2.07 years, HR 0.62 (0.50–0.77)), OS (4.84 vs. 5.81 years, HR 0.78 (0.61–0.99)) and DOR (1.48 vs. 2.08 years, HR 0.67 (0.53–0.86)). Furthermore, Rituximab improved survival across different MCL risk groups. In a post-hoc analysis of OS after relapse comparing patients receiving chemotherapy with / without rituximab, rituximab maintained efficacy with a median OS of 3.10 vs. 2.11 years (HR 0.70, 0.54–0.91). The rate of secondary malignancies was 0.5 and 3.9% for hematological and 7 and 8% for non-hematological malignancies for CHOP and R-CHOP patients, respectively. We present mature results of a pooled MCL cohort, demonstrating prolonged FFS, OS and DOR for the combined immuno-chemotherapy, confirming the standard of care in first line treatment. [ABSTRACT FROM AUTHOR]

Abstract Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal inflammatory clinical condition, in which an exaggerated immune response is ineffectively regulated. Although etoposide-containing regimens are generally recommended for children with HLH, the exact role of etoposide in the adult setting remains unclear. We performed a systematic review of the literature on the use of etoposide in adults with HLH. All articles written in English on the use of etoposide in adults with HLH available from seven databases and published on or before July 2021 were analyzed. Thirteen studies were found to be relevant to the search results. Ten of these studies report a statistical analysis on the effect of etoposide, of which five found etoposide-containing regimens superior to non-etoposide-containing regimens. Seven studies provided sufficient data to be included in the meta-analysis. For these data, the estimated logit relative risk of etoposide on survival was 1.06 (95% confidence interval: 0.92–1.21, standard error: 2.06). The pooled data of the meta-analysis did thus not support a beneficial effect of etoposide. It should be taken into account that the presented results are highly susceptible to bias and that the effect of etoposide differs between HLH-triggers. Although the meta-analysis does not support the effect of etoposide, we do not recommend abandoning etoposide as treatment modality. The limitations of the meta-analysis, together with several individual articles confirming the benefit of etoposide, justify etoposide for select cases in adults with HLH such as refractory or severe disease with (threatening) multiorgan failure.

Purpose: The effect of immuno-chemotherapy on patients with advanced non-small-cell lung cancer (NSCLC) harboring oncogenic mutations remains poorly understood. This study aimed to characterize the efficacy of immuno-chemotherapy and determine the optimal treatment strategy for such patients. Methods: We conducted this retrospective cohort study on patients with NSCLC harboring oncogenic driver alterations and treated with an immune checkpoint inhibitor combined with chemotherapy at five institutions. The clinical characteristics and outcomes of immuno-chemotherapy for NSCLC with oncogenic mutations in a real-world setting were analyzed. Results: Among 846 patients diagnosed with advanced or recurrent NSCLC between April 2017 and April 2021, 43 patients with oncogenic mutations were treated with immuno-chemotherapy. The median age of patients was 68 (range 44–78) years; 42% of patients never smoked, and adenocarcinoma was the most common histology (95%). In patients with KRAS mutations (n = 10) or PD-L1 expression of 50% or greater (n = 10), the disease control rate was 100%. The median progression-free survival (PFS) was 5.4, 6.3, and 8.9 months in patients harboring mutations in EGFR, KRAS, and other genes, respectively (P = 0.22). Patients with PD-L1 expression of 50% or greater had significantly longer median PFS than patients with PD-L1 expression of less than 50% (16.4 vs. 5.1 months; P = 0.001). Two patients experienced grade 3 immuno-related adverse events. Conclusion: Immuno-chemotherapy has a clinical benefit and is safe for patients with oncogenic mutations. Notably, patients with PD-L1 expression of 50% or more experience greater benefit from immuno-chemotherapy than those with PD-L1 expression of less than 50%. [ABSTRACT FROM AUTHOR]

Abstract Background The application of combination therapy for cancer treatment is limited due to poor tumor-specific drug delivery and the abscopal effect. Methods Here, PD-L1- and CD44-responsive multifunctional nanoparticles were developed using a polymer complex of polyethyleneimine and oleic acid (PEI-OA) and loaded with two chemotherapeutic drugs (paclitaxel and chloroquine), an antigen (ovalbumin), an immunopotentiator (CpG), and an immune checkpoint inhibitor (anti-PD-L1 antibody). Results PEI-OA greatly improved the drug loading capacity and encapsulation efficiency of the nanoplatform, while the anti-PD-L1 antibody significantly increased its cellular uptake compared to other treatment formulations. Pharmacodynamic experiments confirmed that the anti-PD-L1 antibody can strongly inhibit primary breast cancer and increase levels of CD4+ and CD8+ T cell at the tumor site. In addition, chloroquine reversed the “immune-cold” environment and improved the anti-tumor effect of both chemotherapeutics and immune checkpoint inhibitors, while it induced strong immune memory and prevented lung metastasis. Conclusions Our strategy serves as a promising approach to the rational design of nanodelivery systems for simultaneous active targeting, autophagy inhibition, and chemotherapy that can be combined with immune-checkpoint inhibitors for enhanced breast cancer treatment.

IntroductionMany randomized controlled trials have indicated that immuno-chemotherapy could generate clinical benefits, though the cost of immuno-chemotherapy was so prohibitive and the options were varied. This investigation aimed at evaluating effectiveness, safety, and cost-effectiveness for immuno-chemotherapy as a first-line therapeutic option for ES-SCLC patients.MethodsMultiple scientific literature repositories were searched for clinical studies where immuno-chemotherapy was regarded as the first-line treatment for ES-SCLC, which were published in English between Jan 1, 2000, and Nov 30, 2021. This study conducted a network meta-analysis (NMA) and cost-effectiveness analysis (CEA) based upon US-resident payer perspectives. Overall survival (OS), progression-free survival (PFS), and adverse events (AEs) were evaluated through NMA. In addition, costings, life-years (LYs), quality-adjusted life-years (QALYs), and incremental cost–benefit ratio (ICER) were estimated by CEA.ResultsWe identified 200 relevant search records, of which four randomized controlled trials (RCTs) (2,793 patients) were included. NMA demonstrated that the effect of atezolizumab plus chemotherapy was ranked at a more elevated position in comparison to other immuno-chemotherapy options and chemotherapy alone, within the general population. The influence of atezolizumab plus chemotherapy and durvalumab plus chemotherapy was ranked higher within populations experiencing non-brain metastases (NBMs) andbrain metastases (BMs), respectively. The CEA revealed that the ICERs of immuno-chemotherapy over chemotherapyalone were higher than the willingness-to-pay (WTP) threshold of $150,000/QALY in any population. However, treatment with atezolizumab plus chemotherapy and durvalumab plus chemotherapy were more favorable health advantages than other immuno-chemotherapy regimens and chemotherapy alone, and the results were 1.02 QALYs and 0.89 QALYs within overall populations and populations with BMs, respectively.ConclusionThe NMA and cost-effectiveness investigation demonstrated that atezolizumab plus chemotherapy could be an optimal first-line therapeutic option for ES-SCLC when compared with other immuno-chemotherapy regimens. Durvalumab plus chemotherapy is likely to be the most favorable first-line therapeutic option for ES-SCLC with BMs.

Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal inflammatory clinical condition, in which an exaggerated immune response is ineffectively regulated. Although etoposide-containing regimens are generally recommended for children with HLH, the exact role of etoposide in the adult setting remains unclear. We performed a systematic review of the literature on the use of etoposide in adults with HLH. All articles written in English on the use of etoposide in adults with HLH available from seven databases and published on or before July 2021 were analyzed. Thirteen studies were found to be relevant to the search results. Ten of these studies report a statistical analysis on the effect of etoposide, of which five found etoposide-containing regimens superior to non-etoposide-containing regimens. Seven studies provided sufficient data to be included in the meta-analysis. For these data, the estimated logit relative risk of etoposide on survival was 1.06 (95% confidence interval: 0.92–1.21, standard error: 2.06). The pooled data of the meta-analysis did thus not support a beneficial effect of etoposide. It should be taken into account that the presented results are highly susceptible to bias and that the effect of etoposide differs between HLH-triggers. Although the meta-analysis does not support the effect of etoposide, we do not recommend abandoning etoposide as treatment modality. The limitations of the meta-analysis, together with several individual articles confirming the benefit of etoposide, justify etoposide for select cases in adults with HLH such as refractory or severe disease with (threatening) multiorgan failure. [ABSTRACT FROM AUTHOR]

Paclitaxel (PTX) is a first-line chemotherapeutic drug for non-small cell lung cancer (NSCLC) but it can induce indoleamine 2,3-dioxygenase (IDO) activation, which severely lowers down its immuno-chemotherapeutic effect. To address this issue, a smart peptide hydrogelator Nap-Phe-Phe-Phe-Lys-Ser-Thr-Gly-Gly-Lys-Ala-Pro-Arg-OH (Nap-T), which co-assembles with PTX and an IDO inhibitor GDC0919 to form a hydrogel GP@Gel Nap-T, is rationally designed. Upon specific phosphorylation by pyruvate kinase M2 (PKM2), an overexpressed biomarker of NSCLC, Nap-T is gradually converted to Nap-Phe-Phe-Phe-Lys-Ser-Thr(H 2 PO 3 )-Gly-Gly-Lys-Ala-Pro-Arg-OH (Nap-Tp), leading to dehydrogelation and sustained release of PTX and GDC0919 within NSCLC tissues. The released PTX exerts chemotherapy on NSCLC cells as well as immunogenic cell death induction, while GDC0919 promotes the immuno-chemotherapeutic effect of PTX through IDO inhibition. We find that GP@Gel Nap-T enhances the infiltration of tumor-infiltrating immune cells and reduces the number of immunosuppressive cells in either tumor tissues or tumor-draining lymph nodes, thus enhancing the immuno-chemotherapy of PTX toward NSCLC. With this PKM2-responsive drug release strategy, the smart peptide hydrogel platform might be applied for NSCLC treatment in clinic in near future., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Background: Combined Immuno-chemotherapy consisting of gemcitabine, cisplatin and the programmed death-ligand one inhibitor durvalumab (GCD) is the new standard of care for patients with biliary tract cancers (BTC) based on positive results of the TOPAZ-1 study., Objective: We here evaluated the efficacy and safety of GCD for BTC in a German multicenter real-world patient cohort., Methods: Patients with BTC treated with GCD from 9 German centers were included. Clinicopathological baseline parameters, overall survival (OS), response rate and adverse events (AEs) were retrospectively analyzed. The prognostic impact was determined by Kaplan-Meier analyses and Cox regression models., Results: A total of 165 patients treated with GCD between 2021 and 2024 were included in the study. Median OS and median progression-free survival were 14 months (95% CI 10.3-17.7) and 8 months (95% CI 6.8-9.2), respectively. The best overall response rate was 28.5% and disease control rate was 65.5%. While extrahepatic and intrahepatic BTC showed similar outcomes, mOS was significantly shorter in patients with gall bladder cancer (GB-CA) with 9 months (95% CI 5.5-12.4; p = 0.02). In univariate analyses age ≥70 years, Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥1, status post cholecystectomy, GB-CA and high baseline CRP values were significantly associated with OS. ECOG PS ≥ 1 and GB-CA remained independent prognostic factors for OS in multivariable cox regression analysis. AEs have been reported in 130 patients (78.8%), including 149 grade 3-4 AEs (25.5%). One patient died of severe infectious pneumonia. Immune-related (ir)AEs occurred in 17 patients (10.3%), including 9 grade 3-4 irAEs (2.2%), which led to treatment interruption in 4 patients., Conclusions: Immuno-chemotherapy in patients with BTC was feasible, effective and safe in a real-life scenario. Our results were comparable to the phase 3 clinical trial results (TOPAZ-1). Reduced efficacy was noted in patients with GB-CA and/or a reduced performance status that warrants further investigation., (© 2024 The Author(s). United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Background: The application of combination therapy for cancer treatment is limited due to poor tumor-specific drug delivery and the abscopal effect.Methods: Here, PD-L1- and CD44-responsive multifunctional nanoparticles were developed using a polymer complex of polyethyleneimine and oleic acid (PEI-OA) and loaded with two chemotherapeutic drugs (paclitaxel and chloroquine), an antigen (ovalbumin), an immunopotentiator (CpG), and an immune checkpoint inhibitor (anti-PD-L1 antibody).Results: PEI-OA greatly improved the drug loading capacity and encapsulation efficiency of the nanoplatform, while the anti-PD-L1 antibody significantly increased its cellular uptake compared to other treatment formulations. Pharmacodynamic experiments confirmed that the anti-PD-L1 antibody can strongly inhibit primary breast cancer and increase levels of CD4+ and CD8+ T cell at the tumor site. In addition, chloroquine reversed the "immune-cold" environment and improved the anti-tumor effect of both chemotherapeutics and immune checkpoint inhibitors, while it induced strong immune memory and prevented lung metastasis.Conclusions: Our strategy serves as a promising approach to the rational design of nanodelivery systems for simultaneous active targeting, autophagy inhibition, and chemotherapy that can be combined with immune-checkpoint inhibitors for enhanced breast cancer treatment. [ABSTRACT FROM AUTHOR]

BackgroundStage III Non-small cell lung cancer (NSCLC) is a heterogenous disease with novel treatment options. Recently, immunotherapy has attracted a lot of attention for advanced NSCLC.ObjectiveThe objective of our study was to assess the efficacy and safety of neoadjuvant immuno-chemotherapy for resectable stage III NSCLC.MethodsWe analyzed 11 stage III primary NSCLC surgical cases who had undergone standard lobectomy or bronchial sleeve resection and lymph node dissection between December 2020 and July 2021. The data analyzed included basic clinical features, serum levels of key biomarkers, clinical efficacy in the perioperative period, postoperative pathological results, postoperative complications and the incidence rates of Immune-Related Adverse Events.ResultsEleven patients were enrolled in our study with a mean age of 67.7 ± 4.8 years, and 10 patients being men with former or current smoking history. Squamous carcinoma (10/11, 91.1%) was the most common cancer type. Six patients had stage IIIa, five had stage IIIb. All patients received two or three cycles of neoadjuvant immuno-chemotherapy, with the median duration between the last treatment and surgery being 39 days (range, 32–46 days). All patients underwent R0 resection with ten patients undergoing single-port video-assisted thoracoscopic surgery. The median operative time was 170 min (range, 120–240 min). Only three (3/11, 27.3%) patients experienced mild postoperative complications and the mean hospital stay time was 6.9 days (range, 4–15 days). Nine (9/11, 81.8%) patients experienced major pathological response of which seven (7/11, 63.6%) was complete pathological response in postoperative results. The pathological stage was downgraded in 10 (10/11, 91.1%) patients, and although the incidence of Immune-Related Adverse Events was slightly higher (8/11, 72.7%), most events were grade 1–2 and did not delay surgery.ConclusionOur study demonstrated that neoadjuvant immuno-chemotherapy is feasible and relatively safe for resectable stage III primary NSCLC patients. We hope this new neoadjuvant immuno-chemotherapy model can improve overall survival and open a new era for stage III primary NSCLC patients.

Mantle cell lymphoma has a dismal prognosis at relapse or in the refractory setting. Among therapies, mTor pathway targeting by temsirolimus has been the first strategy approved for relapse in Europe. While its efficacy in monotherapy has long been demonstrated, its use remains limited. In the T3 phase Ib clinical trial, we investigated the recommended dose of temsirolimus in association with R-CHOP (R-CHOP-T), or high-dose cytarabine plus rituximab (R-DHA-T), or fludarabine, cyclophosphamide plus rituximab (R-FC-T). From November 11, 2011 to February 26, 2015, forty-one patients were enrolled. Patients presented with high MIPI (47.5%) at relapse and a median number of treatments of 1 (1-3). Patients were treated by R-CHOP-T (n = 10), R-FC-T (n = 14), or R-DHA-T (n = 17) according to the choice of local investigators. The maximum tolerated dose (MTD) was 15 mg in the R-CHOP-T arm and has not been determined in other treatment arms because of toxicities. All patients experienced ≥ Grade 3 adverse events, mainly thrombocytopenia (76%). Twenty-six patients discontinued prematurely the treatment, mostly for toxicity (n = 12) and progression of the disease (n = 8). Of note, 6 patients of the R-DHA-T arm reached complete remission (35%). Temsirolimus with immuno-chemotherapy is associated with a high rate of toxicities. Determination of MTD could only be achieved for R-CHOP-T arm. Associations between temsirolimus and other targeted therapies may be warranted for R/R MCL patients. [ABSTRACT FROM AUTHOR]

Abstract Herein, we study an optimal control problem of delay differential model to describe the dynamics of tumour-immune interactions in presence of immuno-chemotherapy. The model includes constant delays in the mitotic phase to justify the time required to stimulate the effector cells and for the effector cells to develop a suitable response to the tumour cells. By applying optimal control theory, we seek to minimize the cost associated with the immuno-chemotherapy and to reduce load of of tumour cells. Non-Negativity of the solutions of the model and existence of an optimal control has also been proven. Optimality conditions and characterization of the control are also discussed. We numerically approximate the solution of the optimal control problem by solving the state system forward and adjoint system backward in time. The numerical simulations show that the combination of immuno-chemotherapy protocol reduces the tumour load in few months of therapy. [ABSTRACT FROM AUTHOR]

Tryptophan 2,3-dioxygenase (TDO), an immunosuppressive enzyme, can involve in immune evasion and tumor tolerance. TDO inhibitors can boost the efficacy of chemotherapeutics by promoting immunity. Herein, a strategy to introduce a TDO inhibitor into Pt(IV) complexes for reversing tumor immune suppression was adopted. A mono-modified Pt(IV) complex, 3, displayed significant antitumor activity against human liver cancer cells. Flow cytometry study revealed that complex 3 could induce cell death via a mitochondrial-dependent apoptosis pathway and arrest the cell cycle at S phase. Furthermore, complex 3 was effective to enhance T-cell immune responses by inhibiting the TDO enzyme expression to block the kynurenine production and inactivating the downstream of aryl hydrocarbon receptor (AHR). A Pt(IV) hybrid containing a tryptophan 2,3-dioxygenase (TDO) inhibitor could enhance antitumor immune response by inhibiting the TDO enzyme expression to block the kynurenine production and induce HepG-2 cancer cell apoptosis via DNA damage through releasing the TDO inhibitor and cisplatin under reduction. Unlabelled Image • Novel Pt(IV) hybrids with a TDO (tryptophan dioxygenase) inhibitor were described. • In vitro anticancer screening for the targeted hybrids was made. • Complex 3 displayed significant antitumor activity against HepG-2 cancer cells. • Complex 3 could inhibit the TDO expression to block the kynurenine production. • Complex 3 was effective to enhance T-cell immune responses. [ABSTRACT FROM AUTHOR]

Exploding interest in immunometabolism as a source of new cancer therapeutics has been driven in large part by studies of tryptophan catabolism mediated by IDO/TDO enzymes. A chief focus in the field is IDO1, a pro-inflammatory modifier that is widely overexpressed in cancers where it blunts immunosurveillance and enables neovascularization and metastasis. The simple racemic compound 1-methyl-D,L-tryptophan (1MT) is an extensively used probe of IDO/TDO pathways that exerts a variety of complex inhibitory effects. The L isomer of 1MT is a weak substrate for IDO1 and is ascribed the weak inhibitory activity of the racemate on the enzyme. In contrast, the D isomer neither binds nor inhibits the purified IDO1 enzyme. However, clinical development focused on D-1MT (now termed indoximod) due to preclinical cues of its greater anticancer activity and its distinct mechanisms of action. In contrast to direct enzymatic inhibitors of IDO1, indoximod acts downstream of IDO1 to stimulate mTORC1, a convergent effector signaling molecule for all IDO/TDO enzymes, thus possibly lowering risks of drug resistance by IDO1 bypass. In this review, we survey the unique biological and mechanistic features of indoximod as an IDO/TDO pathway inhibitor, including recent clinical findings of its ability to safely enhance various types of cancer therapy, including chemotherapy, chemo-radiotherapy, vaccines, and immune checkpoint therapy. We also review the potential advantages indoximod offers compared to selective IDO1-specific blockade, which preclinical studies and the clinical study ECHO-301 suggest may be bypassed readily by tumors. Indoximod lies at a leading edge of broad-spectrum immunometabolic agents that may act to improve responses to many anticancer modalities, in a manner analogous to vaccine adjuvants that act to boost immunity in settings of infectious disease.

Soft tissue mucosa-associated lymphoid tissue (MALT) lymphoma is a rare type of marginal zone lymphoma. Herein, we report a case of a 61-year-old patient who developed soft-tissue marginal zone lymphoma in the right arm. He was treated with rituximab-chlorambucil with good metabolic response and no evidence of disease recurrence after one year of follow-up., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Hammani et al.)

Exploding interest in immunometabolism as a source of new cancer therapeutics has been driven in large part by studies of tryptophan catabolism mediated by IDO/TDO enzymes. A chief focus in the field is IDO1, a pro-inflammatory modifier that is widely overexpressed in cancers where it blunts immunosurveillance and enables neovascularization and metastasis. The simple racemic compound 1-methyl-D,L-tryptophan (1MT) is an extensively used probe of IDO/TDO pathways that exerts a variety of complex inhibitory effects. The L isomer of 1MT is a weak substrate for IDO1 and is ascribed the weak inhibitory activity of the racemate on the enzyme. In contrast, the D isomer neither binds nor inhibits the purified IDO1 enzyme. However, clinical development focused on D-1MT (now termed indoximod) due to preclinical cues of its greater anticancer activity and its distinct mechanisms of action. In contrast to direct enzymatic inhibitors of IDO1, indoximod acts downstream of IDO1 to stimulate mTORC1, a convergent effector signaling molecule for all IDO/TDO enzymes, thus possibly lowering risks of drug resistance by IDO1 bypass. In this review, we survey the unique biological and mechanistic features of indoximod as an IDO/TDO pathway inhibitor, including recent clinical findings of its ability to safely enhance various types of cancer therapy, including chemotherapy, chemo-radiotherapy, vaccines, and immune checkpoint therapy. We also review the potential advantages indoximod offers compared to selective IDO1-specific blockade, which preclinical studies and the clinical study ECHO-301 suggest may be bypassed readily by tumors. Indoximod lies at a leading edge of broad-spectrum immunometabolic agents that may act to improve responses to many anticancer modalities, in a manner analogous to vaccine adjuvants that act to boost immunity in settings of infectious disease. [ABSTRACT FROM AUTHOR]

Severe combined immunodeficiency (SCID) is a rare condition with very high mortality. SCID is mainly caused by the multiple mutations of genes affecting the entire immune cells. Children with this disease are born with an impaired immune system. The child appears healthy but the consequences of the impaired immune system lead to various secondary infections such as meningeal infections and respiratory infections further leading to consolidation, diarrhea, inflammation of skin and other systemic diseases. Severe combined immunodeficiency is also known as "bubble boy disease" or "living in the bubble" syndrome, as in early days for treatment the physicians decided to completely isolate them until they got the perfect match for the bone marrow transplantation. It is one of the pediatric emergencies and is to be treated as soon as possible. SCID involves multiple genes which leads to makes diagnosis of the disease cumbersome. In early years many infants were diagnosed almost after half a year and in severe conditions which led to the decrease in the survival rate of the children. But now due to advanced newborn screening modalities and other monitoring systems it can be diagnosed as early as within three months of age. The various treatment modalities include hematopoietic stem cell transplantation, gene therapy, enzyme replacement therapy and chemotherapy. This narrative review article describes about the severe combined immunodeficiency and its newer treatment modalities., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Wadbudhe et al.)

The last 5 to 10 years have been marked by considerable advances in both our understanding of the biology and treatment of chronic lymphocytic leukaemia ( CLL). Fludarabine-based immuno-chemotherapy is the current standard of care for first line therapy in younger fit patients and although this can be highly effective its use in older co-morbid patients is limited by toxicity, and the prognosis for patients with high risk or fludarabine-refractory disease is poor. The introduction of new antibodies has however, facilitated the use of immuno-chemotherapy in co-morbid patients. Beyond this, the recognition that CLL cells are critically dependent on B-cell receptor ( BCR) signalling and interactions with the cellular micro-environment for proliferation and survival has led to the investigation of BCR inhibitors in CLL treatment. These have been shown to be highly effective although a number of questions remain about how they should be optimally used in clinical practice. [ABSTRACT FROM AUTHOR]

The management of B-cell malignancies continues to pose a clinical challenge. In the past years, rituximab (anti-CD20) emerged as the standard of care in the induction treatment of follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), and mantle cell lymphoma (MCL), as well as in other subsets. Since the benefits of immuno-chemotherapy have been clearly demonstrated in a whole range of lymphomas, several innovative approaches are being explored to achieve significant responses, particularly in refractory B-cell non-Hodgkin lymphoma (NHL) cases. Studies of the comparative effectiveness and structure/function relationship of therapeutic monoclonal antibodies, together with an increased understanding of the molecular features of NHLs, have led to the development of a range of novel therapies, many of which target the tumor in a tailored fashion. Although several molecules can help clinicians to dissect the pathological mechanisms acting in the natural history of the disease, the main purpose of this review emphasize the recent developments in targeting the B-cell NHLs surface. These novel approaches are illustrated, and the new intriguing opportunities offered by bispecific antibodies and antibody-associated immune modulation are addressed. [ABSTRACT FROM AUTHOR]

There is compelling evidence suggesting that the immune-modulating effects of many conventional chemotherapeutics, including platinum-based agents, play a crucial role in achieving clinical response. One way in which chemotherapeutics can engage a tumor-specific immune response is by triggering an immunogenic mode of tumor cell death (ICD), which then acts as an 'anticancer vaccine'. In spite of being a mainstay of chemotherapy, there has not been a systematic attempt to screen both existing and upcoming Pt agents for their ICD ability. A library of chemotherapeutically active Pt agents was evaluated in an in vitro phagocytosis assay, and no correlation between cytotoxicity and phagocytosis was observed. A PtII N-heterocyclic carbene complex was found to display the characteristic hallmarks of a type II ICD inducer, namely focused oxidative endoplasmic reticulum (ER) stress, calreticulin exposure, and both HMGB1 and ATP release, and thus identified as the first small-molecule immuno-chemotherapeutic agent. [ABSTRACT FROM AUTHOR]

Abstract: In order to develop immuno- and chemotherapy agents, self-organized acetylated fucoidan (AcFu) nanoparticles were designed. Doxorubicin (DOX), used as a model drug, was loaded into the AcFu nanoparticles by dialysis. The DOX loading efficacy and content were 71.1% and 3.6%, respectively. Approximately 140nm of spherical nanoparticles were obtained. DOX-loaded AcFu nanoparticles (DOX–AcFu) exhibited first-order drug release behavior for 5 days. Interestingly, AcFu treated Raw264.7 macrophages overexpressed various anti-tumor cytokines, such as tumor necrosis factor-alpha (TNF-α) and granulocyte-macrophage colony-stimulating factor (GM-CSF). The ability of DOX–AcFu to suppress drug efflux was revealed by confocal microscope images and FACS analysis in multidrug resistance (MDR) cells. IC50 (50% inhibitory concentration) value of DOX–AcFu was lower than that of free DOX in the MDR model cells. Based on these results, we strongly suggest that AcFu nanoparticles have a promising potential for development as a one-step therapy containing agents for both immuno- and chemotherapy. [Copyright &y& Elsevier]

Oral mucositis is a painful inflammatory response that can lead to infection, cachexia, and therapy termination. This immune-related adverse event (IRAE) has been well documented within the newly developing field of immunotherapy. This case series presents three patients, aged 73 to 81 years, who were undergoing treatment with programmed death-1 (PD-1) immunotherapy for cancer; each patient developed grade III mucositis, one after the fourth cycle and two after the seventh. All three patients had no prior history of oral pathology, yet each patient reported ulcerated and inflamed oral mucosa that was swollen and painful. These lesions involved various locations within the oral cavity and caused irritation to the point of dysphagia and odynophagia. Conservative treatments such as oral anesthetic and mouthwashes with antimicrobial properties had minimal effects. Each patient thereafter was started on systemic glucocorticoids in addition to the local treatments. The initiation of a systemic treatment resulted in a resolution of the oral lesions allowing each patient the option to return to their prior immunotherapy. Mucositis is uncommon and has no standardized treatment. This case series emphasizes the debilitative result of immunotherapy-induced mucositis and illustrates the need for systemic glucocorticoids. While conservative treatments such as oral mouthwashes can be effective in treating the symptoms of mucositis, the initiation of high-dose steroids with a prolonged taper has been shown to treat the condition at its source. Early recognition of mucositis with prompt initiation of steroids has proven to be the effective mainstay treatment to relieve mucositis while limiting pauses in cancer treatment., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Foster et al.)

Background: Immuno-cell therapy using activated lymphocytes (ALs) and/or dendritic cells (DCs) is considered one of the less toxic supportive therapies compared with conventional chemotherapy and radiotherapy, especially for the treatment for advanced cancers. To improve the efficacy of immuno-cell therapy for such cancer, clinical data were analyzed in this preliminary study. Patients and methods: The clinical data of 38 consecutive patients with advanced cancer who underwent at least one course of treatment with ALs and/or matured DCs, with or without antecedent surgery or additional conventional chemotherapy and/or radiotherapy, were evaluated. Results: Of the 23 patients who received surgery before immuno-cell therapy, 2 (8.7%) showed a complete response (CR) and 15 (65%) showed a partial response (PR) or prolonged stable disease (SD). Of the 15 remaining patients who did not undergo antecedent surgery, there was no CR but 7 (46%) showed PR or prolonged SD. Actuarial survival is one of the important indices for the evaluation of anticancer therapies that present longer durable efficacy of immunotherapy compared with conventional anticancer chemotherapy and radiotherapy, and actuarial survival analysis revealed that immuno-cell therapy with antecedent surgery afforded significantly longer survival than immuno-cell therapy without antecedent surgery ( P < 0.001). Conclusion: Antecedent surgical resection of tumors is advisable for obtaining better efficacy of immuno-cell therapy, even in advanced cancer patients. [ABSTRACT FROM AUTHOR]

[Display omitted] • Separable microneedles provide patient-friendly administration in cancer treatment. • IPN hydrogel-based microneedles offer mechanical strength and drug control release. • Transdermal delivery of LPS and DOX enhanced efficiency in decreasing tumor mass. • LPS and DOX increase the immune activation response and activated T and B cells. An efficient and patient-friendly process for administering immunochemotherapy is achieved through microneedle (MN)-mediated drug delivery into the dermal interstitium across the stratum corneum. Herein, we designed an interpenetrating polymer network (IPN) hydrogel to fabricate separable MNs for transdermal codelivery of lipopolysaccharide (LPS) and doxorubicin (DOX) for a synergistic immunochemotherapeutic outcome. The MN arrays were fabricated from IPN hydrogel which was prepared via sequential photoionic crosslinking of sodium alginate and sulfobetaine methacrylate using N, N'- methylenebisacrylamide and Ca2+ ion for chemical and ionic crosslinking, respectively. Tensile and compression tests revealed that the mechanical strength of the IPN hydrogel increased significantly and the MN array enabled skin penetration. The separable backbone of the MNs was prepared using a disulfide-crosslinked IPN hydrogel that was easily removed by disulfide bond cleavage with 1,4-dithiothreitol and ethylenediaminetetraacetic acid solution, whereas the dual drug-loaded MN patch was left in the skin to allow steady drug release. In vitro drug release tests demonstrated that the MN array allowed the timely release of drugs due to the hydrogel's rapid degradation. The IC 50 value of DOX@MNs (1.088 µg/ml) against the CT-2A-Luc cell line indicated that the drug loaded onto the MNs was more than sufficient to kill cancer cells. Moreover, in vivo tumor suppression experiment on glioma-bearing C57BL/6 mice confirmed that the dual drug-loaded MNs (LPS/DOX@MNs) led to excellent upregulation of immune response and tumor inhibition, signifying its synergistic immunochemotherapeutic effects. Thus, the concept of MN-mediated combined immunochemotherapy provides localized sustained delivery and is a promising new treatment method for obtaining efficient synergistic therapeutic values. [ABSTRACT FROM AUTHOR]

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We report a case of localized sarcomesothelioma detected during screening via a low-dose CT (LDCT) scan. The patient is a 71-year-old female, a current 56-pack-year cigarette smoker with a past medical history of myocardial infarction and stroke with a Zubrod score of zero. A screening LDCT revealed a 1.9 cm × 1.8 cm × 1.4 cm right lower lobe lesion with smooth margins and close association with the hemidiaphragm. A wedge resection with biopsy showed high-grade sarcomatoid mesothelioma with extensive desmoplastic morphology and negative margins. The patient opted for imaging surveillance, and at 12 months has shown no evidence of tumor recurrence on positron emission tomography (PET)/CT. The case shows that LDCT screening discovers cancers and saves lives. It also presented a dilemma for the patient and her oncologist because common guidelines do not define a recommended treatment., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Choudhury et al.)

Ovarian cancer is the second most common gynecologic cancer after uterine cancer in the United States. Ovarian cancer ranks sixth in cancer deaths among women, accounting for more deaths than other female reproductive system cancers. Breast metastasis in ovarian cancer is a rare presentation and predicts a poor prognosis and challenging management. Our case is a 42-year-old Chinese woman with high-grade serous ovarian carcinoma that presents with metastasis to the breast during the course of her illness. Genetic evaluation of the ovarian tumor showed two BRCA1 pathogenic variants. Germline pathogenic variant of c.2110&#95;2111DelAA and a somatic variant of c.4071&#95;4096+14del40. Our patient was offered different treatment regimens but showed progression of her disease. The low survival rate and high recurrence rate in ovarian cancer show that we still need to investigate our current approved treatments. Our report aims to shed light on the genetic evaluation of ovarian tumors and treatment options available in refractory cases of progressive ovarian cancer. Furthermore, we explain our investigational therapy regimen and the reasoning behind it., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Kowsarnia et al.)

We evaluated the combination of rituximab with chlorambucil in patients with mantle cell lymphoma (MCL) not eligible for aggressive therapy. Fourteen patients (male/female: 9/5) were included (two newly diagnosed, 12 relapsed/refractory). The toxicities were neutropenia, thrombopenia and infection. Nine (64%) patients responded; five (36%) achieved complete remission and four (29%) achieved partial remission. The median progression-free survival for responders was 26 months (95% CI, 4–48). Marrow polymerase chain reaction negativity was attained in seven responders. These results suggest that this schedule may have notable antitumour activity in patients with MCL, including patients in relapse after autologous stem cell transplantation. [ABSTRACT FROM AUTHOR]