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Targeted therapies, such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), have revolutionized the treatment landscape for EGFR-mutant non-small cell lung cancer (NSCLC). However, the emergence of resistance to EGFR TKIs especially the third generation TKIs such as osimertinib remains a major clinical challenge. As a broader strategy for combating resistance, several clinical trials have explored the efficacy of immune checkpoint inhibitors (ICIs)+chemotherapy in EGFR-mutated NSCLC. Until now, the ORIENT-31 and IMpower150 trials suggested that ICIs+ chemotherapy may be more effective than chemotherapy alone after failure of EGFR-TKIs (although ORIENT-31 was negative for overall survival [OS] and IMpower150 was a subset analysis, so the study was not powered to detect a difference); however, the CheckMate-722 trial yielded disappointing results. Thus, the results of this global trial KEYNOTE-789 were highly anticipated.

Background: Osimertinib is approved as a standard treatment for non‐small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation by FDA. However, the mechanisms of resistance for nearly half of patients after osimertinib progression are still unknown, and the optimal therapies for these patients are still controversial. In this retrospective study, we compared efficacy and safety between immunotherapy + chemotherapy, chemotherapy alone, and osimertinib + bevacizumab in NSCLC patients after osimertinib progression with unknown resistance mechanisms. Methods: Advanced NSCLC patients with unknown resistance mechanisms after osimertinib progression were retrospectively reviewed and divided into immunotherapy + chemotherapy, chemotherapy alone, and osimertinib + bevacizumab treatment groups according to the treatment they received after osimertinib progression. Clinicopathological features, objective response rate (ORR), progression‐free survival (PFS), and overall survival (OS) were compared between groups. Results: A total of 121 patients were enrolled in this study, 22 in the immunotherapy + chemotherapy group, 72 in the chemotherapy group, and 27 in the osimertinib + bevacizumab group. The ORR was much higher in the immunotherapy + chemotherapy group compared with chemotherapy or osimertinib + bevacizumab group (55.56% vs. 14.81% vs. 0% in patients after progression on 1st line osimertinib treatment; 30.77% vs. 6.67% vs. 13.33% in patients after progression on 2nd/3rd line osimertinib treatment). Median PFS was also significantly longer in the immunotherapy + chemotherapy group compared with other groups (8.2 months vs. 4.0 months vs. 6.0 months in all patients, p = 0.0066). The median OS did not reach remarkable difference among groups, although osimertinib + bevacizumab group had a numerically longer median OS (37.0 months vs. 37.0 months vs. 47.6 months in all patients, p = 0.6357). Compared with immunotherapy + chemotherapy and chemotherapy, treatment‐related adverse events (AEs) of osimertinib + bevacizumab were milder, especially in AEs related to gastrointestinal and bone marrow suppression. Conclusion: Our study provides clinical evidence that NSCLC patients after osimertinib progression with unknown resistance mechanisms may benefit from immunotherapy + chemotherapy, with higher ORR and longer PFS compared with osimertinib + bevacizumab or chemotherapy groups. Osimertinib + bevacizumab treatment was also an optional option for patients because OS was numerically longer and safer in this group. [ABSTRACT FROM AUTHOR]

Background: Granulocyte colony-stimulating factor (G-CSF) has the potential to attenuate the anti-tumor immune responses of T-cells by increasing immune suppressive neutrophils and myeloid-derived suppressor cells. However, the clinical impact of G-CSF on the efficacy of immunotherapy remains unknown. This multi-center retrospective analysis evaluated the impact of G-CSF in patients with extensive-stage small-cell lung cancer (ES-SCLC) treated with chemo-immunotherapy. Methods: We analyzed 65 patients with ES-SCLC who completed four cycles of induction chemo-immunotherapy and evaluated the effects of G-CSF on progression-free survival (PFS), overall survival (OS), and a durable response to immunotherapy (defined as PFS ≥ 12 months). Results: Fifty patients (76.9%) received ≥ 1 dose of G-CSF. The PFS of the patients with G-CSF was poorer than that of the patients without G-CSF (median PFS 8.3 vs. 4.9 months, p = 0.009). The OS of the patients with G-CSF tended to be shorter, but not statistically significant, than that of the patients without G-CSF (median OS 24.3 vs. 16.4 months, p = 0.137). In the multivariate analysis, G-CSF administration was associated with poorer PFS (hazard ratio 2.78, 95% CI 1.36–5.69, p = 0.005) and was identified as a determinant of a durable response (odds ratio 0.18, 95% CI 0.04–0.80, p = 0.024). These results were consistent with other definitions of G-CSF administration (administration of ≥ 1 dose of pegfilgrastim, or either ≥ 5 doses of filgrastim or ≥ 1 dose of pegfilgrastim). Conclusions: G-CSF has the potential to attenuate the efficacy of immunotherapy; therefore, the indication for G-CSF during chemo-immunotherapy should be carefully considered for ES-SCLC. [ABSTRACT FROM AUTHOR]

Solid cancer remains a serious threat to global health despite decades of progress. Traditional chemotherapy treatment has been used to curb the disease despite its inability to reach cancer cells at high enough quantities leading to adverse toxicity on healthy cells, producing severe side effects, and exacerbating patient suffering. Active targeted nano-drugs (ATNDs) acting as transporter systems have become a viable solution to this shortcoming, offering the possibility of more precise cancer targeting. Therefore, in the present study, we develop a numerical model of capturing ATNDs, incorporating movements within and outside the tumor spheroid and the magnetic forces guiding the nanoparticles. By combining a model of ATNDs transport with a tumor-effector dynamic model based on porous media phenomena, we demonstrate how the models may be combined to model drug-loaded nanoparticle transport in an external magnetic field. We analyze the controlled drug delivery against traditional chemotherapy based on the combined effect of immunotherapy and chemotherapy with the dispersion of nano-drugs to lead a solute cloud toward the tumor. We found that the amalgamation of immune and chemotherapy delivered by ATNDs enhances cancer therapy efficacy compared with conventional chemotherapy. Increased drug convection toward the tumor region presented by ascending values of the Peclet number inhibits the growth of tumor cells and prolongs progression-free survival. Increases in source term and vessel permeability also increase the likelihood of tumor suppression, while raising the hematocrit and magnetic number results in reduced tumor cell killing. Sensitivity analysis of the dynamic model parameters has been discussed. This work demonstrates that ATND-delivery systems can improve therapeutic agent delivery to the tumor tissue, and promote tumor cell killing. • Analyze the impact of drug dispersion on the dynamical systems of tumor-effectors with conventional and targeted therapy. • Incorporate drug dispersion phenomena to describing targeted nano-drugs delivery with hematocrit and drug source term. • Numerical and sensitivity simulation shows the impact of the flow and dynamical control parameters on therapy treatment. • Targeted nano-drug delivery shows more prominent in drug accumulation in the tumor than the conventional treatment. • Outcomes demonstrate the effectiveness of targeted drug delivery to the tumor tissue and enhance tumor cell kill. [ABSTRACT FROM AUTHOR]

Paraptosis is a non‐apoptotic and caspase‐independent programmed cell death that can trigger immunogenic cell death (ICD) in tumor cells, representing a potent tactic to overcome immune tolerance to apoptosis. Here, this study demonstrates the construction of a dual‐responsive nanoreactor (MCGDH) to achieve paraptosis‐mediated ICD for chemo‐immunotherapy. Specifically, by doping Cu2+ into glutathione (GSH)‐responsive dendritic mesoporous silica nanoparticles, the platform (CGDMSN) is endowed with partial acid‐sensitivity. After loaded with 8‐hydroxyquinoline (8‐HQ), cell membrane fragments are coated onto the ammoniated CGDMSN surface to construct MCGDH. Upon internalization by tumor cells, the release of Cu2+ and 8‐HQ from MCGDH in response to the acidic pH and high concentration of GSH in the tumor microenvironment stimulates in situ generation of Cu(8‐HQ)2, inducing tumor cells paraptosis at a low copper dose. Moreover, MCGDH‐mediated paraptosis amplifies the immunogenicity of tumor cells, facilitating antigen presentation to dendritic cells and activating CD8+/CD4+ T cells immune responses. Furthermore, the combination of MCGDH and anti‐PD‐1 antibodies (αPD‐1) promotes the systemic anti‐tumor immune responses and long‐term immunological effect to vastly inhibit the primary/distant tumor growth and prevent tumor metastasis. This GSH/pH dual‐responsive nanoreactor serves as a selective platform for accelerating the development of chemo‐immunotherapy. [ABSTRACT FROM AUTHOR]

This study aimed to explore potential radiomics biomarkers in predicting the efficiency of chemo-immunotherapy in patients with advanced non-small cell lung cancer (NSCLC). Eligible patients were prospectively assigned to receive chemo-immunotherapy, and were divided into a primary cohort (n = 138) and an internal validation cohort (n = 58). Additionally, a separative dataset was used as an external validation cohort (n = 60). Radiomics signatures were extracted and selected from the primary tumor sites from chest CT images. A multivariate logistic regression analysis was conducted to identify the independent clinical predictors. Subsequently, a radiomics nomogram model for predicting the efficiency of chemo-immunotherapy was conducted by integrating the selected radiomics signatures and the independent clinical predictors. The receiver operating characteristic (ROC) curves demonstrated that the radiomics model, the clinical model, and the radiomics nomogram model achieved areas under the curve (AUCs) of 0.85 (95% confidence interval [CI] 0.78–0.92), 0.76 (95% CI 0.68–0.84), and 0.89 (95% CI 0.84–0.94), respectively, in the primary cohort. In the internal validation cohort, the corresponding AUCs were 0.93 (95% CI 0.86–1.00), 0.79 (95% CI 0.68–0.91), and 0.96 (95% CI 0.90–1.00) respectively. Moreover, in the external validation cohort, the AUCs were 0.84 (95% CI 0.72–0.96), 0.75 (95% CI 0.62–0.87), and 0.86 (95% CI 0.75–0.96), respectively. In conclusion, the radiomics nomogram provides a convenient model for predicting the effect of chemo-immunotherapy in advanced NSCLC patients. [ABSTRACT FROM AUTHOR]

Despite impressive advances in immune checkpoint blockade therapy, its efficacy as a standalone treatment remains limited. The influence of chemotherapeutic agents on tumor immunotherapy has progressively come to light in recent years, positioning them as promising contenders in the realm of combination therapy options for tumor immunotherapy. Herein, we present the rational design, synthesis, and biological evaluation of the first example of a Co(III) prodrug (Co2) capable of eliciting a localized cytotoxic effect while simultaneously inducing a systemic immune response via type II immunogenic cell death (ICD). To enhance its pharmacological properties, a glutathione-sensitive polymer was synthesized, and Co2 was encapsulated into polymeric nanoparticles (NP-Co2) to improve efficacy. Furthermore, NP-Co2 activates the GRP78/p-PERK/p-eIF2α/CHOP pathway, thereby inducing ICD in cancer cells. This facilitates the transformation of "cold tumors" into "hot tumors" and augments the effectiveness of the PD-1 monoclonal antibody (αPD-1). In essence, this nanomedicine, utilizing Co(III) prodrugs to induce ICD, provides a promising strategy to enhance chemotherapy and αPD-1 antibody-mediated cancer immunotherapy. [Display omitted] • Cobalt(III)-cyclam prodrug (Co2) selectively activated by ascorbate. • The Co2 induces endoplasmic reticulum stress through activation of the GRP78/p-PERK/p-eIF2α/CHOP pathway, leading to type II immunogenic cell death. • The nanomedicine, utilizing Co2 to induce immunogenic cell death, provides a promising strategy to enhance chemotherapy and αPD-1 antibody-mediated cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Currently, the efficacy of albumin-bound paclitaxel (PTX@Alb) is still limited due to the impaired PTX@Alb accumulation in tumors partly mediated by the dense collagen distribution. Meanwhile, acquired immune resistance always occurs due to the enhanced programmed cell death-ligand 1 (PD-L1) expression after PTX@Alb treatment, which then leads to immune tolerance. To fill these gaps, we newly revealed that tamoxifen (TAM), a clinically widely used adjuvant therapy for breast cancer with mitochondrial metabolism blockade capacity, could also be used as a novel effective PD-L1 and TGF- β dual-inhibitor via inducing the phosphorylation of adenosine 5ʹ-monophosphate-activated protein kinase (AMPK) protein. Following this, to obtain a more significant effect, TPP-TAM was prepared by conjugating mitochondria-targeted triphenylphosphine (TPP) with TAM, which then further self-assembled with albumin (Alb) to form TPP-TAM@Alb nanoparticles. By doing this, TPP-TAM@Alb nanoparticles effectively decreased the expression of collagen in vitro , which then led to the enhanced accumulation of PTX@Alb in 4T1 tumors. Besides, TPP-TAM@Alb also effectively decreased the expression of PD-L1 and TGF- β in tumors to better sensitize PTX@Alb-mediated chemo-immunotherapy by enhancing T cell infiltration. All in all, we newly put forward a novel mitochondrial metabolism blockade strategy to inhibit PTX@Alb-resistant tumors, further supporting its better clinical application. TPP-TAM@Alb-mediated mitochondrial metabolism disruption boosted PTX@Alb-based chemo-immunotherapy by inducing enhanced drug accumulation and amplified T cell infiltration. [Display omitted] [ABSTRACT FROM AUTHOR]

Currently, the efficacy of albumin-bound paclitaxel (PTX@Alb) is still limited due to the impaired PTX@Alb accumulation in tumors partly mediated by the dense collagen distribution. Meanwhile, acquired immune resistance always occurs due to the enhanced programmed cell death-ligand 1 (PD-L1) expression after PTX@Alb treatment, which then leads to immune tolerance. To fill these gaps, we newly revealed that tamoxifen (TAM), a clinically widely used adjuvant therapy for breast cancer with mitochondrial metabolism blockade capacity, could also be used as a novel effective PD-L1 and TGF-β dual-inhibitor via inducing the phosphorylation of adenosine 5ʹ-monophosphate-activated protein kinase (AMPK) protein. Following this, to obtain a more significant effect, TPP-TAM was prepared by conjugating mitochondria-targeted triphenylphosphine (TPP) with TAM, which then further self-assembled with albumin (Alb) to form TPP-TAM@Alb nanoparticles. By doing this, TPP-TAM@Alb nanoparticles effectively decreased the expression of collagen in vitro, which then led to the enhanced accumulation of PTX@Alb in 4T1 tumors. Besides, TPP-TAM@Alb also effectively decreased the expression of PD-L1 and TGF-β in tumors to better sensitize PTX@Alb-mediated chemo-immunotherapy by enhancing T cell infiltration. All in all, we newly put forward a novel mitochondrial metabolism blockade strategy to inhibit PTX@Alb-resistant tumors, further supporting its better clinical application.

Abstract This study aimed to explore potential radiomics biomarkers in predicting the efficiency of chemo-immunotherapy in patients with advanced non-small cell lung cancer (NSCLC). Eligible patients were prospectively assigned to receive chemo-immunotherapy, and were divided into a primary cohort (n = 138) and an internal validation cohort (n = 58). Additionally, a separative dataset was used as an external validation cohort (n = 60). Radiomics signatures were extracted and selected from the primary tumor sites from chest CT images. A multivariate logistic regression analysis was conducted to identify the independent clinical predictors. Subsequently, a radiomics nomogram model for predicting the efficiency of chemo-immunotherapy was conducted by integrating the selected radiomics signatures and the independent clinical predictors. The receiver operating characteristic (ROC) curves demonstrated that the radiomics model, the clinical model, and the radiomics nomogram model achieved areas under the curve (AUCs) of 0.85 (95% confidence interval [CI] 0.78–0.92), 0.76 (95% CI 0.68–0.84), and 0.89 (95% CI 0.84–0.94), respectively, in the primary cohort. In the internal validation cohort, the corresponding AUCs were 0.93 (95% CI 0.86–1.00), 0.79 (95% CI 0.68–0.91), and 0.96 (95% CI 0.90–1.00) respectively. Moreover, in the external validation cohort, the AUCs were 0.84 (95% CI 0.72–0.96), 0.75 (95% CI 0.62–0.87), and 0.86 (95% CI 0.75–0.96), respectively. In conclusion, the radiomics nomogram provides a convenient model for predicting the effect of chemo-immunotherapy in advanced NSCLC patients.

AbstractGuidelines historically recommended mono-chemotherapy for the 1st line treatment of elderly patients with non-small cell lung cancer (NSCLC) and poor performance status (PS). Nowadays, there is no clear indication whether chemo-immunotherapy (chemo-IO) combinations can be effectively delivered in this population. We collected induction chemotherapy data in consecutive patients with advanced NSCLC treated with carboplatin-based chemotherapy regimens plus pembrolizumab, to compute the received dose intensity (RDI) from standard regimens or patient-tailored regimens modified due to age, comorbidities and PS. Comorbidities were stratified according to the comorbidity-polypharmacy score (CPS). The established cut-off of ≥85% for RDI was used to define adequate delivery. 116 pts were treated from Feb-20 to July-23, of whom 96 and 20 with non-squamous and squamous NSCLC, treated with carboplatin-pemetrexed or carboplatin-paclitaxel doublets plus pembrolizumab, respectively. The majority of patients were aged ≥ 70 years (52.6%), the median CPS was 5, with 58.6% having a CPS ≥5, whilst 47.4%, 44.8% and 7.8% had an Eastern Cooperative Oncology Group (ECOG) - PS of 0, 1 and 2, respectively. PD-L1 TPS were <1% in 31.9% and 1-49% in 65.4%. Overall, 47.4% received a priori modified regimens due to poor PS, age, or comorbidities. Among patients with non-squamous NSCLC, median received doses of carboplatin and pemetrexed were 1.37 AUC/week and 138.8 mg/m2/week, with RDIs of 86% and 75% (p < 0.01) for patients treated with standard or modified regimens, respectively. Of note, the RDI was 57.9% among patients with ECOG-PS 2. However, patients treated with modified regimens experienced similar toxicities as those treated with standard regimens, despite being older (p < 0.01), with higher PS (p < 0.01) and more comorbid (p = 0.03). Patients treated with modified regimens achieved a shorter survival (7.1 vs 13.9 months), which is comparable to IO-free historical controls. Among patients with squamous NSCLC, 90% received modified regimens upfront, with median received doses of carboplatin and paclitaxel of 1.19 AUC/week and 40 mg/m2/week, and an overall RDI of 73.5%. Although regimen modifications ensure a safe administration of chemotherapy plus pembrolizumab in frail patients, the RDI seems to be subtherapeutic, especially in those with squamous histology. Dedicated trials are needed to implement combination strategies in this population. [ABSTRACT FROM AUTHOR]

Background: Advanced non-small cell lung cancer (NSCLC) presents significant treatment challenges, with chemo-immunotherapy emerging as a promising approach. This study explores the potential of lipidomic biomarkers to predict responses to chemo-immunotherapy in advanced non-small cell lung cancer (NSCLC) patients. Methods: A prospective analysis was conducted on 68 NSCLC patients undergoing chemo-immunotherapy, divided into disease control (DC) and progressive disease (PD) groups based on treatment response. Pre-treatment serum samples were subjected to lipidomic profiling using liquid chromatography-mass spectrometry (LC-MS). Key predictive lipids (biomarkers) were identified through projection to latent structures discriminant analysis. A biomarker combined model and a clinical combined model were developed to enhance the prediction accuracy. The predictive performances of the clinical combined model in different histological subtypes were also performed. Results: Six lipids were identified as the key lipids. The expression levels of PC (16:0/18:2), PC(16:0/18:1), PC(16:0/18:0), CE(20:1), and PC(14:0/18:1) were significantly up-regulated. While the expression level of TAG56:7-FA18:2 was significantly down-regulated. The biomarker combined model demonstrated a receiver operating characteristic (ROC) curve of 0.85 (95% CI: 0.75-0.95) in differentiating the PD from the DC. The clinical combined model exhibited an AUC of 0.87 (95% CI: 0.79-0.96) in differentiating the PD from the DC. The clinical combined model demonstrated good discriminability in DC and PD patients in different histological subtypes with the AUC of 0.78 (95% CI: 0.620.96), 0.79 (95% CI: 0.64-0.94), and 0.86 (95% CI: 0.52-1.00) in squamous cell carcinoma, large cell carcinoma, and adenocarcinoma subtype, respectively. Pathway analysis revealed the metabolisms of linoleic acid, alpha-linolenic acid, glycerolipid, arachidonic acid, glycerophospholipid, and steroid were implicated in the chemo-immunotherapy response in advanced NSCLC. Conclusion: Lipidomic profiling presents a highly accurate method for predicting responses to chemo-immunotherapy in patients with advanced NSCLC, offering a potential avenue for personalized treatment strategies. [ABSTRACT FROM AUTHOR]

[Display omitted] Chemo-immunotherapy, in which chemotherapeutic drugs activate immune system to suppress tumor growth and metastases, has great potential for clinical application. However, insufficient immunogenic cell death and serious side effects caused by tumor multidrug resistance and non-specific drug distribution, as well as inadequate and dysfunctional immune cells, greatly impair the effectiveness of chemo-immunotherapy. Herein, taking advantage of the functional diversity and structural programmability of nucleic acids, a DNA-based bioorthogonal nanoagonist is constructed to initiate and augment immune responses for robust chemo-immunotherapy. Benefiting from polyvalent targeting and template effects of DNA, the tailor-made nanoagonist shows prior bioorthogonal catalytic performance. Chemotherapeutic drug is bioorthogonally synthesized in situ under the catalysis of the nanoagonist, maximizing immunogenic cell death and minimizing systemic toxicity. The large amount of antigen and damage-associated molecular patterns released from dying tumor cells effectively initiates antitumor immunity. Meanwhile, the integration of high density of immunologic adjuvant can more effectively stimulate immune cells. The combination of bioorthogonal catalytic drug synthesis and immunostimulatory effect of DNA adjuvant not only destroys local primary tumors, but also eliminates distal metastasis. Moreover, the nanoagonist triggered the immune memory effect. The work extends the application of bioorthogonal chemistry to immunotherapy and provides a safe and powerful strategy for cancer chemo-immunotherapy. [ABSTRACT FROM AUTHOR]

Lung cancer is the most leading cause of cancer death. Traditional chemotherapy has unavoidable drawbacks of nonspecific tumor targeting, high toxicity, and poor therapeutic efficiency. Nanocarriers can achieve accurate delivery and reduce adverse reactions of drugs, which have received extensive attention. In this work, hollow manganese dioxide (HMnO2) nanoparticle (NP) that is highly responsive to tumor microenvironment, was simultaneously loaded with paclitaxel (PTX), a chemotherapy drug, and imiquimod (R837), a toll-like receptor 7 agonist. Those NPs were then coated with bacterial outer-membrane vesicles (OMVs-HMnO2@PTX + R837 NPs), whose surface proteins could act as tumor-specific antigens. The obtained nanovaccine inherited superior tumor-targeting capacity of OMVs and promoted retention in tumors. As a result, intravenous injection of the nanovaccine led to remarkable tumor growth inhibition. Furthermore, we found that the nanovaccine effectively boosted dendritic cells maturation and increased cytotoxic T lymphocytes infiltration. Taken together, these results demonstrated the great potential in applying OMVs-enveloped nano-activator in cancer chemo-immunotherapy.

ABSTRACT Background Osimertinib is approved as a standard treatment for non‐small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation by FDA. However, the mechanisms of resistance for nearly half of patients after osimertinib progression are still unknown, and the optimal therapies for these patients are still controversial. In this retrospective study, we compared efficacy and safety between immunotherapy + chemotherapy, chemotherapy alone, and osimertinib + bevacizumab in NSCLC patients after osimertinib progression with unknown resistance mechanisms. Methods Advanced NSCLC patients with unknown resistance mechanisms after osimertinib progression were retrospectively reviewed and divided into immunotherapy + chemotherapy, chemotherapy alone, and osimertinib + bevacizumab treatment groups according to the treatment they received after osimertinib progression. Clinicopathological features, objective response rate (ORR), progression‐free survival (PFS), and overall survival (OS) were compared between groups. Results A total of 121 patients were enrolled in this study, 22 in the immunotherapy + chemotherapy group, 72 in the chemotherapy group, and 27 in the osimertinib + bevacizumab group. The ORR was much higher in the immunotherapy + chemotherapy group compared with chemotherapy or osimertinib + bevacizumab group (55.56% vs. 14.81% vs. 0% in patients after progression on 1st line osimertinib treatment; 30.77% vs. 6.67% vs. 13.33% in patients after progression on 2nd/3rd line osimertinib treatment). Median PFS was also significantly longer in the immunotherapy + chemotherapy group compared with other groups (8.2 months vs. 4.0 months vs. 6.0 months in all patients, p = 0.0066). The median OS did not reach remarkable difference among groups, although osimertinib + bevacizumab group had a numerically longer median OS (37.0 months vs. 37.0 months vs. 47.6 months in all patients, p = 0.6357). Compared with immunotherapy + chemotherapy and chemotherapy, treatment‐related adverse events (AEs) of osimertinib + bevacizumab were milder, especially in AEs related to gastrointestinal and bone marrow suppression. Conclusion Our study provides clinical evidence that NSCLC patients after osimertinib progression with unknown resistance mechanisms may benefit from immunotherapy + chemotherapy, with higher ORR and longer PFS compared with osimertinib + bevacizumab or chemotherapy groups. Osimertinib + bevacizumab treatment was also an optional option for patients because OS was numerically longer and safer in this group.

BackgroundHistorically, adults with relapsed-refractory acute lymphoblastic leukemia (ALL) experienced poor outcomes with intensive chemotherapy. This mature analysis explores the benefit of the addition of sequential blinatumomab to low-intensity mini-Hyper-CVD chemotherapy with inotuzumab ozogamicin in this setting.MethodsMini-Hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 83% dose reduction) was combined with inotuzumab during the first 4 courses. From Patient #68 and onwards, inotuzumab was given in reduced and fractionated doses, and blinatumomab was added sequentially for 4 courses. Maintenance therapy with prednisone, vincristine, 6-mercaptopurine and methotrexate was given for 12 courses, and blinatumomab for 4 additional courses.ResultsAmong 110 patients (median age, 37 years) treated, 91 (83%) responded (complete response, 69 patients, 63%). Measurable residual disease negativity was documented in 75 patients (82% of responders). Fifty-three patients (48%) received allogeneic stem cell transplantation (SCT). Hepatic sinusoidal obstruction syndrome occurred in 9/67 patients (13%) on the original inotuzumab schedule and in 1/43 (2%) on the modified schedule. With a median follow-up of 48 months, the median overall survival (OS) was 17 months, and the 3 year OS was 40%. The 3 year OS was 34% with mini-Hyper-CVD plus inotuzumab and 52% with additional blinatumomab (P = 0.16). By landmark analysis at 4 months, the 3 year OS was 54%, similar between patients who did or did not receive allogeneic SCT.ConclusionLow-intensity mini-Hyper-CVD plus inotuzumab with or without blinatumomab showed efficacy in patients with relapsed-refractory ALL, with better survival after the addition of blinatumomab. Trial registration The trial was registered on clinicaltrials.gov with the identifier NCT01371630.

Mitochondrial membrane remodeling can trigger the release of mitochondrial DNA (mtDNA), leading to the activation of cellular oxidative stress and immune responses. While the role of mitochondrial membrane remodeling in promoting inflammation in hepatocytes is well-established, its effects on tumors have remained unclear. In this study, we designed a novel Pt(IV) complex, OAP2, which is composed of oxaliplatin (Oxa) and acetaminophen (APAP), to enhance its anti-tumor effects and amplify the immune response. Our findings demonstrate that OAP2 induces nuclear DNA damage, resulting in the production of nuclear DNA. Additionally, OAP2 downregulates the expression of mitochondrial Sam50, to promote mitochondrial membrane remodeling and trigger mtDNA secretion, leading to double-stranded DNA accumulation and ultimately synergistically activating the intracellular cGAS-STING pathway. The mitochondrial membrane remodeling induced by OAP2 overcomes the limitations of Oxa in activating the STING pathway and simultaneously promotes gasdermin-D-mediated cell pyroptosis. OAP2 also promotes dendritic cell maturation and enhances the quantity and efficacy of cytotoxic T cells, thereby inhibiting cancer cell proliferation and metastasis. Briefly, our study introduces the first novel small-molecule inhibitor that regulates mitochondrial membrane remodeling for active immunotherapy in anti-tumor research, which may provide a creative idea for targeting organelle in anti-tumor therapy.

Molecular engineering of drug delivering platforms to provide collaborative biological effects with loaded drugs is of great medical significance. Herein, cannabinoid receptor 1 (CB1)‐ and reactive oxygen species (ROS)‐targeting electrosprayed microspheres (MSs) are fabricated by loading with the CB1 agonist arachidonoyl 2′‐chloroethylamide (ACEA) and producing ROS in a photoresponsive manner. The synergistic anti‐tumor effects of ACEA and ROS released from the MSs are assessed. ACEA inhibits epidermal growth factor receptor signaling and altered tumor microenvironment (TME) by activating CB1 to induce tumor cell death. The MSs are composed of glycidyl methacrylate‐conjugated xanthan gum (XGMA) and Fe3+, which form dual molecular networks based on a Fe3+‐(COO−)3 network and a C═C addition reaction network. Interestingly, the Fe3+‐(COO−)3 network can be disassembled instantly under the conditions of lactate sodium and ultraviolet exposure, and the disassembly is accompanied by massive ROS production, which directly injures tumor cells. Meanwhile, the transition of dual networks to a single network boosts the ACEA release. Together, the activities of the ACEA and MSs promote immunogenic tumor cell death and create a tumor‐suppressive TME by increasing M1‐like tumor‐associated macrophages and CD8+ T cells. In summation, this study demonstrates strong prospects of improving anti‐tumor effects of drug delivering platforms through molecular design. [ABSTRACT FROM AUTHOR]

This article is a guideline from the British Society for Haematology on the management of newly diagnosed large B-cell lymphoma. It provides recommendations for the initial investigation and first-line management of this type of lymphoma, emphasizing the importance of accurate diagnosis, patient involvement in decision-making, and supportive care. The document discusses different treatment approaches for early-stage lymphoma, specific subtypes of lymphoma, and the use of clinical trials. It suggests offering six cycles of R-CHOP chemotherapy as the standard treatment for various types of lymphoma and highlights the importance of individualized treatment decisions based on patient factors. The document also provides recommendations for the treatment and follow-up of patients with large B-cell lymphoma, emphasizing holistic, multidisciplinary care and various treatment options. The recommendations aim to improve patient outcomes and quality of life. [Extracted from the article]

FOLFOX regimen, composed of folinic acid, 5-fluorouracil (5-FU) and oxaliplatin (OXP), has been used as clinical standard therapeutic regimen in treatments of colorectal cancer (CRC) and esophageal squamous cell carcinoma (ESCC). To further improve its therapeutic outcomes, FOLFOX was combined with anti-PD-1 antibody to form an advanced chemo-immune combination strategy, which has been proven more efficient in controlling cancer progression and prolonging patients' survival in various clinical trials. However, bad tumor accumulation, relative high toxicity, numerous treatment cycles with high fees and low compliance as well as drug resistance seriously limit the prognosis of FOLFOX regimen. The "all-in-one" formulations, which could precisely delivery multidrug regimen into tumor sites and cells, showed a promising application prospect for targeted drug delivery as well as reducing side effects. However, the design and preparation of the "all-in-one" formulation with high drug encapsulation efficiencies for all drugs was still challenging. Herein, a lipid core-shell nanoparticle codelivery platform was designed for simultaneous encapsulation of variant FOLFOX composed of miriplatin (MiPt), 5-Fluoro-2′-deoxyuridine 5′-monophosphate (FdUMP), calcium folinate (CF) and PD-L1 siRNA (siPD-L1) with high efficiencies, and their synergistic anti-tumor mechanisms were studied, respectively. MiPt, a precursor of OXP, was validated capable of inducing efficient immunogenic cell death (ICD) in this work. Additionally, ICD-mediated release of damage associated molecular patterns functionalized synergistically with PD-L1 silence by siPD-L1 to overcome chemoresistance, reverse suppressive tumor microenvironment and recruit more CD8+ T cells. FdUMP, as the intracellular active form of 5-FU, could induce large amounts of reactive oxygen species to enhance the ICD. CF worked as the sensitizer of FdUMP. The enhanced long-term anti-tumor effect of the prepared "all-in-one" formulation compared to free drug regimen and other controls, was verified in heterotopic CRC mice models and ESCC mice models, providing new thoughts for researchers and showing a promising prospect of translation into clinical applications. [Display omitted] • To overcome the poor prognosis of FOLFOX regimen in clinical practice. • Validated a new variant form of FOLFOX and combined it with siPD-L1 therapy. • "All-in-one" precise codelivery platform with high encapsulation efficiency. • Combined ICD, apoptosis, immune-checkpoint blockade for chemo-immunotherapy. • Gained significantly better outcomes with much lower doses compared to FOLFOX. [ABSTRACT FROM AUTHOR]

Mitochondrial membrane remodeling can trigger the release of mitochondrial DNA (mtDNA), leading to the activation of cellular oxidative stress and immune responses. While the role of mitochondrial membrane remodeling in promoting inflammation in hepatocytes is well-established, its effects on tumors have remained unclear. In this study, we designed a novel Pt(IV) complex, OAP2, which is composed of oxaliplatin (Oxa) and acetaminophen (APAP), to enhance its anti-tumor effects and amplify the immune response. Our findings demonstrate that OAP2 induces nuclear DNA damage, resulting in the production of nuclear DNA. Additionally, OAP2 downregulates the expression of mitochondrial Sam50, to promote mitochondrial membrane remodeling and trigger mtDNA secretion, leading to double-stranded DNA accumulation and ultimately synergistically activating the intracellular cGAS-STING pathway. The mitochondrial membrane remodeling induced by OAP2 overcomes the limitations of Oxa in activating the STING pathway and simultaneously promotes gasdermin-D-mediated cell pyroptosis. OAP2 also promotes dendritic cell maturation and enhances the quantity and efficacy of cytotoxic T cells, thereby inhibiting cancer cell proliferation and metastasis. Briefly, our study introduces the first novel small-molecule inhibitor that regulates mitochondrial membrane remodeling for active immunotherapy in anti-tumor research, which may provide a creative idea for targeting organelle in anti-tumor therapy. A novel Pt(IV) complex OAP2 could activate mitochondrial membrane remodeling to release mtDNA, induces the STING pathway and pyroptosis, ultimately promoting the immune activation of tumor cells. [Display omitted] [ABSTRACT FROM AUTHOR]

Activation of stimulator of interferon genes (STING) by cyclic dinucleotides (CDNs) has been considered as a powerful immunotherapy strategy. While promising, the clinical translation of CDNs is still overwhelmed by its limited biostability and the resulting systemic immunotoxicity. Being differentiating from current application of exogenous CDNs to address these challenges, we herein developed one perylene STING agonist PDIC‐NS, which not only promotes the production of endogenous CDNs but also inhibits its hydrolysis. More significantly, PDIC‐NS can well reach lung‐selective enrichment, and thus mitigates the systemic immunotoxicity upon intravenous administration. As a result, PDIC‐NS had realized remarkable in vivo antitumor activity, and backward verified on STING knock out mice. Overall, this study states that PDIC‐NS can function as three‐in‐one small‐molecule STING agonist characterized by promoting the content and biostability of endogenous CDNs as well as possessing good tissue specificity, and hence presents an innovative strategy and platform for tumor chemo‐immunotherapy. [ABSTRACT FROM AUTHOR]

Background: No studies have identified combined biomarkers that may be more reasonable for the assessment of current chemo-immunotherapy in patients with extensive stage small-cell lung cancer (ES-SCLC). Methods: This study was conducted to investigate a combined biomarker with prognostic or predictive value in ES-SCLC. We determined the best independent prognostic biomarker among the four complete blood-count-derived inflammatory biomarkers (CBC-IBs). Subsequently, we analyzed the prognostic or predictive value of combining this independent CBC-IB with PD-L1 (SP142) expression. We prospectively assessed the SP142 analyses in tumor samples at diagnosis. Results: All in all, 55 patients with ES-SCLC were classified into four groups according to the systemic immune inflammation index (SII) (low/high) and SP142 (positive/negative). The best survival was observed in the low-SII/ SP142-positive group, whereas the worst survival was observed in the high-SII/SP142-negative group (p = 0.002). The combined SII-SP142 biomarker was better for predicting both survival and disease progression in patients with ES-SCLC. Conclusions: The combined SII-SP142 biomarker can be readily and universally obtained at a low cost in clinical practice, without requiring advanced genomics technology or specialized expertise. Although further studies are needed to confirm that the combined SII-SP142 biomarker is widely applicable, it should help clinicians to identify the best patients for combined chemotherapy with atezolizumab in ES-SCLC. [ABSTRACT FROM AUTHOR]

In the pursuit of advancing cancer therapy, this study explores the predictive power of machine learning in analyzing tumor characteristics, specifically focusing on the effects of tumor stiffness and perfusion (i.e., blood flow) on treatment efficacy. Recent advancements in oncology have highlighted the significance of these physiological properties of the tumor microenvironment in determining treatment outcomes. We delve into the relationship between these tumor attributes and the effectiveness of cancer therapies in preclinical tumor models. Utilizing robust statistical methods and machine learning algorithms, our research analyzes data from 1365 cases of various cancer types, assessing how tumor stiffness and perfusion influence the efficacy of treatment protocols. We also investigate the synergistic potential of combining drugs that modulate tumor stiffness and perfusion with standard cytotoxic treatments. By incorporating these predictors into treatment planning, our study aims to enhance the precision of cancer therapy, tailoring treatment to individual tumor profiles. Our findings demonstrate a significant correlation between stiffness/perfusion and treatment efficacy, highlighting a new way for personalized cancer treatment strategies.

Zhaohui Liao Arter,1,2 Misako Nagasaka1– 3 1Department of Medicine, Division of Hematology-Oncology, University of California Irvine School of Medicine, Orange, CA, USA; 2Chao Family Comprehensive Cancer Center, Orange, CA, USA; 3Department of Medicine, St. Marianna University School of Medicine, Kawasaki, JapanCorrespondence: Misako Nagasaka, Department of Medicine, Division of Hematology-Oncology, University of California Irvine School of Medicine, Orange, CA, 92602, USA, Email nagasakm@hs.uci.eduAbstract: Targeted therapies, such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), have revolutionized the treatment landscape for EGFR-mutant non-small cell lung cancer (NSCLC). However, the emergence of resistance to EGFR TKIs especially the third generation TKIs such as osimertinib remains a major clinical challenge. As a broader strategy for combating resistance, several clinical trials have explored the efficacy of immune checkpoint inhibitors (ICIs)+chemotherapy in EGFR-mutated NSCLC. Until now, the ORIENT-31 and IMpower150 trials suggested that ICIs+ chemotherapy may be more effective than chemotherapy alone after failure of EGFR-TKIs (although ORIENT-31 was negative for overall survival [OS] and IMpower150 was a subset analysis, so the study was not powered to detect a difference); however, the CheckMate-722 trial yielded disappointing results. Thus, the results of this global trial KEYNOTE-789 were highly anticipated.Keywords: EGFR, post-osimertinib, chemo-immunotherapy, targeted therapy

Herein, we designed Comp. 1 to simultaneously respond to two enzymes: alkaline phosphatase and matrix metalloproteinase 2, which is commonly found in highly malignant cancer cell lines containing B16–F10 murine melanoma cells and CT26 murine colon carcinoma cells. We used the regional differences in the expression levels of dual-markers to accurately release immune molecule IND into tumor microenvironment for the activation of anti-tumor related immune effects, while in-situ self-assembly occurs. The dual-enzyme response process can further regulate the peptide precursors’ self-assembly in the form of short rod-shaped nanofibers, enabling the delivery of the loaded chemotherapeutic drug HCPT into the cancer cells and further allowing the peptide assemblies to escape from lysosomes and return to cytoplasm in the form of tiny nanoparticles to induce apoptosis of cancer cells. This process does not occur in the single-positive breast cancer cell line MCF-7 or the normal hepatocytes cell line LO2, indicating the selectivity of the cancer cells exhibited using our strategy. In vivo studies revealed that Comp. 1 can effectively cooperate with chemotherapy to enhance the immunotherapy effect and induce immune responses associated with elevated pro-inflammatory cytokines in vivo to inhibit malignant tumors growth. Our dual-enzyme responsive chemo-immunotherapy strategy feasible in anti-tumor treatment, provides a new avenue for regulating peptide self-assembly to adapt to diverse tumor properties and may eventually be used for the development of novel multifunctional anti-tumor nanomedicines.

Although toll-like receptor (TLR) agonists hold great promise as immune modulators for reprogramming the suppressive immune landscape in pancreatic ductal adenocarcinoma (PDAC), their use is limited by poor pharmacokinetics (PK) and off-target systemic inflammatory effects. To overcome these challenges as well as to attain drug synergy, we developed a lipid bilayer (LB)-coated mesoporous silica nanoparticle (silicasome) platform for co-delivery of the TLR7/8 agonist 3M-052 with the immunogenic chemotherapeutic agent irinotecan. This was accomplished by incorporating the C18 lipid tail of 3M-052 in the coated LB, also useful for irinotecan remote loading in the porous interior. Not only did the co-formulated carrier improve PK, but it strengthened the irinotecan-induced immunogenic cell death response by 3M-052-mediated dendritic cell activation at the tumor site as well as participating lymph nodes. The accompanying increase in CD8+ T-cell infiltration along with a reduced number of regulatory T-cells was associated with tumor shrinkage and metastasis disappearance in subcutaneous and orthotopic KRAS-mediated pancreatic carcinoma tumor models. Moreover, this therapeutic outcome was accomplished without drug or nanocarrier toxicity. All considered, dual-delivery strategies that combine chemo-immunotherapy with co-formulated TLR agonists or other lipid-soluble immune modulators predict successful intervention in heterogeneous PDAC immune landscapes.

Tumor recurrence and unfavorable bacterial biofilm formation on implants after bone tumor resection remain challenging in clinical settings. However, this dilemma also provides inspiration for the development of bioactive implants and a new route for the management of bone tumors through biofilm formation. Here, based on the characteristic that bacteria prefer to adhere to implants, 3D‐printing bioceramic scaffolds modified with probiotic biofilms are designed to augment antitumor immunity. In comparison with Akkermansia muciniphila, Lactobacillus rhamnosus GG (LGG) is demonstrated to more easily form biofilms on bioceramics and is selected to engineer etched bioceramics. The LGG biofilm subjected to pasteurization guarantees good biocompatibility and enhanced doxorubicin (Dox) loading. Furthermore, the LGG biofilm combined with Dox imparts the scaffolds with multiple properties of direct chemo‐killing for tumor cells and potent immune activation. The modified scaffolds efficiently inhibit bone tumor recurrence and bone metastasis in murine tumor model receives surgical resection. Moreover, based on 3D‐printing technology, the probiotic biofilm modified scaffolds with adjustable shapes are also demonstrated to repair shape‐specific bone defects after tumor elimination. Collectively, the multifunctional 3D‐printing scaffolds realize the integrated treatment of tumor elimination and bone repair, providing a promising strategy for clinical treatment of bone tumors. [ABSTRACT FROM AUTHOR]

Poor immunogenicity seriously hampers the broader implementation of antitumor immunotherapy. Enhanced immunogenicity capable of achieving greater antitumor immunity is urgently required. Here, a novel polymer that contains hydrophobic ferrocene (Fc) units and thioketal bonds in the main chain, which further delivered a prodrug of oxaliplatin and artesunate, i.e., Artoxplatin, to cancer cells is described. This polymer with Fc units in the nanoparticle can work as a polyigniter to spark the peroxide bonds in Artoxplatin and generate abundant reactive oxygen species (ROS) to kill cancers as nanobombig for cancer therapy. Moreover, ROS can trigger the breakdown of thioketal bonds in the polymer, resulting in the biodegradation of the polymer. Importantly, nanobombig can facilitate the maturation of dendritic cells and promote the activation of antitumor immunity, through the enhanced immunogenic cell death effect by ROS generated in situ. Furthermore, metabolomics analysis reveals a decrease in glutamine in nanobombig‐treated cancer cells, resulting in the upregulation of programmed death ligand 1 (PD‐L1). Consequently, it is further demonstrated enhanced tumor inhibitory effects when using nanobombig combined with anti‐PD‐L1 therapy. Overall, the nanosystem offers a rational design of an efficient chemo‐immunotherapy regimen to promote antitumor immunity by improving tumor immunogenicity, addressing the key challenges cancer immunotherapy faced. [ABSTRACT FROM AUTHOR]

Background: Venous thromboembolism (VTE) is a serious complication in non-small cell lung cancer (NSCLC) patients. The use of thromboprophylactic therapy is subject to an accurate assessment of the VTE risk depending on patients, tumor characteristics and type of systemic antineoplastic treatments. However, little is known concerning the risk of VTE in patients suffering from an advanced NSCLC treated with first-line chemo-immunotherapy and the impact of tumor biomarkers such as PD-L1 expression. Methods: We performed a retrospective, observational, single-centre study in a cohort of advanced NSCLC patients treated with first-line chemo-immunotherapy. The primary endpoint was the incidence of VTE. Secondary endpoints were the cumulative incidence of VTE, the impact of PD-L1 on VTE occurrence, overall survival, the rate of VTE recurrence under anticoagulant treatment and the rate of bleeding complications. Results: 109 patients were included, of whom 21 (19.3%) presented a VTE event during a median follow-up of 13 months. VTE incidence at 3, 6 and 12 months was 12.1%, 15.1% and 17.5% respectively. 61% were pulmonary embolisms, 9.5% were isolated deep vein thrombosis and 14.3% were central venous catheter-related thrombosis. Our study did not show a significant impact of PD-L1 on VTE occurrence. Overall survival at 6, 12 and 24 months was 81.9%, 74.4% and 70.3% respectively. Four patients developed a recurrent VTE under anticoagulation therapy 3 to 5 months after the first VTE event. One patient suffered from a major bleeding complication while under anticoagulation therapy, leading to death. Conclusion: VTE is a common complication in advanced NSCLC patients treated with concomitant chemo-immunotherapy. In our study, 19.3% of patients developed a VTE during a median follow-up of 13 months. PD-L1 did not appear to be associated with VTE occurrence. We recorded high VTE recurrence rates despite anticoagulant treatment. Further investigations are needed to determine if high PD-L1 expression is associated with VTE. [ABSTRACT FROM AUTHOR]

Chemotherapy is a critical modality in cancer therapy to combat malignant cell proliferation by directly attacking cancer cells and inducing immunogenic cell death, serving as a vital component of multi‐modal treatment strategies for enhanced therapeutic outcomes. However, chemotherapy may inadvertently contribute to the immunosuppression of the tumor microenvironment (TME), inducing the suppression of antitumor immune responses, which can ultimately affect therapeutic efficacy. Chemo‐immunotherapy, combining chemotherapy and immunotherapy in cancer treatment, has emerged as a ground‐breaking approach to target and eliminate malignant tumors and revolutionize the treatment landscape, offering promising, durable responses for various malignancies. Notably, functional nanomaterials have substantially contributed to chemo‐immunotherapy by co‐delivering chemo‐immunotherapeutic agents and modulating TME. In this review, recent advancements in chemo‐immunotherapy are thus summarized to enhance treatment effectiveness, achieved by reversing the immunosuppressive TME (ITME) through the exploitation of immunotherapeutic drugs, or immunoregulatory nanomaterials. The effects of two‐way immunomodulation and the causes of immunoaugmentation and suppression during chemotherapy are illustrated. The current strategies of chemo‐immunotherapy to surmount the ITME and the functional materials to target and regulate the ITME are discussed and compared. The perspective on tumor immunosuppression reversal strategy is finally proposed. [ABSTRACT FROM AUTHOR]

To reduce recurrence rate after transurethral resection of bladder tumor, long-term intravesical instillations of Bacillus Calmette-Guérin (BCG) and/or chemotherapeutic drugs is the standard treatment for non-muscle invasive bladder carcinoma. However, the main challenges of intravesical therapy, such as short retention time and poor permeability of drugs in the bladder, often require frequent and high-dose administrations, leading to significant adverse effects and financial burden for patients. Aiming at addressing these challenges, we developed a novel approach, in which the cell-penetrating peptide modified oxaliplatin prodrug liposomes and a low-dose BCG were co-delivered via a viscous chitosan solution (LRO-BCG/CS). LRO-BCG/CS addressed these challenges by significantly improving the retention capability and permeability of chemotherapy agents across the bladder wall. Then, oxaliplatin triggered the immunogenic cell death, and the combination of BCG simultaneously further activated the systemic anti-tumor immune response in the MB49 orthotopic bladder tumor model. As a result, LRO-BCG/CS demonstrated superior anti-tumor efficacy and prolonged the survival time of tumor-bearing mice significantly, even at relatively low doses of oxaliplatin and BCG. Importantly, this combinational chemo-immunotherapy showed negligible side effects, offering a promising and well-tolerated therapeutic strategy for bladder cancer patients. [Display omitted] • Positive charged liposomes can penetrate the bladder tumor tissue deeper. • Chitosan solution promotes the retention capability of drugs in bladder. • Oxaliplatin and Bacillus Calmette-Guérin synergistically activate immune responses. [ABSTRACT FROM AUTHOR]

Patients with colorectal cancer (CRC) and diffuse peritoneal metastasis (PM) are not eligible for surgical intervention. Thus, palliative treatment remains the standard of care in clinical practice. Systemic chemotherapy fails to cause drug accumulation at the lesion sites, while intraperitoneal chemotherapy (IPC) is limited by high clearance rates and associated complications. Given the poor prognosis, a customized OxP/R848@PLEL hydrogel delivery system has been devised to improve the clinical benefit of advanced CRC with diffuse PM. This system is distinguished by its simplicity, security, and efficiency. Specifically, the PLEL hydrogel exhibits excellent injectability and thermosensitivity, enabling the formation of drug depots within the abdominal cavity, rendering it an optimal carrier for IPC. Oxaliplatin (OxP), a first‐line drug for advanced CRC, is cytotoxic and enhances the immunogenicity of tumors by inducing immunogenic cell death. Furthermore, OxP and resiquimod (R848) synergistically enhance the maturation of dendritic cells, promote the expansion of cytotoxic T lymphocytes, and induce the formation of central memory T cells. Moreover, R848 domesticates macrophages to an anti‐tumor phenotype. OxP/R848@PLEL effectively eradicates peritoneal metastases, completely inhibits ascites production, and significantly prolongs mice lifespan. As such, it provides a promising approach to managing diffuse PM in patients with CRC without surgical indications. [ABSTRACT FROM AUTHOR]

Mitoxantrone (MX) can induce the immunogenic-cell death (ICD) of tumor cells and activate anti-tumor immune responses. However, it can also cause high expression of indole amine 2, 3-dioxygenase (IDO) during ICD, leading to T-cell apoptosis and a weakened immune response. An IDO inhibitor, 1-methyl tryptophan (1-MT), can inhibit the activity of IDO caused by MX, resulting in enhanced chemo-immunotherapy. Here, MX-1-MT was connected by ester bond which could be broken in an acidic tumor microenvironment. MX-1-MT was combined with polyethylene glycol (PEG) via a disulfide bond which could be reduced by glutathione overexpressed in tumors, thereby accelerating drug release at target sites. Folic acid-modified distearoyl phosphoethanolamine-polyethylene glycol (DSPE-PEG-FA) was introduced to form targeting micelles. The micelles were of uniform particle size, high stability, and high responsiveness. They could be taken-up by drug-resistant MCF-7/ADR cells, displayed high targeting ability, and induced enhanced cytotoxicity and ICD. Due to 1-MT addition, micelles could inhibit IDO. In vivo studies demonstrated that micelles could accumulate in the tumor tissues of nude mice, resulting in an enhanced antitumor effect and few side-effects. [ABSTRACT FROM AUTHOR]

Chemotherapy remains one of the irreplaceable treatments for cancer therapy. The use of immunogenic cell death (ICD)-inducing chemotherapeutic drugs offers a practical strategy for killing cancer cells, simultaneously eliciting an antitumor immune response by promoting the recruitment of cytotoxic immune cells and production of granzyme B (GrB). However, numerous malignant cancers adaptively acquired the capacity of secreting serpinb9 (Sb9), a physiological inhibitor of GrB, which can reversibly inhibit the biological activity of GrB. To circumvent this dilemma, in this study, an integrated tailor-made nanomedicine composed of tumor-targeting peptide (Arg-Gly-Asp, RGD) decorated liposome, doxorubicin (DOX, an effective ICD inducer), and the compound 3034 (an inhibitor of Sb9), is developed (termed as D3RL) for breast cancer chemo-immunotherapy. In vitro and in vivo studies show that D3RL can directly kill tumor cells and trigger the host immune response by inducing ICD. Meanwhile, D3RL can competitively relieve the inhibition of Sb9 to GrB. The restored GrB can not only effectively induce tumor immunotherapy, but also degrade matrix components in the tumor microenvironment, consequently improving the infiltration of immune cells and the penetration of nanomedicines, which in return enhance the combined antitumor effect. Taken together, this work develops an integrated therapeutic solution for targeted production and restoration of GrB to achieve a combined chemoimmunotherapy for breast cancer. [ABSTRACT FROM AUTHOR]

Abstract Molecular engineering of drug delivering platforms to provide collaborative biological effects with loaded drugs is of great medical significance. Herein, cannabinoid receptor 1 (CB1)‐ and reactive oxygen species (ROS)‐targeting electrosprayed microspheres (MSs) are fabricated by loading with the CB1 agonist arachidonoyl 2′‐chloroethylamide (ACEA) and producing ROS in a photoresponsive manner. The synergistic anti‐tumor effects of ACEA and ROS released from the MSs are assessed. ACEA inhibits epidermal growth factor receptor signaling and altered tumor microenvironment (TME) by activating CB1 to induce tumor cell death. The MSs are composed of glycidyl methacrylate‐conjugated xanthan gum (XGMA) and Fe3+, which form dual molecular networks based on a Fe3+‐(COO−)3 network and a C═C addition reaction network. Interestingly, the Fe3+‐(COO−)3 network can be disassembled instantly under the conditions of lactate sodium and ultraviolet exposure, and the disassembly is accompanied by massive ROS production, which directly injures tumor cells. Meanwhile, the transition of dual networks to a single network boosts the ACEA release. Together, the activities of the ACEA and MSs promote immunogenic tumor cell death and create a tumor‐suppressive TME by increasing M1‐like tumor‐associated macrophages and CD8+ T cells. In summation, this study demonstrates strong prospects of improving anti‐tumor effects of drug delivering platforms through molecular design.

Abstract Background Triple negative breast cancers (TNBC) account for approximately 15% of all breast cancers and are associated with a shorter median survival mainly due to locally advanced tumor and high risk of metastasis. The current neoadjuvant treatment for TNBC consists of a regimen of immune checkpoint blocker and chemotherapy (chemo-ICB). Despite the frequent use of this combination for TNBC treatment, moderate results are observed and its clinical benefit in TNBC remains difficult to predict. Patient-derived tumor organoids (PDTO) are 3D in vitro cellular structures obtained from patient’s tumor samples. More and more evidence suggest that these models could predict the response of the tumor from which they are derived. PDTO may thus be used as a tool to predict chemo-ICB efficacy in TNBC patients. Method The TRIPLEX study is a single-center observational study conducted to investigate the feasibility of generating PDTO from TNBC and to evaluate their ability to predict clinical response. PDTO will be obtained after the dissociation of biopsies and embedding into extra cellular matrix. PDTO will be cultured in a medium supplemented with growth factors and signal pathway inhibitors. Molecular and histological analyses will be performed on established PDTO lines to validate their phenotypic proximity with the original tumor. Response of PDTO to chemo-ICB will be assessed using co-cultures with autologous immune cells collected from patient blood samples. PDTO response will finally be compared with the response of the patient to evaluate the predictive potential of the model. Discussion This study will allow to assess the feasibility of using PDTO as predictive tools for the evaluation of the response of TNBC patients to treatments. In the event that PDTO could faithfully predict patient response in clinically relevant time frames, a prospective clinical trial could be designed to use PDTO to guide clinical decision. This study will also permit the establishment of a living biobank of TNBC PDTO usable for future innovative strategies evaluation. Trial registration The clinical trial (version 1.2) has been validated by local research ethic committee on December 30th 2021 and registered at ClinicalTrials.gov with the identifier NCT05404321 on June 3rd 2022, version 1.2.

Sintilimab combined with pemetrexed and platinum met the primary endpoint of improving progression-free survival (PFS) as a first-line therapy for nonsquamous non-small cell lung cancer (NSCLC) in the phase 3 trial ORIENT-11 (NCT03607539). As seen in similar trials, the addition of sintilimab, a PD-1 inhibitor, to chemotherapy improved the PFS without significantly worsening the toxicity, with improvements in response rate and duration of response. In contrast to previous trials, the ORIENT-11 trial was conducted completely in China. Both intrinsic and extrinsic factors are important to consider when reviewing foreign clinical trial data, as they may influence the efficacy and the safety outcomes. Here we discuss the applicability of ORIENT-11 clinical results to a Western population.

Introduction: Primary thyroid lymphoma is defined as a lymphoma involving only the thyroid gland, or thyroid gland with regional lymph nodes without contiguity or metastasis to other areas at the time of diagnosis. Hashimoto’s thyroiditis is a known risk factor for the disease. It responds well to chemotherapy but since it is a rare clinical entity, the diagnosis is often missed, thereby subjecting the patient to extensive surgery. Case report: A 69 years old male presented with rapidly progressive swelling in front of neck for 10 days associated with dysphagia, odynophagia and dyspnoea. He had right lobe thyromegaly with multiple cervical lymphadenopathy with ultrasonographic risk stratification of TIRADS 5. Diagnosis was clinched by core biopsy report on immunohistochemistry as Diffuse Large B Cell Non-Hodgkin’s Lymphoma. Positron emission tomography computerized scan revealed 18-fluorodeoxyglucose avid grossly enlarged thyroid lobes and isthmus with multiple bilateral cervical lymph nodes. Documenting the stage of disease as III E, he was managed with Chemo-immunotherapy consisting of RCVP regime with complete remission. Conclusion: Primary thyroid lymphoma with extra-thyroid involvement can be rapidly progressing and life threatening. However, timely investigation leads to correct diagnosis, appropriate curative medical management and can avoid unwarranted surgery.

Abstract Typical chemo-immunotherapy against malignant carcinoma, is characterized by the combined application of chemotherapeutic agents and monoclonal antibodies for immune checkpoint blockade (ICB). Temporary ICB with antibodies would not depress tumor intrinsic PD-L1 expression and potential PD-L1 adaptive upregulation during chemotherapy, thus exerting limited immunotherapy efficacy. Herein, we developed novel polymer-lipid hybrid nanoparticles (2-BP/CPT-PLNs) for inducing PD-L1 degradation by inhibiting palmitoylation with bioactive palmitic acid analog 2-bromopalmitate (2-BP) to replace PD-L1 antibody (αPD-L1) for ICB therapy, thus achieving highly efficient antitumor immune via immunogenic cell death (ICD) induced by potentiated chemotherapy. GSH-responsive and biodegradable polymer-prodrug CPT-ss-PAEEP10 assisted as a cationic helper polymer could help to stabilize 2-BP/CPT-PLNs co-assembled with 2-BP, and facilitate the tumor site-specific delivery and intracellular release of water-insoluble camptothecin (CPT) in vivo. 2-BP/CPT-PLNs would reinforce cytotoxic CD8+ T cell-mediated antitumor immune response via promoting intratumoral lymphocytes cells infiltration and activation. 2-BP/CPT-PLNs significantly prevented melanoma progression and prolonged life survival of mice beyond the conventional combination of irinotecan hydrochloride (CPT-11) and αPD-L1. Our work first provided valuable instructions for developing bioactive lipid analogs-derived nanoparticles via lipid metabolism intervention for oncotherapy. Graphical Abstract

BackgroundVenous thromboembolism (VTE) is a serious complication in non-small cell lung cancer (NSCLC) patients. The use of thromboprophylactic therapy is subject to an accurate assessment of the VTE risk depending on patients, tumor characteristics and type of systemic antineoplastic treatments. However, little is known concerning the risk of VTE in patients suffering from an advanced NSCLC treated with first-line chemo-immunotherapy and the impact of tumor biomarkers such as PD-L1 expression.MethodsWe performed a retrospective, observational, single-centre study in a cohort of advanced NSCLC patients treated with first-line chemo-immunotherapy. The primary endpoint was the incidence of VTE. Secondary endpoints were the cumulative incidence of VTE, the impact of PD-L1 on VTE occurrence, overall survival, the rate of VTE recurrence under anticoagulant treatment and the rate of bleeding complications.Results109 patients were included, of whom 21 (19.3%) presented a VTE event during a median follow-up of 13 months. VTE incidence at 3, 6 and 12 months was 12.1%, 15.1% and 17.5% respectively. 61% were pulmonary embolisms, 9.5% were isolated deep vein thrombosis and 14.3% were central venous catheter-related thrombosis. Our study did not show a significant impact of PD-L1 on VTE occurrence. Overall survival at 6, 12 and 24 months was 81.9%, 74.4% and 70.3% respectively. Four patients developed a recurrent VTE under anticoagulation therapy 3 to 5 months after the first VTE event. One patient suffered from a major bleeding complication while under anticoagulation therapy, leading to death.ConclusionVTE is a common complication in advanced NSCLC patients treated with concomitant chemo-immunotherapy. In our study, 19.3% of patients developed a VTE during a median follow-up of 13 months. PD-L1 did not appear to be associated with VTE occurrence. We recorded high VTE recurrence rates despite anticoagulant treatment. Further investigations are needed to determine if high PD-L1 expression is associated with VTE.

Abstract Poor immunogenicity seriously hampers the broader implementation of antitumor immunotherapy. Enhanced immunogenicity capable of achieving greater antitumor immunity is urgently required. Here, a novel polymer that contains hydrophobic ferrocene (Fc) units and thioketal bonds in the main chain, which further delivered a prodrug of oxaliplatin and artesunate, i.e., Artoxplatin, to cancer cells is described. This polymer with Fc units in the nanoparticle can work as a polyigniter to spark the peroxide bonds in Artoxplatin and generate abundant reactive oxygen species (ROS) to kill cancers as nanobombig for cancer therapy. Moreover, ROS can trigger the breakdown of thioketal bonds in the polymer, resulting in the biodegradation of the polymer. Importantly, nanobombig can facilitate the maturation of dendritic cells and promote the activation of antitumor immunity, through the enhanced immunogenic cell death effect by ROS generated in situ. Furthermore, metabolomics analysis reveals a decrease in glutamine in nanobombig‐treated cancer cells, resulting in the upregulation of programmed death ligand 1 (PD‐L1). Consequently, it is further demonstrated enhanced tumor inhibitory effects when using nanobombig combined with anti‐PD‐L1 therapy. Overall, the nanosystem offers a rational design of an efficient chemo‐immunotherapy regimen to promote antitumor immunity by improving tumor immunogenicity, addressing the key challenges cancer immunotherapy faced.

Abstract Patients with colorectal cancer (CRC) and diffuse peritoneal metastasis (PM) are not eligible for surgical intervention. Thus, palliative treatment remains the standard of care in clinical practice. Systemic chemotherapy fails to cause drug accumulation at the lesion sites, while intraperitoneal chemotherapy (IPC) is limited by high clearance rates and associated complications. Given the poor prognosis, a customized OxP/R848@PLEL hydrogel delivery system has been devised to improve the clinical benefit of advanced CRC with diffuse PM. This system is distinguished by its simplicity, security, and efficiency. Specifically, the PLEL hydrogel exhibits excellent injectability and thermosensitivity, enabling the formation of drug depots within the abdominal cavity, rendering it an optimal carrier for IPC. Oxaliplatin (OxP), a first‐line drug for advanced CRC, is cytotoxic and enhances the immunogenicity of tumors by inducing immunogenic cell death. Furthermore, OxP and resiquimod (R848) synergistically enhance the maturation of dendritic cells, promote the expansion of cytotoxic T lymphocytes, and induce the formation of central memory T cells. Moreover, R848 domesticates macrophages to an anti‐tumor phenotype. OxP/R848@PLEL effectively eradicates peritoneal metastases, completely inhibits ascites production, and significantly prolongs mice lifespan. As such, it provides a promising approach to managing diffuse PM in patients with CRC without surgical indications.

AbstractMitoxantrone (MX) can induce the immunogenic-cell death (ICD) of tumor cells and activate anti-tumor immune responses. However, it can also cause high expression of indole amine 2, 3-dioxygenase (IDO) during ICD, leading to T-cell apoptosis and a weakened immune response. An IDO inhibitor, 1-methyl tryptophan (1-MT), can inhibit the activity of IDO caused by MX, resulting in enhanced chemo-immunotherapy. Here, MX-1-MT was connected by ester bond which could be broken in an acidic tumor microenvironment. MX-1-MT was combined with polyethylene glycol (PEG) via a disulfide bond which could be reduced by glutathione overexpressed in tumors, thereby accelerating drug release at target sites. Folic acid-modified distearoyl phosphoethanolamine-polyethylene glycol (DSPE-PEG-FA) was introduced to form targeting micelles. The micelles were of uniform particle size, high stability, and high responsiveness. They could be taken-up by drug-resistant MCF-7/ADR cells, displayed high targeting ability, and induced enhanced cytotoxicity and ICD. Due to 1-MT addition, micelles could inhibit IDO. In vivo studies demonstrated that micelles could accumulate in the tumor tissues of nude mice, resulting in an enhanced antitumor effect and few side-effects.

Chemo-immunotherapy has become the best first-line treatment for advanced lung cancer patients without oncogenic drivers. However, it may also lead to an increased incidence and severity of treatment-related adverse events. In this retrospective study, lung cancer patients administrated with either anti-PD-1 or anti-PD-L1 treatment plus chemotherapy were included. Data on demographic characteristics, disease characteristics, treatment strategies, laboratory results, and clinical outcomes were collected from the Electronic Medical Records System and evaluation scales. Chi-square, univariate, and multivariate logistic regression analyses were used to identify the risk factors for immune-related adverse events (irAEs). A total of 116 patients were included in the study, and the majority experienced treatment-related adverse events. Adverse events of any grade were reported in 114 (98.3%) patients, with 73 (62.9%) experiencing Grade 3 or higher events. The most frequent adverse events were anemia (67.2%), decreased appetite (62.9%), and alopecia (53.4%). Fifty-four (46.6%) patients were diagnosed with irAEs, with hypothyroidism (28.4%) being the most commonly reported. Multivariable analysis demonstrated a significant correlation between the number of treatment cycles, elevated baseline levels of thyroid stimulating hormone (TSH) and interleukin-6 (IL-6) with irAEs (OR = 1.222, P = 0.009, OR = 1.945, P = 0.016, OR = 1.176, P = 0.004), and IL-6 was identified as a strong predictor of severe irAEs (OR = 1.084, P = 0.014). Our study demonstrated the safety of chemo-immunotherapy in lung cancer patients without additional toxicity. The number of treatment cycles, higher baseline levels of TSH and IL-6 were identified as potential clinical biomarkers for irAEs. The findings of this study demonstrate that immunotherapy combination treatments did not lead to additional toxicity in lung cancer patients. Moreover, the results indicate that a higher number of treatment cycles, elevated baseline IL-6 levels and TSH are associated with an increased risk of irAEs. [ABSTRACT FROM AUTHOR]

Chemo-immunotherapy has made significant progress in cancer treatment. However, the cancer cell self-defense mechanisms, including cell cycle checkpoint and programmed cell death-ligand 1 (PD-L1) upregulation, have greatly hindered the therapeutic efficacy. Herein, norcantharidin (NCTD)-platinum (Pt) codelivery nanoparticles (NC-NP) with tumor-sensitive release profiles are designed to overcome the self-defense mechanisms via synergistic chemo-immunotherapy. NC-NP remains stable under normal physiological conditions but quickly releases 1,2-diaminocyclohexane-platinum(II) (DACHPt, a parent drug of oxaliplatin) and NCTD in response to the tumor acidity. NCTD inhibits protein phosphatase 2A (PP2A) activity to relieve cell cycle arrest and downregulates the tumor PD-L1 expression to disrupt the programmed cell death-1 (PD-1)/PD-L1 interaction, synergistically enhancing Pt-based chemotherapy and immunogenic cell death-induced immunotherapy. As a result, NC-NP exhibits potent synergistic cytotoxicity and promotes T cell recruitment to generate robust antitumor immune responses. The dual synergism exhibits potent antitumor activity against orthotopic 4T1 tumors, providing a promising chemo-immunotherapy paradigm for cancer treatment. [ABSTRACT FROM AUTHOR]

Injectable hydrogels have attracted increasing attention for promoting systemic antitumor immune response through the co-delivery of chemotherapeutics and immunomodulators. However, the biosafety and bioactivity of conventional hydrogel depots are often impaired by insufficient possibilities for post-gelling injection and means for biofunction integration. Here, an unprecedented injectable stimuli-responsive immunomodulatory depot through programming a super-soft DNA hydrogel adjuvant is reported. This hydrogel system encoded with adenosine triphosphate aptamers can be intratumorally injected in a gel formulation and then undergoes significant molecular conformation change to stimulate the distinct release kinetics of co-encapsulated therapeutics. In this scenario, doxorubicin is first released to induce immunogenic cell death that intimately works together with the polymerized cytosine-phosphate-guanine oligodeoxynucleotide (CpG ODN) in gel scaffold for effectively recruiting and activating dendritic cells. The polymerized CpG ODN not only enhances tumor immunogenicity but minimizes free CpG-induced splenomegaly. Furthermore, the subsequently released anti-programmed cell death protein ligand 1 (aPDL1) blocks the corresponding immune inhibitory checkpoint molecule on tumor cells to sensitize antitumor T-cell immunity. This work thus contributes to the first proof-of-concept demonstration of a programmable super-soft DNA hydrogel system that perfectly matches the synergistic therapeutic modalities based on chemotherapeutic toxicity, in situ vaccination, and immune checkpoint blockade. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with high-risk neuroblastoma who are unable to achieve a complete response to induction chemotherapy are known as primary refractory and have poor outcomes. We investigated the combination of chemotherapy (irinotecan (I) and temozolomide (T)) plus anti-GD2 immunotherapy (naxitamab and sargramostim (GM-CSF)), the so-called HITS, against primary resistant high-risk neuroblastoma. Patients were treated when they had measurable chemo-resistant disease at the end of induction treatment but no evidence of progressive disease. Each cycle of HITS comprised Irinotecan 50 mg/m2/day intravenously plus Temozolomide 150 mg/m2/day orally (days 1–5); naxitamab 2.25 mg/kg/day IV on days 2, 4, 8 and 10, (total 9 mg/kg or 270 mg/m2 per cycle), and GM-CSF 250 mg/m2/day subcutaneously, for days 6–10 was used. Thirty-four patients received a median of four cycles. Treatment was outpatient and, overall, well tolerated. Patients treated with HITS immediately after induction failure (cohort 1 or early treatment) had a statistically significant improved survival rate compared to patients treated late (cohort 2). In summary, naxitamab-based chemo-immunotherapy is effective against primary chemo-resistant neuroblastoma, significantly improving long-term outcomes when administered early during the course of treatment. Patients with high-risk neuroblastoma (HR-NB) who are unable to achieve a complete response (CR) to induction therapy have worse outcomes. We investigated the combination of humanized anti-GD2 mAb naxitamab (Hu3F8), irinotecan (I), temozolomide (T), and sargramostim (GM-CSF)—HITS—against primary resistant HR-NB. Eligibility criteria included having a measurable chemo-resistant disease at the end of induction (EOI) treatment. Patients were excluded if they had progressive disease (PD) during induction. Prior anti-GD2 mAb and/or I/T therapy was permitted. Each cycle, administered four weeks apart, comprised Irinotecan 50 mg/m2/day intravenously (IV) plus Temozolomide 150 mg/m2/day orally (days 1–5); naxitamab 2.25 mg/kg/day IV on days 2, 4, 8 and 10, (total 9 mg/kg or 270 mg/m2 per cycle), and GM-CSF 250 mg/m2/day subcutaneously was used (days 6–10). Toxicity was measured using CTCAE v4.0 and responses through the modified International Neuroblastoma Response Criteria (INRC). Thirty-four patients (median age at treatment initiation, 4.9 years) received 164 (median 4; 1–12) HITS cycles. Toxicities included myelosuppression and diarrhea, which was expected with I/T, and pain and hypertension, expected with naxitamab. Grade ≥3-related toxicities occurred in 29 (85%) of the 34 patients; treatment was outpatient. The best responses were CR = 29% (n = 10); PR = 3% (n = 1); SD = 53% (n = 18); PD = 5% (n = 5). For cohort 1 (early treatment), the best responses were CR = 47% (n = 8) and SD = 53% (n = 9). In cohort 2 (late treatment), the best responses were CR = 12% (n = 2); PR = 6% (n = 1); SD = 53% (n = 9); and PD = 29% (n = 5). Cohort 1 had a 3-year OS of 84.8% and EFS 54.4%, which are statistically significant improvements (EFS p = 0.0041 and OS p = 0.0037) compared to cohort 2. In conclusion, naxitamab-based chemo-immunotherapy is effective against primary chemo-resistant HR-NB, increasing long-term outcomes when administered early during the course of treatment. [ABSTRACT FROM AUTHOR]

Background: Triple negative breast cancers (TNBC) account for approximately 15% of all breast cancers and are associated with a shorter median survival mainly due to locally advanced tumor and high risk of metastasis. The current neoadjuvant treatment for TNBC consists of a regimen of immune checkpoint blocker and chemotherapy (chemo-ICB). Despite the frequent use of this combination for TNBC treatment, moderate results are observed and its clinical benefit in TNBC remains difficult to predict. Patient-derived tumor organoids (PDTO) are 3D in vitro cellular structures obtained from patient's tumor samples. More and more evidence suggest that these models could predict the response of the tumor from which they are derived. PDTO may thus be used as a tool to predict chemo-ICB efficacy in TNBC patients. Method: The TRIPLEX study is a single-center observational study conducted to investigate the feasibility of generating PDTO from TNBC and to evaluate their ability to predict clinical response. PDTO will be obtained after the dissociation of biopsies and embedding into extra cellular matrix. PDTO will be cultured in a medium supplemented with growth factors and signal pathway inhibitors. Molecular and histological analyses will be performed on established PDTO lines to validate their phenotypic proximity with the original tumor. Response of PDTO to chemo-ICB will be assessed using co-cultures with autologous immune cells collected from patient blood samples. PDTO response will finally be compared with the response of the patient to evaluate the predictive potential of the model. Discussion: This study will allow to assess the feasibility of using PDTO as predictive tools for the evaluation of the response of TNBC patients to treatments. In the event that PDTO could faithfully predict patient response in clinically relevant time frames, a prospective clinical trial could be designed to use PDTO to guide clinical decision. This study will also permit the establishment of a living biobank of TNBC PDTO usable for future innovative strategies evaluation. Trial registration: The clinical trial (version 1.2) has been validated by local research ethic committee on December 30th 2021 and registered at ClinicalTrials.gov with the identifier NCT05404321 on June 3rd 2022, version 1.2. [ABSTRACT FROM AUTHOR]