Orchestrated metal-coordinated carrier-free celastrol hydrogel intensifies T cell activation and regulates response to immune checkpoint blockade for synergistic chemo-immunotherapy.

The challenges generated by insufficient T cell activation and infiltration have constrained the application of immunotherapy. Making matters worse, the complex tumor microenvironment (TME), resistance to apoptosis collectively poses obstacles for cancer treatment. The carrier-free small molecular self-assembly strategy is a current research hotspot to overcome these challenges. This strategy can transform multiple functional agents into sustain-released hydrogel without the addition of any excipients. Herein, a coordination and hydrogen bond mediated tricomponent hydrogel (Cel hydrogel) composed of glycyrrhizic acid (GA), copper ions (Cu2+) and celastrol (Cel) was initially constructed. The hydrogel can regulate TME by chemo-dynamic therapy (CDT), which increases reactive oxygen species (ROS) in conjunction with GA and Cel, synergistically expediting cellular apoptosis. What's more, copper induced cuproptosis also contributes to the anti-tumor effect. In terms of regulating immunity, ROS generated by Cel hydrogel can polarize tumor-associated macrophages (TAMs) into M1-TAMs, Cel can induce T cell proliferation as well as activate DC mediated antigen presentation, which subsequently induce T cell proliferation, elevate T cell infiltration and enhance the specific killing of tumor cells, along with the upregulation of PD-L1 expression. Upon co-administration with aPD-L1, this synergy mitigated both primary and metastasis tumors, showing promising clinical translational value.

Capturing Hydrophilic Chemotherapeutics Agents Into siRNA-Encapsulated Vesicle-Like Nanoparticles for Convenient ICB-Chemo Combination Therapy.

Clinical evidence has demonstrated that combining immune checkpoint blockade (ICB) therapy with chemotherapy significantly improves response rates to ICB therapy and therapeutic efficacy in various tumor types. However, a convenient method for achieving synergistic ICB therapy and chemotherapy with precise co-delivery of both agents is still highly desirable. In this study, a strategy for co-delivering small interfering RNA (siRNA) encapsulated in vesicle-like nanoparticles (VNPsiRNA) and chemotherapeutic drugs is aimed to develop. It is discovered that the hydrophilic chemotherapeutic drug mitoxantrone hydrochloride (MTO·2HCl) can be captured into VNPsiRNA. The resulting VNPsiRNACpMTO can simultaneously block immune checkpoints via RNA silencing and induce chemotherapeutic effects on tumor cells. The mechanism of MTO·2HCl is elucidates, captures, and demonstrates the superior therapeutic effect of VNPsiRNACpMTO through chemo-immunotherapy. This strategy can also be extended to deliver other hydrochloride anticancer drugs, such as doxorubicin hydrochloride (DOX·HCl), for achieving synergistic combination therapy. This study provides a facile strategy for enhancing combined ICB and chemotherapy via co-delivering siRNA and chemotherapeutic drugs, offering a promising approach to cancer treatment.

Muramyl Dipeptide-Presenting Polymersomes as Artificial Nanobacteria to Boost Systemic Antitumor Immunity.

The clinical efficacy of cancer vaccines is closely related to immunoadjuvants that play a crucial role in magnifying and prolonging the immune response. Muramyl dipeptide (MDP), a minimal and conserved peptidoglycan found in almost all bacteria, can trigger robust immune activation by uniquely antagonizing the nucleotide-binding oligomerization domain 2 (NOD2) pathway. However, its effectiveness has been hindered by limited solubility, poor membrane penetration, and rapid clearance from the body. Here, we introduce MDP-presenting polymersomes as artificial nanobacteria (NBA) to boost the antitumor immune response. The NBA, featuring abundant MDP molecules, induces superior stimulation of immune cells including macrophages and bone marrow-derived dendritic cells (BMDCs) compared to free MDP, likely via facilitating immune cell uptake and cooperatively stimulating systemic NOD2 signaling. Importantly, systemic administration of NBA significantly enhances the chemo-immunotherapy of B16-F10 melanoma-bearing mice pretreated with doxorubicin by reversing the immunosuppressive tumor microenvironment. Furthermore, NBA carrying ovalbumin and B16-F10 cell lysates induces robust OVA-IgG antibody production and effectively inhibit tumor growth, respectively. The artificial nanobacteria hold great promise as a potent systemic immunoadjuvant for cancer immunotherapy.

Blood biomarkers to predict the efficacy of neoadjuvant chemo-immunotherapy in non-small cell lung cancer patients.

Background: Neoadjuvant chemo-immunotherapy has increased the number of patients with advanced lung cancer eligible for surgery. However, only a small number of such patients respond to this approach. Intensive research is being conducted to identify biomarkers to predict the efficacy of neoadjuvant chemo-immunotherapy. Among these, blood predictive biomarkers are particularly promising, and have the advantages of being both non-invasive and cost effective. This study aims to evaluate the predictive value of blood biomarkers in determining the efficacy of neoadjuvant chemo-immunotherapy for patients with non-small cell lung cancer (NSCLC), addressing a critical need for more personalized treatment strategies in clinical practice. Methods: We retrospectively collected the data of 199 NSCLC patients who received neoadjuvant chemo-immunotherapy from January 1, 2021 to December 31, 2023, at Zhejiang Cancer Hospital. We then analyzed the performance of blood biomarkers in predicting the efficacy of neoadjuvant chemo-immunotherapy. Results: The patients in the major pathological response (MPR) group had significantly higher pre-treatment squamous cell carcinoma antigen (SCCA) levels, and a significantly lower post-treatment platelet-lymphocyte ratio (PLR) than those in the non-MPR group. For patients with higher pre-treatment SCCA levels, the 1- and 2-year event-free survival (EFS) rates were 97.87% [95% confidence interval (CI): 94.99-100.00%] and 93.21% (95% CI: 84.32-100.00%), respectively. In those with lower pre-treatment SCCA levels, the 1- and 2-year EFS rates were 91.39% (95% CI: 84.93-98.35%) and 82.24% (95% CI: 72.42-93.39%), respectively. The survival analysis showed that higher pre-treatment SCCA levels were correlated with improved EFS (P=0.02) in patients receiving neoadjuvant chemo-immunotherapy. Conversely, for patients undergoing surgery alone, high pre-treatment SCCA levels were correlated with a poorer prognosis [disease-free survival (DFS), P=0.001]. These findings confirm the value of SCCA levels in predicting which patients will have a more favorable response to neoadjuvant chemo-immunotherapy. In patients receiving neoadjuvant chemo-immunotherapy, a high post-treatment PLR indicated a poorer prognosis (P=0.02). The Cox regression analysis indicated that the pre-treatment SCCA level (P=0.04) and post-treatment PLR (P=0.04) were independent predictive factors of EFS. Conclusions: In patients receiving neoadjuvant chemo-immunotherapy, high pre-treatment SCCA levels and low post-treatment PLRs were significantly associated with better efficacy and survival. Thus, these biomarkers could be used to guide the choice of treatment modalities.

Clinical Management in NSCLC Patients With EGFR Mutation After Osimertinib Progression With Unknown Resistance Mechanisms.

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.

Synergistic Chemo-Immunotherapy Using pH-Responsive Nanoparticles in Breast Cancer Treatment: In Vitro and In Vivo Studies.

Recent research underscores the pivotal role of the heterogeneous multicellular interactome within the tumor microenvironment (TME) in tumor progression and survival. Tumor-associated macrophages (TAMs), among other nonmalignant cells in the TME, promote an immunosuppressive environment, fostering tumor cell survival, proliferation, and resistance. Hence, combining chemotherapy with immunomodulatory agents to transition TAMs to an immunostimulatory phenotype holds immense therapeutic potential. The present study focuses on developing tumor-responsive nanoparticles (NPs) for combined chemo-immunotherapy using resiquimod (RSQ), a TLR 7/8 agonist as an immunomodulator, and paclitaxel (PTX) as chemotherapeutics. A pH-responsive NP known as PHNP, tailored with a star-shaped PLGA conjugated with poly histidine, was engineered to selectively deliver a consistent ratio of PTX and RSQ directly to the tumor site. In vitro studies demonstrate enhanced drug release at pH 6.4, increased penetration in tumor spheroids, and increased cytotoxic efficacy against breast cancer cells. Furthermore, PHNPs activate macrophages for antitumor activity. In vivo studies demonstrated a notable rise in plasma AUC and improved delivery of drugs to the tumor using PHNPs, resulting in enhanced effectiveness against tumor growth in a mouse orthotopic breast cancer model. Notably, PHNP treatment elevated intratumoral ROS and apoptosis levels and inhibited lung metastasis. Overall, this study underscores the potential of the PTX and RSQ combination as a prospective combined chemo-immunotherapeutic modality.

Biomolecular Condensates Based on Amino Acid for Enhancing Oral Bioavailability and Therapeutic Efficacy of Hydrophobic Drugs.

The oral administration of chemo- or immunotherapeutic drugs presents a compelling alternative for patients with malignant colorectal cancer, offering a convenient and patient-compliant "hospital-free" strategy. Unfortunately, the hydrophobic nature of many drug candidates, alongside the harsh conditions of the gastrointestinal tract, frequently results in suboptimal bioavailability and heightened systemic toxicity. To address these challenges, we harnessed the unique properties of biomolecular condensates, which form through a liquid-liquid phase separation mechanism, to develop a versatile platform for drug encapsulation and delivery. In this study, we introduce a reliable and effective amorphous oral drug delivery system based on biomolecular condensates derived from the amino acid derivative N-(benzyloxycarbonyl)-l-proline (ZP). These ZP condensates exhibit dynamic intermolecular interactions and possess unique physicochemical attributes such as fluidity and viscoelasticity. They significantly improve the solubility of hydrophobic drugs, ensuring enhanced stability and optimized pharmacokinetics under physiological and gastrointestinal conditions. By maintaining drugs in an amorphous state, we substantially increased drug bioavailability and markedly improved pharmacokinetics. Furthermore, the ZP condensates demonstrate potential as an integrated therapeutic platform capable of potentiating the synergies between chemotherapy and immunotherapy while concurrently reducing systemic toxicity. This has resulted in a significant enhancement of chemo-immunotherapy efficacy in the treatment of colorectal cancer, representing a notable advancement in drug delivery and oncology.

Paclitaxel Prodrug Enables Glutathione Depletion to Boost Cancer Treatment.

Herein, we constructed a paclitaxel (PTX) prodrug (PA) by conjugating PTX with acrylic acid as a cysteine-depleting agent. The as-synthesized PA can assemble with diacylphosphatidylethanolamine-PEG2000 to form stable nanoparticles (PA NPs). After endocytosis into cells, PA NPs can specifically react with cysteine and trigger release of PTX for chemotherapy. On the other hand, the depletion of cysteine can greatly downregulate the intracellular content of glutathione and lead to oxidative stress outburst-provoking ferroptosis. The released PTX can elicit antitumor immune response by inducing immunogenic cell death, thus promoting dendritic cells maturation and cascaded cytotoxic T lymphocytes activation, which not only produces a robust immunotherapy effect but also synergizes the ferroptosis therapy by inhibiting cysteine transport via the release of interferon-γ in the activated immune system. As a result, PA NPs exhibit favorable in vitro and in vivo antitumor performance with reduced systemic toxicity. Our work highlights the potential of simple molecular design of prodrugs for enhancing the therapeutic efficacy toward malignant cancer.

The Chemo-Immunotherapeutic Roles of Tumor-Derived Extracellular Vesicle-Based Paclitaxel Delivery System in Hepatocarcinoma.

As a first-line chemotherapeutic agent, albumin-bound paclitaxel (PA) has a considerable effect on the treatment of various cancers. However, in chemotherapy for hepatocarcinoma, the sensitivity to PA is low owing to the innate resistance of hepatocarcinoma cells; the toxicity and side effects are severe, and the clinical treatment impact is poor. In this study, we present a unique nanodrug delivery system. The ultraviolet (UV)-induced tumor-cell-derived extracellular vesicles (EVs) were isolated and purified by differential centrifugation. Then, PA was loaded by coextrusion to create a vesicle drug delivery system (EVPA). By employing the EV-dependent enhanced retention effect and specific homing effect, EVPA would passively and actively target tumor tissues, activate the immune response to release PA, and achieve the combination therapeutic effect of chemo-immunotherapy on hepatocarcinoma. We demonstrated that the tumor-killing effect of EVPA is superior to that of PA, both in vivo and in vitro and that EVPA can be effectively taken up by hepatocarcinoma and dendritic cells, activate the body's specific immune response, promote the infiltration of CD4+ and CD8+ T cells in tumor tissues, and exert a precise killing effect on hepatocarcinoma cells via chemo-immunotherapy.

A thermo-responsive chemically crosslinked long-term-release chitosan hydrogel system increases the efficiency of synergy chemo-immunotherapy in treating brain tumors.

Glioblastoma multiforme (GBM) is an aggressive and common brain tumor. The blood-brain barrier prevents several treatments from reaching the tumor. This study proposes a Chemo-Immunotherapy synergy treatment chemically crosslinked hydrogel system that is injected into the tumor to treat GBM. The strategy uses doxorubicin and BMS-1 with a thermo-responsive and chemically crosslinked hydrogel for extended drug release into the affected area. The hydrogels are produced by mixing with Chitosan (Chi), modified Pluronic F-127 (PF-127) with aldehyde end group and doxorubicin and then chemically crosslinking the aldehyde and amine bonds to increase the drug retention time. PF-127-CHO/Chi, which gels at body temperatures and chemically crosslinks between PF-127-CHO and Chitosan, increases the time that the drug remains in the affected area and prevents the hydrogel from swelling and compressing surrounding tissue. The drug is released from the chemically crosslinked hydrogels, prevents tumor progression and increases survival for subjects with GBM tumors. The Synergy Chemo-Immunotherapy also allows more efficient treatment of GBM than chemotherapy. The PF-127-CHO/Chi DOX and BMS-1 group have a tumor that is 43 times smaller than the untreated group. These results show that the proposed chemically crosslinking hydrogel is an efficient intratumoral delivery platform for the treatment of tumors.

Radiomics nomogram for predicting chemo-immunotherapy efficiency in advanced non-small cell lung cancer.

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.

The MOEO algorithm for multi-objective optimization of the cancer immuno-chemotherapy.

In cancer treatment, chemotherapy has the disadvantage of killing both healthy and cancerous cells. Hence, the mixed-treatment of cancer such as chemo-immunotherapy is recommended. However, deriving the optimal dosage of each drug is a challenging issue. Although metaheuristic algorithms have received more attention in solving engineering problems due to their simplicity and flexibility, they have not consistently produced the best results for every problem. Thus, the need to introduce novel algorithms or extend the previous ones is felt for important optimization problems. Hence, in this paper, the multi-objective Equilibrium Optimizer algorithm, as an extension of the single-objective Equilibrium Optimizer algorithm, is recommended for cancer treatment problems. Then, the performance of the proposed algorithm is considered in both chemotherapy and mixed chemo-immunotherapy of cancer, considering the constraints of the tumor-immune dynamic system and the health level of the patients. For this purpose, two different patients with real clinical data are considered. The Pareto front obtained from the multi-objective optimization algorithm shows the points that can be selected for treatment under different criteria. Using the proposed multi-objective algorithm has reduced the total chemo-drug dose to 138.92 and 5.84 in the first patient, and 16.9 and 0.4384 in the second patient, for chemotherapy and chemo-immunotherapy, respectively. Comparing the results with previous studies demonstrates MOEO's superior performance in both chemotherapy and chemo-immunotherapy. However, it is shown that the proposed algorithm is more suitable for mixed-treatment approaches.

Mitochondrial metabolism blockade nanoadjuvant reversed immune-resistance microenvironment to sensitize albumin-bound paclitaxel-based chemo-immunotherapy.

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-ß dual-inhibitor via inducing the phosphorylation of adenosine 5'-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-ß 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.

Stimulator of Interferon Genes-Activated Biomimetic Dendritic Cell Nanovaccine as a Chemotherapeutic Booster to Enhance Systemic Fibrosarcoma Treatment.

Fibrosarcoma, a malignant mesenchymal tumor, is characterized by aggressive invasiveness and a high recurrence rate, leading to poor prognosis. Anthracycline drugs, such as doxorubicin (DOX), represent the frontline chemotherapy for fibrosarcoma, but often exhibit suboptimal efficacy. Recently, exploiting the stimulator of interferon genes (STING)-mediated innate immunity has emerged as a hopeful strategy for cancer treatment. Integrating chemotherapy with immunomodulators in chemo-immunotherapy has shown potential for enhancing treatment outcomes. Herein, we introduce an advanced dendritic cell (DC) nanovaccine, cGAMP@PLGA@CRTM (GP@CRTM), combined with low-dose DOX to enhance fibrosarcoma chemo-immunotherapy. The nanovaccine consists of poly(lactic-co-glycolic acid) (PLGA) nanoparticles encapsulating the STING agonist 2,3-cGAMP (cGAMP@PLGA, GP) as its core, and a calreticulin (CRT) high-expressing fibrosarcoma cell membrane (CRTM) as the shell. Exposing CRT on the vaccine surface aids in recruiting DCs and stimulating uptake, facilitating efficient simultaneous delivery of STING agonists and tumor antigens to DCs. This dual delivery method effectively activates the STING pathway in DCs, triggering sustained immune stimulation. Simultaneously, low-dose DOX reduces chemotherapy-related side effects, directly kills a subset of tumor cells, and increases tumor immunogenicity, thus further amplifying immune therapeutic performance. Hence, these findings demonstrate the potential of DC nanovaccine GP@CRTM as a booster for chemotherapy. Synergistically combining low-dose DOX with the DC nanovaccine emerges as a powerful chemo-immunotherapy strategy, optimizing systemic fibrosarcoma therapy.

Effect of TTF-1 expression on progression free survival of immunotherapy and chemo-/immunotherapy in patients with non-small cell lung cancer.

BACKGROUND: The choice between immunotherapy with a checkpoint inhibitor (CPI) and chemo-/immunotherapy (CIT) in patients with NSCLC stage IV is often discussed. There is some data that the effect of chemotherapy is influenced by TTF-1 expression. Little is known about the influence of thyreoid transcription factor 1 (TTF-1) expression on CIT and CPI therapy. We aimed to investigate the relationship between tumor TTF-1 expression and efficacy of CIT and CPI therapy. PATIENTS AND METHODS: We retrospectively analysed 130 patients (age 68 ± 7 y) with NSCLC stage IV. Only patients with lung adenocarcinoma were included. Patients with ALK, ROS1, RET, MET, NTRK, EGFR, BRAF mutation were excluded. Patients were treated according to the guidelines with either CPI alone (pembrolizumab, nivolumab, atezolizumab, cemiplimab) or CIT (Carboplatin/Pemetrexed/Pembrolizumab, Carboplatin/Paclitaxel/Atezolizumab). We registered patients' characteristics including TTF-1 expression. Group 1 consisted of 40 patients with CPI and TTF-1 expression, group 2 were 26 patients with CPI and with no TTF-1 expression. Group 3 consisted of 41 patients with CIT and TTF-1 expression, group 4 were 23 patients with CIT and with no TTF-1 expression. RESULTS: Group 1-4 showed comparable patients characteristics. Using cox-regression analysis, we found that TTF-1 expression resulted in an improved progression free survival (PFS) compared to patients with CPI and no TTF-1 expression (18 ± 3,15 vs. 5 ± 0,85 months, p = 0.004, 95% CI: 0,23 - 0,984). In patients, who were treated with CIT, PFS was also increased in patients with TTF-1 expression (9 ± 3,17 vs. 3 ± 0,399 months, p = 0.001, 95% CI: 0,23 - 0,85). CONCLUSIONS: In a real-life setting, we found that TTF-1 expression is associated with an increased PFS. Patients with chemo-/immunotherapy and immunotherapy seem to have a better therapy response in pulmonary adenocarcinoma with TTF-1 expression.

Induction chemotherapy backbone in frail patients with advanced NSCLC treated with chemotherapy plus pembrolizumab: a single institution retrospective audit of dose intensities from modified regimens.

Guidelines 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.

Evolving approaches in advanced gallbladder cancer with complete pathological response using chemo­immunotherapy: A case report.

The combination of chemotherapy and immunotherapy for metastatic cholangiocarcinoma (CCA) offers promising improvements in survival and response rates beyond traditional treatments. TOPAZ-1 and KEYNOTE-966 have demonstrated the efficacy of combining immunotherapy (durvalumab and pembrolizumab) with chemotherapy, even in gallbladder cancer (GBC), with a complete response rate of 2.7% in the TOPAZ-1 trial. Advanced CCA treated with immunotherapy combinations has shown complete responses influenced by high programmed death-ligand 1 (PD-L1) or Epstein-Barr virus expression. These responses were enhanced by combining radiotherapy with programmed cell death protein 1 (PD-1) blockade. A 62-year-old man was diagnosed with unresectable GBC, distant lymphatic metastases, and local invasion of liver segments 4i and 5, the colonic hepatic flexure, the duodenal bulb, and the pancreatic head. Immunohistochemical examination revealed poorly differentiated squamous cell carcinoma, without expression of PD-L1. Next generation sequencing revealed the mutation of ERBB2 R678Q and a microsatellite stable tumour. The patient started chemo-immunotherapy with cisplatin-gemcitabine plus durvalumab in June 2022. After eight cycles, a significant reduction in tumour volume and markers was reported, and therapy with durvalumab was maintained through November 2023. The subsequent computed tomography scans showed further reduction in the tumour volume, and surgical resection was performed. Histological examinations confirmed the absence of residual tumour or lymph node metastases. As of June 2024, the patient has shown no signs of disease recurrence. Several reports of conversion surgery in GBC exist, but data on pre-surgical chemo-immunotherapy are limited. Furthermore, a complete response without pathological confirmation in CCA and GBC raises several questions regarding the need for surgery after immunotherapy. Although effective disease control and tumour regression have been reported in advanced GBC with combined anti-cytotoxic T-lymphocyte associated protein 4 and anti-PD-1 agents and chemotherapy, further studies are needed to identify reliable predictive biomarkers due to unclear associations with PD-L1 expression or tumour mutational burden. Overall, chemo-immunotherapy has been effective in treating metastatic CCA, especially when tailored to specific molecular profiles. These treatments may lead to complete responses and novel strategies.

Granulocyte colony-stimulating factor has the potential to attenuate the therapeutic efficacy of chemo-immunotherapy for extensive-stage small-cell lung cancer.

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.

Cobalt(III) prodrug-based nanomedicine for inducing immunogenic cell death and enhancing chemo-immunotherapy.

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.

Multifunctional Nanoparticle-Loaded Injectable Alginate Hydrogels with Deep Tumor Penetration for Enhanced Chemo-Immunotherapy of Cancer.

Chemo-immunotherapy has become a promising strategy for cancer treatment. However, the inability of the drugs to penetrate deeply into the tumor and form potent tumor vaccines in vivo severely restricts the antitumor effect of chemo-immunotherapy. In this work, an injectable sodium alginate platform is reported to promote penetration of the chemotherapeutic doxorubicin (DOX) and delivery of personalized tumor vaccines. The injectable multifunctional sodium alginate platform cross-links rapidly in the presence of physiological concentrations of Ca2+, forming a hydrogel that acts as a drug depot and releases loaded hyaluronidase (HAase), DOX, and micelles (IP-NPs) slowly and sustainedly. By degrading hyaluronic acid (HA) overexpressed in tumor tissue, HAase can make tumor tissue "loose" and favor other components to penetrate deeply. DOX induces potent immunogenic cell death (ICD) and produces tumor-associated antigens (TAAs), which could be effectively captured by polyethylenimine (PEI) coated IP-NPs micelles and form personalized tumor vaccines. The vaccines efficaciously facilitate the maturation of dendritic cells (DCs) and activation of T lymphocytes, thus producing long-term immune memory. Imiquimod (IMQ) loaded in the core could further activate the immune system and trigger a more robust antitumor immune effect. Hence, the research proposes a multifunctional drug delivery platform for the effective treatment of colorectal cancer.