Combination Therapy Strategies Research Articles

Melanoma Derived Exosomes Amplify Radiotherapy Induced Abscopal Effect via IRF7/I-IFN Axis in Macrophages.

Radiotherapy (RT) can induce tumor regression outside the irradiation field, known as the abscopal effect. However, the detailed underlying mechanisms remain largely unknown. A tumor-bearing mouse model is successfully constructed by inducing both subcutaneous tumors and lung metastases. Single-cell RNA sequencing, immunofluorescence, and flow cytometry are performed to explore the regulation of tumor microenvironment (TME) by RT. A series of in vitro assays, including luciferase reporter, RNA Pulldown, and fluorescent in situ hybridization (FISH) assays, are performed to evaluate the detailed mechanism of the abscopal effect. In addition, in vivo assays are performed to investigate combination therapy strategies for enhancing the abscopal effect. The results showed that RT significantly inhibited localized tumor and lung metastasis progression and improved the TME. Mechanistically, RT promoted the release of tumor-derived exosomes carrying circPIK3R3, which is taken up by macrophages. circPIK3R3 promoted Type I interferon (I-IFN) secretion and M1 polarization via the miR-872-3p/IRF7 axis. Secreted I-IFN activated the JAK/STAT signaling pathway in CD8+ T cells, and promoted IFN-γ and GZMB secretion. Together, the study shows that tumor-derived exosomes promote I-IFN secretion via the circPIK3R3/miR-872-3p/IRF7 axis in macrophages and enhance the anti-tumor immune response of CD8+ T cells.

Prodrug Celecoxib‐Derived Nanoparticles Potentiate the Efficacy of Cancer Immunotherapy by Remodeling the Tumor Microenvironment

AbstractCyclooxygenase‐2 (COX‐2) and prostaglandin E2 (PGE2) play crucial roles in promoting tumor growth and facilitating immune evasion within the tumor microenvironment (TME)—functions that limit responses to immunotherapy. Recent research has highlighted the potential of celecoxib (CXB), a potent COX‐2 selective inhibitor, for enhancing the effectiveness of immunotherapy by blocking the COX‐2/PGE2 axis. However, the clinical application of CXB for cancer treatment is still hindered by its systemic adverse effects and lack of tumor‐targeting. Here, to address these limitations, PEGylated prodrug CXB‐derived nanoparticles (CXB‐NPs) are developed, a nanomedicine designed to improve the tumor delivery of CXB while minimizing its adverse side effects. CXB‐NPs demonstrate enhanced tumor accumulation and effectively inhibit tumor growth by improving the immunosuppressive TME in immunocompetent mice, surpassing the performance of parental CXB. Furthermore, when combined with anti‐PD‐1 antibody (αPD‐1) immunotherapy, CXB‐NPs exhibit superior suppression of CT26 tumor growth compared with αPD‐1 monotherapy. This combination approach reduces the infiltration of immunosuppressive immune cells while promoting the infiltration and cytotoxicity of CD8+ T cells. The findings indicate that CXB‐NPs capable of remodeling the TME provide a new combination therapy strategy for potentiating antitumor efficacy.

What Have We Learned from Molecularly Informed Clinical Trials on Thymomas and Thymic Carcinomas-Current Status and Future Directions?

Thymic epithelial tumors (TETs), which include thymomas and thymic carcinomas, are a rare, heterogeneous group of malignancies that originate from the thymus gland. As an important organ of immune cell development, thymic tumors, particularly thymomas, are often associated with paraneoplastic autoimmune disorders. The advances in targeted therapies for both solid and hematologic malignancies have resulted in improved patient outcomes, including better and more durable efficacy and improved toxicity. Targeted therapies have also been investigated in the treatment of TETs, though the results have largely been modest. These have included somatostatin-receptor-targeting therapies, KIT- and EGFR-directed tyrosine kinase inhibitors, epigenetic modulators, anti-angiogenesis agents, and agents targeting the cell proliferation and survival pathways and cell cycle regulators. Numerous investigated treatments have failed or underperformed due to a lack of a strong biomarker of efficacy. Ongoing trials are attempting to expand on previous experiences, including the exploration of effective drugs in early-stage disease. Novel combination therapy strategies are also undergoing evaluation, with the goal of augmenting efficacy and understanding the toxicity while expanding the biomarkers of efficacy and safety. With advances in technology to improve target identification and drug delivery, old targets may become new opportunities, and the subsequently developed drugs may find their place in the treatment of thymic tumors.

T lymphocyte-derived immunogenic hybrid nanovesicles for immunosuppression reversion and boosted photothermal immunotherapy

Photothermal therapy (PTT) can mediate the immunogenic cell death (ICD) of tumors through photothermal transformation, thus releasing tumor-associated antigens (TAAs) and damage-associated molecular patterns (DAMPs) to stimulate the maturation of dendritic cells (DCs) and elicit the immune response against tumors. However, PTT-mediated upregulation of the immune checkpoint molecule programmed cell death ligand 1 (PD-L1) will cause the immune evasion of tumor cells and thus increases the immunosuppression of cytotoxic T lymphocytes (CTLs), resulting in restricted photothermal immune activation. Taking advantage of the high expression of programmed cell death protein 1 (PD-1) in T lymphocytes, we develop an immunogenic photothermal hybrid nanovesicle to reverse immunosuppression and enhance PTT-induced ICD. The hybrid vesicle (TMVL-I) is constructed by phospholipid bilayer fusion of T cell-derived membrane vesicle (TMV) with high PD-1 expression and the indocyanine green (ICG)-loaded thermosensitive liposome (L-I). TMVL-Is bind to the tumor cells with PTT-induced upregulation of PD-L1, effectively blocking the PD-1/PD-L1 pathway between CTLs and tumor cells, thus reversing PD-L1-mediated tumor immunosuppression and intensifying photothermal-induced ICD effects. These processes significantly induce the maturation of DCs and enhance the infiltration of CTLs into both primary and distal tumors and the activation of spleen CTLs, strongly inhibiting the growth of B16 xenograft tumors and greatly improving the survival rate of B16 xenograft mice. This work provides a feasible strategy for immunosuppressive microenvironment reprogramming-based combination therapy.

Advances and perspectives in phototherapy-based combination therapy for cancer treatment.

Phototherapy, including photothermal therapy (PTT) and photodynamic therapy (PDT), has the advantages of spatiotemporal selectivity, non-invasiveness, and negligible drug resistance. Phototherapy has been approved for treating superficial epidermal tumors. However, its therapeutic efficacy is limited by the hypoxic tumor microenvironment and the highly expressed heat shock protein. Moreover, poor tissue penetration and focused irradiation laser region in phototherapy make treating deep tissues and metastatic tumors challenging. Combination therapy strategies, which integrate the advantages of each treatment and overcome their disadvantages, can significantly improve the therapeutic efficacy. Recently, many combination therapy strategies have been reported. Our study summarizes the strategies used for combining phototherapy with other cancer treatments such as chemotherapy, immunotherapy, sonodynamic therapy, gas therapy, starvation therapy, and chemodynamic therapy. Some research cases were selected to analyze the combination therapy effect, delivery platform feature, and synergetic anticancer mechanisms. Moreover, additional research cases are summarized in the tables. This review provides strong evidence that phototherapy-based combination strategies can enhance the anticancer effect compared with phototherapy alone. Additionally, the challenges and future perspectives associated with these combinational therapies are discussed.

GSDMD is associated with survival in human breast cancer but does not impact anti-tumor immunity in a mouse breast cancer model.

Inflammation plays a pivotal role in cancer development, with chronic inflammation promoting tumor progression and treatment resistance, whereas acute inflammatory responses contribute to protective anti-tumor immunity. Gasdermin D (GSDMD) mediates the release of pro-inflammatory cytokines such as IL-1β. While the release of IL-1β is directly linked to the progression of several types of cancers, the role of GSDMD in cancer is less clear. In this study, we show that GSDMD expression is upregulated in human breast, kidney, liver, and prostate cancer. Higher GSDMD expression correlated with increased survival in primary breast invasive carcinoma (BRCA), but not in liver hepatocellular carcinoma (LIHC). In BRCA, but not in LIHC, high GSDMD expression correlated with a myeloid cell signature associated with improved prognosis. To further investigate the role of GSDMD in anticancer immunity, we induced breast cancer and hepatoma tumors in GSDMD-deficient mice. Contrary to our expectations, GSDMD deficiency had no effect on tumor growth, immune cell infiltration, or cytokine expression in the tumor microenvironment, except for Cxcl10 upregulation in hepatoma tumors. In vitro and in vivo innate immune activation with TLR ligands, that prime inflammatory responses, revealed no significant difference between GSDMD-deficient and wild-type mice. These results suggest that the impact of GSDMD on anticancer immunity is dependent on the tumor type. They underscore the complex role of inflammatory pathways in cancer, emphasizing the need for further exploration into the multifaceted effects of GSDMD in various tumor microenvironments. As several pharmacological modulators of GSDMD are available, this may lead to novel strategies for combination therapy in cancer.

Using Combination therapy to overcome diverse challenges of Immune Checkpoint Inhibitors treatment.

Immune checkpoint inhibitors (ICIs) have heralded a new era in immunotherapy, representing a pivotal breakthrough in cancer treatment. Their impact is profound, with ICIs standing as some of the most prescribed anticancer therapies today. Notably, their ability to induce long-term remission even after treatment cessation provides genuine hope for achieving durable cures. However, despite these strides, challenges persist in the landscape of oncology, including resistance phenomena, immune-related adverse events, and suboptimal response rates. In response to these challenges, combination therapy emerges as a promising approach, poised to enhance treatment outcomes and address limitations inherent to single-agent ICI therapy. By synergistically targeting multiple pathways, combination therapy holds the potential to augment therapeutic efficacy while mitigating toxicity and impeding the emergence of resistance mechanisms. Understanding the intricacies underlying resistance development and adverse events is paramount in devising novel and refined combination strategies. A timeline showing FDA approvals of ICIs combination is shown in Figure 1. This review aims to provide a comprehensive and up-to-date examples of different combined therapy strategies that can be used to overcome various challenges regarding ICI treatment. Through the exploration of innovative therapeutic combinations, we aim to provide clinicians and researchers with actionable knowledge to optimize patient outcomes and propel the field of immuno-oncology forward.

Advanced combination therapy: is it the best way to break the therapeutic ceiling?

Current therapeutic strategies for inflammatory bowel disease (IBD) have reached a plateau in the rates of response and/or remission achieved with a single therapeutic agent. Consequently, the advanced combination therapy (ACT) strategy has emerged as a novel treatment concept for IBD. ACT involves the use of two different targeted therapies, whether biologic or small molecules, with the primary goal of overcoming the therapeutic plateau. Real-world evidence is accumulating among patients undergoing ACT, especially those dealing with concurrent IBD and extraintestinal manifestations or grappling with medically refractory IBD. The recently conducted VEGA study, a randomized clinical trial, has provided crucial insights by demonstrating that the short-term combination of dual biological agents can lead to superior disease control compared to single agents in patients diagnosed with ulcerative colitis (UC). This suggests that ACT holds promise as a therapeutic option to enhance disease control effectively. However, there is still limited evidence of ACT in UC patients who have proven refractory to biologic therapy and patients with Crohn's disease. This review aims to discuss whether ACT represents the optimal approach for overcoming the therapeutic ceiling in IBD.

Recent updates on nano-phyto-formulations based therapeutic intervention for cancer treatment.

Cancer is a leading cause of death globally, with limited treatment options and several limitations. Chemotherapeutic agents often result in toxicity which long-term conventional treatment. Phytochemicals are natural constituents that are more effective in treating various diseases with less toxicity than the chemotherapeutic agents providing alternative therapeutic approaches to minimize the resistance. These phytoconstituents act in several ways and deliver optimum effectiveness against cancer. Nevertheless, the effectiveness of phyto-formulations in the management of cancers may be constrained due to challenges related to inadequate solubility, bioavailability, and stability. Nanotechnology presents a promising avenue for transforming current cancer treatment methods through the incorporation of phytochemicals into nanosystems, which possess a range of advantageous characteristics such as biocompatibility, targeted and sustained release capabilities, and enhanced protective effects. This holds significant potential for future advancements in cancer management. Herein, this review aims to provide intensive literature on diverse nanocarriers, highlighting their applications as cargos for phytocompounds in cancer. Moreover, it offers an overview of the current advancements in the respective field, emphasizing the characteristics that contribute to favourable outcomes in both in vitro and in vivo settings. Lastly, clinical development and regulatory concerns are also discussed to check on the transformation of the concept as a promising strategy for combination therapy of phytochemicals and chemotherapeutics that could lead to cancer management in the future.

Current Treatment of Acquired Immune Deficiency Syndrome

Infection with the human immunodeficiency virus (HIV) has grown to be an important humanitarian problem influencing people worldwide. After a long period of research and practice, antiretroviral therapy (ART) and immunotherapy have gradually become the two main methods of treating HIV. However, there are still many questions to be explored regarding the comparison of these two treatments and the future direction of their development. Therefore, the aim of this study was to compare ART therapy and immunotherapy in HIV treatment and to explore their differences in terms of viral suppression, immune recovery, and patient quality of life. The potential and challenges of these two treatments in the future are envisioned.A thorough literature review and analysis were used to thoroughly assess research advancements in immunotherapy and antiretroviral therapy. ART entails long-term medication compliance and runs the risk of developing drug resistance. Immunotherapy has a lot of potential for inducing the immune system to manufacture particular antibodies and cellular immunological responses, but research is still being done to determine its usefulness and safety. The effectiveness of antiretroviral medication in preventing HIV infection and preserving patients’ health has been astounding, but issues with long-term drug use and drug resistance need to be addressed. While immunotherapy, a young science, presents prospects to create novel treatments, more study is required to guarantee their efficacy.Future HIV treatment may take advantage of both ideologies’ strengths to create a more effective combination therapy strategy with the ultimate objective to enhance HIV control and elimination.

Strategy of combining CDK4/6 inhibitors with other therapies and mechanisms of resistance.

Cell cycle-dependent protein kinase 4/6 (CDK4/6) is a crucial kinase that regulates the cell cycle, essential for cell division and proliferation. Hence, combining CDK4/6 inhibitors with other anti-tumor drugs is a pivotal clinical strategy. This strategy can efficiently inhibit the growth and division of tumor cells, reduce the side effects, and improve the quality of life of patients by reducing the dosage of combined anticancer drugs. Furthermore, the combination therapy strategy of CDK4/6 inhibitors could ameliorate the drug resistance of combined drugs and overcome the CDK4/6 resistance caused by CDK4/6 inhibitors. Various tumor treatment strategies combined with CDK4/6 inhibitors have entered the clinical trial stage, demonstrating their substantial clinical potential. This study reviews the research progress of CDK4/6 inhibitors from 2018 to 2022, the related resistance mechanism of CDK4/6 inhibitors, and the strategy of combination medication.

Progress in the study of anti-tumor drugs targeting mitochondria

Cancer poses a significant yet concealed threat to human health, necessitating the prompt pursuit of efficacious anti-tumor tactics. Mitochondria, functioning as a intracellular energy generator, participate in numerous vital physiological processes and serve as pivotal determinants in the proliferation and metabolism of tumor cells. Consequently, targeting of mitochondria is deemed a burgeoning and auspicious anti-tumor strategy that can leverage the highly negative electrical characteristics of the mitochondrial inner membrane to selectively aim at tumor cells via specific targets. Moreover, targeting of mitochondria has the potential to decrease the emergence of tumor drug resistance and partially surmount the multidrug resistance (MDR) of tumors that arise from conventional chemotherapy, thereby augmenting the effectiveness of conventional drugs. The aim of this manuscript is to examine the design principles and mechanisms of action of targeted mitochondrial antitumor drugs, and to introduce innovative and efficacious mitochondria-targeted adjuvant combination therapy strategies in cancer chemotherapy, with the intention of furnishing a point of reference for the advancement of mitochondria-targeted drugs.

Research Progress on the Synergistic Anti-Tumor Effect of Natural Anti-Tumor Components of Chinese Herbal Medicine Combined with Chemotherapy Drugs.

The application of chemotherapy drugs in tumor treatment has a long history, but the lack of selectivity of drugs often leads to serious side effects during chemotherapy. The natural anti-tumor ingredients derived from Chinese herbal medicine are attracting increased attention due to their diverse anti-tumor effects, abundant resources, and minimal side effects. An effective anti-tumor strategy may lie in the combination of these naturally derived anti-tumor ingredients with conventional chemotherapy drugs. This approach could potentially inhibit tumor growth and the development of drug resistance in tumor cells while reducing the adverse effects of chemotherapy drugs. This review provides a comprehensive overview of the combined therapy strategies integrating natural anti-tumor components from Chinese herbal medicine with chemotherapy drugs in current research. We primarily summarize various compounds in Chinese herbal medicine exhibiting natural anti-tumor activities and the relevant mechanisms in synergistic anti-tumor combination therapy. The focus of this paper is on underlining that this integrative approach, combining natural anti-tumor components of Chinese herbal medicine with chemotherapy drugs, presents a novel cancer treatment methodology, thereby providing new insights for future oncological research.

Microbiota: A key factor affecting and regulating the efficacy of immunotherapy.

Immunotherapy has made significant progress in cancer treatment; however, the responsiveness to immunotherapy varies widely among patients. Growing evidence has demonstrated the role of the gut microbiota in the efficacy of immunotherapy. Herein, we summarise the changes in the microbiota in different cancers under various immunotherapies. The microbial-host signal transmission on immunotherapeutic responses and mechanisms associated with microbial translocation to tumours in the context of immunotherapy are also discussed. In addition, we have highlighted the clinical application value of methods for regulating the microbiota. Finally, we elaborate on the relationship between the microbiota, host and immunotherapy, and provide potential directions for future research. Different microbiota cause changes in the tumour microenvironment through microbial signals thereby affecting immunotherapy efficacy. Translocation of gut microbiota and the role of extraintestinal microbiota in immunotherapy deserve attention. Microbiota regulation is a novel strategy for combination therapy with immunotherapy. Although there are several aspects that deserve further refinement and exploration with regard to administration and clinical translation. Nevertheless, it is foreseeable that the microbiota will become an integral part of cancer treatment.

Abstract C003: A quantitative mass spectrometry workflow for highly multiplexed measurement of immunomodulatory proteins to support immunotherapy clinical trials

Abstract Background: Since the approval of the first immune checkpoint-directed immunotherapies, it has been well-known that the efficacy of these therapies has been limited to a subset of cancer patients. As the number of new potential immunotherapy targets has grown, including novel combination therapy strategies, improved immune-related biomarker measurement has played a key role in understanding novel mechanisms of action and response to drugs. To support these efforts, we have developed an analytically validated assay for the multiplexed quantitation of up to 113 immunomodulatory proteins in various matrices (e.g., human plasma, PBMC, cells, or tissue) based on anti-peptide immunoaffinity capture followed by LC-MRM mass spectrometry analysis. Methods: Remnant samples from commercial biobanks were acquired in a variety of solid tumor indications. Briefly, matrices were denatured, reduced, alkylated, and digested using trypsin. Immunoaffinity capture of the peptide targets consisted of overnight incubation of the digested sample with anti-peptide antibodies coupled to protein G magnetic beads, followed by automated washing and elution of the peptides from the antibodies using the KingFisher platform. The peptides were analyzed in a multiplexed method by LC-MRM mass spectrometry. Endogenous levels for each target were measured relative to a stable isotopically labeled peptide standard. Results: In panel experiments, we found that the targets can be quantified precisely and accurately over 3 orders of magnitude with an intra-/inter-assay precision and accuracy of less than 20%. In total, 107 peptide targets were detected endogenously in cell lines. We expand on these data with analysis of solid tumor FFPE specimens where the results will be compared to immunohistochemical staining for selected targets. Conclusions: This study shows how multiplex immunoaffinity methods can complement classical methods of tissue-based protein expression for simultaneous and quantitative interpretation of protein levels. Citation Format: Ons Ousji, Anne Jang, Luca Genovesi, Nicholas Dupuis, Timon Geib, Gwenael Pottiez, Michael Schirm. A quantitative mass spectrometry workflow for highly multiplexed measurement of immunomodulatory proteins to support immunotherapy clinical trials [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C003.

Abstract A117: Evaluation of nab-sirolimus in combination with PI3K pathway inhibitors to overcome PI3K/mTOR resistance in PI3K-mutant breast cancer cell lines

Abstract Background: The PI3K-AKT-mTOR pathway is frequently activated in many cancer types and plays a central role in tumorigenesis. However, clinical use of therapies targeting this pathway is limited by compensatory vertical and horizontal feedback activation loops, which limit antitumor efficacy and lead to drug resistance. Combination therapy strategies employing simultaneous inhibition of multiple PI3K-AKT-mTOR pathway elements may overcome these resistance mechanisms and improve antitumor activity. nab-Sirolimus is a novel albumin-bound nanoparticle form of the mTOR inhibitor sirolimus that has significantly greater tumor accumulation, mTOR target suppression, and improved antitumor effects compared with conventional first generation mTOR inhibitors in preclinical models. Here, we analyzed the effects of nab-sirolimus combinations in PI3K-mutant breast cancer (BrCa) cells. Methods: PI3K mutated BrCa cell lines (MDA-MD-453, hormone receptor [HR]-; and MDA-MB-361, HR+) were incubated for 5 days with increasing concentrations of nab-sirolimus, the PI3K pathway inhibitors gedatolisib and alpelisib, or the AKT inhibitors miransertinib and capivasertib. The antiproliferative and cytotoxic effects of single agent and combination treatment were assessed using cell viability and cell death assays. Cell signaling was analyzed by western blot. Results: The antiproliferative effects of gedatolisib at low doses (2.5-10 nM) were enhanced by 61-71% in combination with nab-sirolimus (20 or 80 nM) in MDA-MB-453 cells. Limited cell death (4.2-9.6%) was observed in HR- MDA-MB-453 cells with low doses (2.5, 5, and 10 nM) of gedatolisib alone. In contrast, and despite the well-established cytostatic action of mTOR inhibitors, the addition of 20 and 80 nM nab-sirolimus led to high levels of cell death (up to 48.9%). Similar results were observed with alpelisib at 1 µM in combination with nab-sirolimus (20 or 80 nM), and also with capivasertib (1 µM) or miransertib (250 nM) combined with 80 nM nab-sirolimus. Western blot analysis demonstrated that gedatolisib or alpelisib alone each triggered upregulation of p4EBP1 whereas nab-sirolimus treatment alone activated a negative feedback loop through increased pAKT. Importantly, these compensatory feedback activation loops were both reversed by the combination of PI3K inhibitors and nab-sirolimus. Similar cell death and cell viability results were observed with nab-sirolimus plus PI3K inhibitors (gedatolisib or alpelisib) and AKT inhibitors (capivasertib or miransertib) in HR+ MDA-MB-361 cells. Conclusions: The antitumor effects of PI3K and AKT inhibitors were enhanced by the addition of the novel mTOR inhibitor nab-sirolimus. The improved effectiveness of the PI3K and mTOR inhibitor combination was due to the reciprocal overcoming of resistance mechanisms induced by single agent treatment. These data support a vertical PI3K pathway inhibition strategy using nab-sirolimus and PI3K/AKT inhibitors in PIK3CA-mutated BrCa, regardless of HR status. Citation Format: Sean Wallace, Khine Nyein Myint, Shihe Hou, Maria Zalath, Andrew Kwon, Brian McMorran, Igor Vivanco. Evaluation of nab-sirolimus in combination with PI3K pathway inhibitors to overcome PI3K/mTOR resistance in PI3K-mutant breast cancer cell lines [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A117.

Nano Strategies for Artemisinin Derivatives to Enhance Reverse Efficiency of Multidrug Resistance in Breast Cancer.

Artemisinin (ART) has been found to exert anti-tumor activity by regulating the cell cycle, inducing apoptosis, inhibiting angiogenesis and tumor invasion and metastasis. Its derivatives (ARTs) can regulate the expression of drug-resistant proteins and reverse the multidrug resistance (MDR) of tumor cells by inhibiting intracellular drug efflux, inducing apoptosis and autophagy of tumor cells, thus enhancing the sensitivity of tumor cells to chemotherapy and radiotherapy. Recent studies have shown that nanodrugs play an important role in the diagnosis and treatment of cancer, which can effectively solve the shortcomings of poor hydrophilicity and low bioavailability of ARTs in the human body, prolong the in vivo circulation time, improve the targeting of drugs (including tumor tissues or specific organelles), and control the release of drugs in target tissues, thereby reducing the side effect. This review systematically summarized the latest research progress of nano-strategies of ARTs to enhance the efficiency of MDR reversal in breast cancer (BC) from the following two aspects: (1) Chemicals encapsulated in nanomaterials based on innovative anti-proliferation mechanism: non-ABC transporter receptor candidate related to ferroptosis (dihydroartemisinin/DHA analogs). (2) Combination therapy strategy of nanomedicine (drug-drug combination therapy, drug-gene combination, and chemical-physical therapy). Self-assembled nano-delivery systems enhance therapeutic efficacy through increased drug loading, rapid reactive release, optimized delivery sequence, and realization of cascade-increasing effects. New nanotechnology methods must be designed for specific delivery routines to achieve targeting administration and overcome MDR without affecting normal cells. The significance of this review is to expect that ART and ARTs can be widely used in clinical practice. In the future, nanotechnology can help people to treat multidrug resistance of breast cancer more accurately and efficiently.

Dendritic Cell Vaccines Extend CD19 CAR-T Cell Persistence and Improve the Outcomes in Refractory/Relapsed Adult B-ALL

Introduction: The long-term efficacy of anti-CD19 chimeric antigen receptor (CAR)-T cell in refractory or relapsed (r/r) adult B-cell acute lymphoblastic (B-ALL) patients is limited, and the recurrence rate is high. CAR-T cell depletion and limited CAR-T cell persistence are some of the most common reasons for relapse. Our previous in vitro studies confirmed that dendritic cell (DC) vaccines targeting tumor antigens could induce CAR-T cell rejuvenation and increase the killing function of CAR-T cells. So, we designed a clinical trial to study CD19 CAR-T cell combined with DC vaccination for adult r/r B-ALL to explore whether this therapy improves LFS. (clinicaltrials.gov, no: NCT03291444). Methods: Adult r/r B-ALL patients who expressed HLA-A1101, A2402, or A0201 and had high expression of EPS8 or WT1 were eligible. An EPS8 peptide-derived DC (EPS8-DCs) vaccine was used in EPS8-high patients, while a WT1 peptide-derived DC (WT1-DC) vaccine was used in EPS8-negative patients with WT1 positivity. Lymphodepleting chemotherapy comprising fludarabine (30 mg/m²) and cyclophosphamide (300 mg/m²) was administered intravenously daily for 3 days before CD19 CAR-T cells infusion. After 4 weeks of CAR-T infusion, if bone marrow morphologic remission had been achieved, DC vaccination was administered intradermally every 2 weeks for 4 doses. Results: Eight adult patients with r/r B-ALL were enrolled and successfully received CAR-T cells and DC cells, of which 4 (50%) relapsed after allogeneic hematopoietic stem cell transplantation. They were successfully administered one dose of CD19 CAR-T with a median dose of 2.26×10 6/kg (range 6.4×10 5/kg to 4.46×10 6/kg) on day 0 and four doses of DC vaccination with a median dose of 5.44×10 6 (range 2.97×10 6/dose to 2.68×10 7/dose) every 2 weeks after 4 weeks of CAR-T infusion. All eight evaluable patients achieved complete response (CR) after receiving CD19 CAR-T. With a median follow-up of 608 days, the median LFS time was 489 days, and the median OS was not reached. Seven of the eight evaluable patients were still alive. Four (50%) were in continuous MRD-negative remission at the cutoff time, and two of them (pt 02 and pt 03) maintained MRD-negative CR for more than 4 years. The median peak of CAR-T cell expansion in the PB was detected on day 7 after infusion of CD19 CAR-T. The median persistence time of CAR-T was 336 days (range 84 to 1549 days). CAR-T cells were reamplified after infusion of the DC vaccine. For patients with an LFS of more than 2 years (pt 02, pt 03, and pt 05), CD19 CAR-T cells were still detectable for more than 1 year, with a maximum of 4.2 years in pt 03. The activity of the CTLs measured by IFN-γ ELIspot showed that IFN-γ-secreting CTLs were significantly increased after DC vaccination. These assays showed that antigen-specific cellular immune activity was enhanced after vaccination. No grade ≥3 cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) occurred after infusion of 4sCAR19. No grade ≥3 events occurred during the infusion of the DC vaccine. Only 1 of 8 patients experienced local skin reactions after infusion of the DC vaccine. Conclusions: This study reports a novel combination therapy strategy (CAR-T cell combining with individualized DC vaccination) for adult r/r B-ALL. DC vaccination has higher safety, may prolong the persistence of CAR-T cells, and may prolong the survival time and quality of life. CAR-T cell therapy combining with DC vaccination is a potential therapy strategy for adult r/r ALL patients who are not eligible for transplantation or who relapse after transplantation.

Current Status and Progress in Stem Cell Therapy for Intracerebral Hemorrhage.

Intracerebral hemorrhage is a highly prevalent and prognostically poor disease, imposing immeasurable harm on human life and health. However, the treatment options for intracerebral hemorrhage are severely limited, particularly in terms of improving the microenvironment of the lesion, promoting neuronal cell survival, and enhancing neural function. This review comprehensively discussed the application of stem cell therapy for intracerebral hemorrhage, providing a systematic summary of its developmental history, types of transplants, transplantation routes, and transplantation timing. Moreover, this review presented the latest research progress in enhancing the efficacy of stem cell transplantation, including pretransplantation preconditioning, genetic modification, combined therapy, and other diverse strategies. Furthermore, this review pioneeringly elaborated on the barriers to clinical translation for stem cell therapy. These discussions were of significant importance for promoting stem cell therapy for intracerebral hemorrhage, facilitating its clinical translation, and improving patient prognosis.

Targosomes: Anti-HER2 PLGA nanocarriers for bioimaging, chemotherapy and local photothermal treatment of tumors and remote metastases

Developing combined cancer therapy strategies is of utmost importance as it can enhance treatment efficacy, overcome drug resistance, and ultimately improve patient outcomes by targeting multiple pathways and mechanisms involved in cancer growth and progression. Specifically, the potential of developing a combination chemo&photothermal therapy using targeted polymer nanoparticles as nanocarriers offers a promising approach for synergistic cancer treatment by combining the benefits of both therapies, such as targeted drug delivery and localized hyperthermia. Here, we report the first targeted anti-HER2 PLGA nanocarriers, called targosomes, that simultaneously possess photothermal, chemotherapeutic and diagnostic properties using only molecular payloads. Biocompatible poly(lactic-co-glycolic acid), PLGA, nanoparticles were loaded with photosensitizer phthalocyanine, diagnostic dye Nile Blue, and chemotherapeutic drug irinotecan, which was chosen as a result of screening a panel of theragnostic nanoparticles. The targeted delivery to cell surface oncomarker HER2 was ensured by nanoparticle modification with the anti-HER2 monoclonal antibody, trastuzumab, using the one-pot synthesis method without chemical conjugation. The irradiation tests revealed prominent photothermal properties of nanoparticles, namely heating by 35 °C in 10 min. Nanoparticles exhibited a 7-fold increase in binding and nearly an 18-fold increase in cytotoxicity for HER2-overexpressing cells compared to cells lacking HER2 expression. This enhancement of cytotoxicity was further amplified by >20-fold under NIR light irradiation. In vivo studies proved the efficacy of nanoparticles for bioimaging of primary tumor and metastasis sites and demonstrated 93% tumor growth inhibition, making these nanoparticles excellent candidates for translation into theragnostic applications.