Immunotherapy For Treatment Of Cancer Research Articles

Spatial context of immune checkpoints as predictors of overall survival in patients with resectable colorectal cancer independent of standard TNM stages.

While immune checkpoint blockade (ICB) therapy has shown promising results in a small subset of colorectal cancer patients with high microsatellite instability (MSI-H), the majority of patients with colorectal cancer do not respond to ICB therapy. The main obstacle to the success of immunotherapy in cancer treatment is the exhaustion of tumor-infiltrating lymphocytes (TILs). Elucidating the spatial organization of immune checkpoints within the tumor microenvironment could pave the way for the development of novel prognostic tools and therapeutic strategies to enhance antitumor immune responses. To clarify the spatial and functional diversity of tumor-infiltrating lymphocytes (TILs) in the colorectal tumor microenvironment (TME), we performed multiplexed IHC to examine the exhaustion of TILs in the TME (the expression of PD-1 and TIM-3 (T-cell immunoglobulin and mucin-domain-containing protein 3), which are major biomarkers of T-cell exhaustion) and Lasso-Cox analyses of the correlation between CRC prognosis and TME features. For proof of concept, the antitumor efficacy of TIM-3 and PD-1 dual blockade in CRC was further evaluated in a CT26 subcutaneous tumor model of human CRC. We found that the spatial context of PD-1 and TIM-3 successfully predicted the overall survival of CRC patients independent of TNM stage. Dual targeting of PD-1 and TIM-3 in mouse tumor models inhibited tumor progression and reduced T-cell exhaustion, indicating a potential strategy for improving the clinical treatment of CRC.

CAR T-cell therapy for gliomas.

To review the landscape of chimeric antigen receptor T-cell (CAR T) therapy for gliomas as seen in recently published trials and discuss on-going challenges with new cancer immunotherapy treatments. Given how CAR T therapy has revolutionized the treatment of several hematologic malignancies, there has been increasing interest in using immunotherapy, and particularly CAR T therapy for gliomas. Within the past decade, several first in human trials have published early patient experiences showing treatment is generally well tolerated but with limited efficacy, which may be improving with newer evolutions in CAR T design to overcome known resistance mechanisms in glioma treatment. CAR T therapy is a promising avenue of treatment for high-grade gliomas, which have a universally poor prognosis as well as limited therapeutics. There are a growing number of CAR T clinical trials for CNS tumors and thus, an understanding of their treatment strategies, toxicity management, and overcoming resistance mechanisms will be important for both clinical practice and to identify areas for future research.

Advances in immunotherapy for cancer treatment: A literature review

Advances in immunotherapy for cancer treatment: A literature review

Spatial computational modelling illuminates the role of the tumour microenvironment for treating glioblastoma with immunotherapies

Glioblastoma is the most common and deadliest brain tumour in adults, with a median survival of 15 months under the current standard of care. Immunotherapies like immune checkpoint inhibitors and oncolytic viruses have been extensively studied to improve this endpoint. However, most thus far have failed. To improve the efficacy of immunotherapies to treat glioblastoma, new single-cell imaging modalities like imaging mass cytometry can be leveraged and integrated with computational models. This enables a better understanding of the tumour microenvironment and its role in treatment success or failure in this hard-to-treat tumour. Here, we implemented an agent-based model that allows for spatial predictions of combination chemotherapy, oncolytic virus, and immune checkpoint inhibitors against glioblastoma. We initialised our model with patient imaging mass cytometry data to predict patient-specific responses and found that oncolytic viruses drive combination treatment responses determined by intratumoral cell density. We found that tumours with higher tumour cell density responded better to treatment. When fixing the number of cancer cells, treatment efficacy was shown to be a function of CD4 + T cell and, to a lesser extent, of macrophage counts. Critically, our simulations show that care must be put into the integration of spatial data and agent-based models to effectively capture intratumoral dynamics. Together, this study emphasizes the use of predictive spatial modelling to better understand cancer immunotherapy treatment dynamics, while highlighting key factors to consider during model design and implementation.

Bacterial outer membrane vesicles in the fight against cancer.

Bacterial outer membrane vesicles (OMVs) are diminutive vesicles naturally released by Gram-negative bacteria. These vesicles possess distinctive characteristics that attract attention for their potential use in drug administration and immunotherapy in cancer treatment. Therapeutic medicines may be delivered via OMVs directly to the tumor sites, thereby minimizing exposure to healthy cells and lowering the risk of systemic toxicity. Furthermore, the activation of the immune system by OMVs has been demonstrated to facilitate the recognition and elimination of cancer cells, which makes them a desirable tool for immunotherapy. They can also be genetically modified to carry specific antigens, immunomodulatory compounds, and small interfering RNAs, enhancing the immune response to cancerous cells and silencing genes associated with disease progression. Combining OMVs with other cancer treatments like chemotherapy and radiation has shown promising synergistic effects. This review highlights the crucial role of bacterial OMVs in cancer, emphasizing their potential as vectors for novel cancer targeted therapies. As researchers delve deeper into the complexities of these vesicles and their interactions with tumors, there is a growing sense of optimism that this avenue of study will bring positive outcomes and renewed hope to cancer patients in the foreseeable future.

A Comprehensive Review on Novel Pathways in Cancer Treatment: Clinical Applications and Future Prospects.

Cancer is a global health issue that requires ongoing therapeutic advances. This review provides an overview of recent treatment strategies focusing on novel pathways in cancer therapy. Emerging research has unveiled promising targets that go beyond traditional modalities, offering new avenues for precision medicine and improved patient outcomes. One key area of innovation lies in targeted therapies directed at specific molecular pathways implicated in cancer progression. The identification of novel biomarkers has paved the way for the development of precision medicines tailored to individual patient profiles. Immunotherapy has also revolutionised cancer treatment by using the immune system to identify and remove cancer cells. Moreover, advancements in epigenetic therapies and RNA-based interventions demonstrate unprecedented potential in modulating gene expression and disrupting cancer-specific signalling pathways. We have discussed the pathophysiology of cancer, different immune checkpoint inhibitors, and targeted therapies in signalling therapies. The epigenetic modulators, such as Histone deacetylase (HDACs) inhibitors and DNA methyltransferase (DNMT) inhibitors, were studied. Recent breakthroughs in cancer immunotherapy treatment (CAR-T) cell therapy showcase the potential to enhance the immune response against various cancers; thus, related information was incorporated. Further, RNA-based therapies like RNA interference and mRNA-based vaccines and therapies, combination therapies, and novel therapies were discussed in the present article.

GSH-responsive bithiophene Aza-BODIPY@HMON nanoplatform for achieving triple-synergistic photoimmunotherapy

Photoimmunotherapy represents an innovative approach to enhancing the efficiency of immunotherapy in cancer treatment. This approach involves the fusion of immunotherapy and phototherapy (encompassing techniques like photodynamic therapy (PDT) and photothermal therapy (PTT)). Boron-dipyrromethene (BODIPY) has the potential to trigger immunotherapy owing to its excellent PD and PT efficiency. However, the improvements in water solubility, bioavailability, PD/PT combined efficiency, and tumor tissue targeting of BODIPY require introduction of suitable carriers for potential practical application. Herein, a disulfide bond-based hollow mesoporous organosilica (HMON) with excellent biocompatibility and GSH-responsive degradation properties was used as a carrier to load a bithiophene Aza-BODIPY dye (B5), constructing a sample chemotherapy reagent-free B5@HMON nanoplatform achieving triple-synergistic photoimmunotherapy. HMON, involving disulfide bond, is utilized to improve water solubility, tumor tissue targeting, and PD efficiency by depleting GSH and enhancing host-guest interaction between B5 and HMO. The study reveals that HMON’s large specific surface area and porous properties significantly enhance the light collection and oxygen adsorption capacity. The HMON’s rich mesoporous structure and internal cavity achieved a loading rate of B5 at 11 %. It was found that the triple-synergistic nanoplatform triggered a stronger anti-tumor immune response, including tumor invasion, cytokine production, calreticulin translocation, and dendritic cell maturation, eliciting specific tumor-specific immunological responses in vivo and in vitro. The BALB/c mouse model with 4T1 tumors was used to assess tumor suppression efficiency in vivo, showing that almost all tumors in the B5@HMON group disappeared after 14 days. Such a simple chemotherapy reagent-free B5@HMON nanoplatform achieved triple-synergistic photoimmunotherapy.

GIHP: Graph convolutional neural network based interpretable pan-specific HLA-peptide binding affinity prediction.

Accurately predicting the binding affinities between Human Leukocyte Antigen (HLA) molecules and peptides is a crucial step in understanding the adaptive immune response. This knowledge can have important implications for the development of effective vaccines and the design of targeted immunotherapies. Existing sequence-based methods are insufficient to capture the structure information. Besides, the current methods lack model interpretability, which hinder revealing the key binding amino acids between the two molecules. To address these limitations, we proposed an interpretable graph convolutional neural network (GCNN) based prediction method named GIHP. Considering the size differences between HLA and short peptides, GIHP represent HLA structure as amino acid-level graph while represent peptide SMILE string as atom-level graph. For interpretation, we design a novel visual explanation method, gradient weighted activation mapping (Grad-WAM), for identifying key binding residues. GIHP achieved better prediction accuracy than state-of-the-art methods across various datasets. According to current research findings, key HLA-peptide binding residues mutations directly impact immunotherapy efficacy. Therefore, we verified those highlighted key residues to see whether they can significantly distinguish immunotherapy patient groups. We have verified that the identified functional residues can successfully separate patient survival groups across breast, bladder, and pan-cancer datasets. Results demonstrate that GIHP improves the accuracy and interpretation capabilities of HLA-peptide prediction, and the findings of this study can be used to guide personalized cancer immunotherapy treatment. Codes and datasets are publicly accessible at: https://github.com/sdustSu/GIHP.

PIKfyve controls dendritic cell function and tumor immunity.

The modern armamentarium for cancer treatment includes immunotherapy and targeted therapy, such as protein kinase inhibitors. However, the mechanisms that allow cancer-targeting drugs to effectively mobilize dendritic cells (DCs) and affect immunotherapy are poorly understood. Here, we report that among shared gene targets of clinically relevant protein kinase inhibitors, high PIKFYVE expression was least predictive of complete response in patients who received immune checkpoint blockade (ICB). In immune cells, high PIKFYVE expression in DCs was associated with worse response to ICB. Genetic and pharmacological studies demonstrated that PIKfyve ablation enhanced DC function via selectively altering the alternate/non-canonical NF-κB pathway. Both loss of Pikfyve in DCs and treatment with apilimod, a potent and specific PIKfyve inhibitor, restrained tumor growth, enhanced DC-dependent T cell immunity, and potentiated ICB efficacy in tumor-bearing mouse models. Furthermore, the combination of a vaccine adjuvant and apilimod reduced tumor progression in vivo. Thus, PIKfyve negatively controls DCs, and PIKfyve inhibition has promise for cancer immunotherapy and vaccine treatment strategies.

Advances in Immunotherapy for Cancer Treatment: Targeting the Immune System to Fight Tumors

A revolutionary new method for treating cancer, immunotherapy uses the immune system to specifically target and kill tumor cells. Recent developments in immunotherapy and its function in cancer treatment are summarized in this article. This article provides a comprehensive overview of immunotherapeutic techniques, including bispecific antibodies, cancer vaccines, immune checkpoint combo therapy, checkpoint inhibitors, TIL therapy, CAR T-cell therapy, and cancer vaccines. It also discusses the mechanisms of action of these strategies and their clinical uses. Immunotherapy has shown tremendous promise in the treatment of many malignancies, according to recent important advances in the area as well as clinical data and case studies.

Advances in Immunotherapy for Cancer Treatment: Targeting the Immune System to Fight Tumors

Immunotherapy has emerged as a ground-breaking approach in the treatment of cancer, harnessing the power of the immune system to target and destroy tumor cells. This paper provides an overview of recent advances in immunotherapy and its role in combating cancer. Various immunotherapeutic strategies, including checkpoint inhibitors, CAR T-cell therapy, TIL therapy, cancer vaccines, immune checkpoint combination therapy, and bispecific antibodies, are discussed in detail, highlighting their mechanisms of action and clinical applications. Key advancements in the field, supported by clinical evidence and case studies, underscore the remarkable efficacy of immunotherapy in treating a wide range of cancers.

Advances in Immunotherapy for Cancer Treatment: Targeting the Immune System to Fight Tumors

Advances in Immunotherapy for Cancer Treatment: Targeting the Immune System to Fight Tumors

PIKfyve, expressed by CD11c-positive cells, controls tumor immunity

Cancer treatment continues to shift from utilizing traditional therapies to targeted ones, such as protein kinase inhibitors and immunotherapy. Mobilizing dendritic cells (DC) and other myeloid cells with antigen presenting and cancer cell killing capacities is an attractive but not fully exploited approach. Here, we show that PIKFYVE is a shared gene target of clinically relevant protein kinase inhibitors and high expression of this gene in DCs is associated with poor patient response to immune checkpoint blockade (ICB) therapy. Genetic and pharmacological studies demonstrate that PIKfyve ablation enhances the function of CD11c+ cells (predominantly dendritic cells) via selectively altering the non-canonical NF-κB pathway. Both loss of Pikfyve in CD11c+ cells and treatment with apilimod, a potent and specific PIKfyve inhibitor, restrained tumor growth, enhanced DC-dependent T cell immunity, and potentiated ICB efficacy in tumor-bearing mouse models. Furthermore, the combination of a vaccine adjuvant and apilimod reduced tumor progression in vivo. Thus, PIKfyve negatively regulates the function of CD11c+ cells, and PIKfyve inhibition has promise for cancer immunotherapy and vaccine treatment strategies.

The Role of Immunotherapy in Cancer Treatment: Mechanisms, Efficacy, and Future Directions

The Role of Immunotherapy in Cancer Treatment: Mechanisms, Efficacy, and Future Directions

Manipulating the tumour immune microenvironment by N6-methyladenosine RNA modification.

N6-methyladenosine (m6A), a posttranscriptional regulatory mechanism, is the most common epigenetic modification in mammalian mRNA. M6A modifications play a crucial role in the developmental network of immune cells. The expression of m6A-related regulators often affects carcinogenesis and tumour suppression networks. In the tumour microenvironment, m6A-modified enzymes can affect the occurrence and progression of tumours by regulating the activation and invasion of tumour-associated immune cells. Immunotherapy, which utilises immune cells, has been demonstrated to be a powerful weapon in tumour treatment and is increasingly being used in the clinic. Here, we provide an updated and comprehensive overview of how m6A modifications affect invasive immune cells and their potential role in immune regulation. In addition, we summarise the regulation of epigenetic regulators associated with m6A modifications in tumour cells on the antitumour response of immune cells in the tumour immune microenvironment. These findings provide new insights into the role of m6A modifications in the immune response and tumour development, leading to the development of novel immunotherapies for cancer treatment.

Sex influence on cancer immunotherapy efficacy and safety in advanced non-small cell lung cancer (NSCLC): A Canadian institution real-world experience.

e20618 Background: Males and females differ in innate and adaptive immune responses. This difference may also be reflected in their response to cancer immunotherapies. Immune checkpoint inhibitors (ICIs) have revolutionized the treatment for advanced NSCLC, however the impact of sex on treatment outcomes in these patients remains unclear. The aim of this retrospective cohort study was to evaluate sex-related differences in immunotherapy outcome in a real-world population of NSCLC patients treated with ICIs. Methods: Demographics, clinical, pathological and treatment characteristics were assessed. Treatment-related variables were analyzed to understand the differences in efficacy and safety outcomes including response rates, PFS, OS and all-cause treatment discontinuation (TD) in relation to sex. Results: 152 advanced NSCLC patients receiving first-line immunotherapy, either alone or in conjunction with chemotherapy, were included in the study cohort. Females were younger age, were more likely to be non-smokers, have non-squamous tumors and had a higher prevalence of pre-existing autoimmune diseases compared to males. Disease control (CR/PR/SD) was achieved in 65.8% of patients. Median PFS was 12.0 mo in females and 14.1 mo in males. Median OS for all patients was 15.8 mo; 16.1 and 15.7 mo in females and males respectively. No statistical differences based on gender were observed in PFS and OS (P = 0.767 and P = 0.657). In regression analysis older age and presence of liver metastases were independent poor prognostic factors. Gender was not an independent prognostic factor in PFS and OS. Notably, 44 or 28.9% patients developed symptomatic immune-related adverse events (ir-AEs) that led to TD (Table 1). ir-AE-related TD occurred at a significantly higher rate in females compared with males (Table 1; 38.2% vs 19.7%, RR = 1.90; 95% CI: 1.12 to 3.26; p = 0.018). GI toxicity, including hepatitis and colitis was predominantly observed in females, whereas pneumonitis was the most frequent ir-AE leading to TD in males. Conclusions: Despite no significant differences based on gender were observed in PFS and OS, our study showed that female patients with advanced NSCLC receiving ICIs are at a substantially greater risk of severe symptomatic ir-AEs and TD. This finding indicates that broad-based sex differences in this context could potentially exist and emphasizes the need for further investigations into the role played by gender in immunity and cancer immunotherapy treatment.[Table: see text]

Recent advances in immunotherapy in cancer treatment.

Immunotherapy has emerged as a transformative approach in cancer treatment, leveraging the body's own immune system to recognize and eradicate cancer cells. This review provides an overview of the recent advances and aspects in immunotherapy in cancer biology, from established therapies like checkpoint inhibitors and CAR-T cells to emerging innovative approaches and the challenges associated with their clinical translation. The exploration includes an examination of checkpoint inhibitors, elucidating the mechanisms behind programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors. Recent clinical successes and ongoing trials demonstrate the efficacy of checkpoint inhibitors across diverse malignancies, underscoring the potential for durable responses and improved patient outcomes. CAR-T cell therapy represents a groundbreaking avenue in immunotherapy, involving the genetic modification of a patient's T cells to express chimeric antigen receptors (CARs) for targeted cancer cell recognition. Furthermore, the review touches on the challenges associated with immunotherapy, including resistance mechanisms and adverse effects. Insightful discussions on overcoming resistance through combination therapies, adaptive treatment strategies, and emerging technologies underscore the ongoing efforts to enhance the long-term efficacy of immunotherapeutic interventions. In summary, this extensive review provides a comprehensive overview of recent advances in immunotherapy in cancer biology, highlighting the transformative impact of these therapies on patient outcomes, the challenges faced, and the promising directions for future research and clinical applications.

Chemotherapy, immunotherapy, or combination first-line treatment for metastatic urothelial carcinoma of the bladder: A large real-world experience

IntroductionFirst-line systemic therapy for metastatic urothelial carcinoma of the bladder (mUC) consists of platinum-based chemotherapy in most patients and PD1/L1 inhibitors in selected patients. Multiple combination chemoimmunotherapy trials failed to show a clear benefit over chemotherapy alone. We used real-world data to evaluate clinical and sociodemographic factors associated with receipt of first-line chemotherapy, immunotherapy, or combination chemoimmunotherapy treatment for metastatic bladder cancer and examined differences in overall survival (OS). Materials and MethodsWe used the National Cancer Database to identify patients with stage IV mUC diagnosed between 2014 and 2018, who were treated with first-line immunotherapy, chemotherapy, or combination treatment. We performed multivariable logistic regression modeling to determine factors associated with treatment receipt Adjusted Kaplan-Meier survival analysis and multivariable Cox proportional hazards regression were used to evaluate the association between treatment and OS. ResultsIn our cohort of 4,169 patients, multivariable analysis identified increasing age (RRR: 1.07, 95%CI, 1.06–1.08) and comorbidity burden (, as independent predictors of receiving immunotherapy. Treatment at an academic facility was associated with increased likelihood of combination treatment (RRR: 1.29, 95%CI, 1.01–1.65). After IPTW, we found that combination therapy (hazard ratio [HR]: 0.72; 95%CI, 0.62–0.83) was associated with improved survival compared to chemotherapy. ConclusionsPatients with older age and more comorbidities were more likely to receive immunotherapy than chemotherapy for first-line treatment of metastatic urothelial carcinoma of the bladder. Utilization of chemoimmunotherapy was observed to be higher in academic centers and was associated with improved survival compared to chemotherapy.

Zebularine potentiates anti-tumor immunity by inducing tumor immunogenicity and improving antigen processing through cGAS-STING pathway

DNA methylation is an important epigenetic mechanism involved in the anti-tumor immune response, and DNA methyltransferase inhibitors (DNMTi) have achieved impressive therapeutic outcomes in patients with certain cancer types. However, it is unclear how inhibition of DNA methylation bridges the innate and adaptive immune responses to inhibit tumor growth. Here, we report that DNMTi zebularine reconstructs tumor immunogenicity, in turn promote dendritic cell maturation, antigen-presenting cell activity, tumor cell phagocytosis by APCs, and efficient T cell priming. Further in vivo and in vitro analyses reveal that zebularine stimulates cGAS-STING-NF-κB/IFNβ signaling to enhance tumor cell immunogenicity and upregulate antigen processing and presentation machinery (AgPPM), which promotes effective CD4+ and CD8+ T cell-mediated killing of tumor cells. These findings support the use of combination regimens that include DNMTi and immunotherapy for cancer treatment.

Mathematical modeling of the synergistic interplay of radiotherapy and immunotherapy in anti-cancer treatments.

While radiotherapy has long been recognized for its ability to directly ablate cancer cells through necrosis or apoptosis, radiotherapy-induced abscopal effect suggests that its impact extends beyond local tumor destruction thanks to immune response. Cellular proliferation and necrosis have been extensively studied using mathematical models that simulate tumor growth, such as Gompertz law, and the radiation effects, such as the linear-quadratic model. However, the effectiveness of radiotherapy-induced immune responses may vary among patients due to individual differences in radiation sensitivity and other factors. We present a novel macroscopic approach designed to quantitatively analyze the intricate dynamics governing the interactions among the immune system, radiotherapy, and tumor progression. Building upon previous research demonstrating the synergistic effects of radiotherapy and immunotherapy in cancer treatment, we provide a comprehensive mathematical framework for understanding the underlying mechanisms driving these interactions. Our method leverages macroscopic observations and mathematical modeling to capture the overarching dynamics of this interplay, offering valuable insights for optimizing cancer treatment strategies. One shows that Gompertz law can describe therapy effects with two effective parameters. This result permits quantitative data analyses, which give useful indications for the disease progression and clinical decisions. Through validation against diverse data sets from the literature, we demonstrate the reliability and versatility of our approach in predicting the time evolution of the disease and assessing the potential efficacy of radiotherapy-immunotherapy combinations. This further supports the promising potential of the abscopal effect, suggesting that in select cases, depending on tumor size, it may confer full efficacy to radiotherapy.