Advancing Prostate Cancer Treatment: Innovations and Challenges in Immunotherapy.

Advancing together and moving forward: Combination gene and cellular immunotherapies

879 Reversal of lactate and PD-1-mediated macrophage immunosuppression controls growth of PTEN/p53-deficient prostate cancer

Immune checkpoints are differentially expressed on various immune cells to regulate immune responses in tumor microenvironment. Tumor cells can activate the immune checkpoint pathway to establish an immunosuppressive tumor microenvironment and inhibit the anti-tumor immune response, which may lead to tumor progression by evading immune surveillance. Interrupting co-inhibitory signaling pathways with immune checkpoint inhibitors (ICIs) could reinvigorate the anti-tumor immune response and promote immune-mediated eradication of tumor cells. As a milestone in tumor treatment, ICIs have been firstly used in solid tumors and subsequently expanded to hematological malignancies, which are in their infancy. Currently, immune checkpoints have been investigated as promising biomarkers and therapeutic targets in hematological malignancies, and novel immune checkpoints, such as signal regulatory protein α (SIRPα) and tumor necrosis factor-alpha-inducible protein 8-like 2 (TIPE2), are constantly being discovered. Numerous ICIs have received clinical approval for clinical application in the treatment of hematological malignancies, especially when used in combination with other strategies, including oncolytic viruses (OVs), neoantigen vaccines, bispecific antibodies (bsAb), bio-nanomaterials, tumor vaccines, and cytokine-induced killer (CIK) cells. Moreover, the proportion of individuals with hematological malignancies benefiting from ICIs remains lower than expected due to multiple mechanisms of drug resistance and immune-related adverse events (irAEs). Close monitoring and appropriate intervention are needed to mitigate irAEs while using ICIs. This review provided a comprehensive overview of immune checkpoints on different immune cells, the latest advances of ICIs and highlighted the clinical applications of immune checkpoints in hematological malignancies, including biomarkers, targets, combination of ICIs with other therapies, mechanisms of resistance to ICIs, and irAEs, which can provide novel insight into the future exploration of ICIs in tumor treatment.

Chapter 10 - Immunotherapeutic strategies and immunotherapy resistance in prostate cancer

Cancer immunotherapy has fundamentally reshaped oncology by harnessing the immune system to eliminate malignant cells. Immune checkpoint inhibitors targeting CTLA-4 and PD-1/PD-L1 have achieved durable remissions in select cancers, yet most patients exhibit resistance due to tumor heterogeneity, immunometabolic rewiring, and the immunosuppressive tumor microenvironment. To address these limitations, next-generation immunotherapies have emerged, targeting multiple layers of immune regulation. These include co-inhibitory and co-stimulatory checkpoint modulators, bispecific antibodies, adoptive cell therapies, cancer vaccines, oncolytic viruses, cytokine-based strategies, and synthetic immunomodulators that activate innate sensors. Nanotechnology and in vivo immune engineering further enhance specificity, reduce toxicity, and broaden applicability. Combination immunotherapy has become central to overcoming resistance, with rational regimens integrating ICIs, cytokines, vaccines, and targeted agents. Biomarker-guided strategies, leveraging tumor mutational burden, immune cell infiltration, and multi-omic profiling, are enabling personalized approaches. However, immune-related adverse events and variability in therapeutic responses necessitate predictive biomarkers and improved patient stratification. Emerging frontiers include microbiome-targeted interventions, chronotherapy, and AI-driven modeling of tumor–immune dynamics. Equally critical is ensuring global equity through inclusive trial design, diverse biomarker validation, and expanded access to cutting-edge therapies. This review provides a comprehensive analysis of multimodal immunotherapeutic strategies, their mechanistic basis, and clinical integration. By unifying innovation in immunology, synthetic biology, and systems medicine, next-generation cancer immunotherapy is poised to transition from a transformative intervention to a curative paradigm across malignancies.

Oncolytic viruses have found a good place in the treatment of cancer. Administering oncolytic viruses directly or by applying genetic changes can be effective in cancer treatment through the lysis of tumor cells and, in some cases, by inducing immune system responses. Moreover, oncolytic viruses induce antitumor immune responses via releasing tumor antigens in the tumor microenvironment (TME) and affect tumor cell growth and metabolism. Despite the success of virotherapy in cancer therapies, there are several challenges and limitations, such as immunosuppressive TME, lack of effective penetration into tumor tissue, low efficiency in hypoxia, antiviral immune responses, and off‐targeting. Evidence suggests that oncolytic viruses combined with cancer immunotherapy‐based methods such as immune checkpoint inhibitors and adoptive cell therapies can effectively overcome these challenges. This review summarizes the latest data on the use of oncolytic viruses for the treatment of cancer and the challenges of this method. Additionally, the effectiveness of mono, dual, and triple therapies using oncolytic viruses and other anticancer agents has been discussed based on the latest findings.

BackgroundDespite multimodal management strategies, outcomes for patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) remain poor. Immune checkpoint inhibitors have demonstrated promise as a neoadjuvant strategy to reduce relapse rates1 ; however, the immunosuppressive SCCHN tumour microenvironment (TME) has limited the efficacy of immunotherapy to date. This ‘cold’ TME is characterised by an absence of T-cell activation/inflammation2 and high levels of stromal fibroblast activating protein (FAP),3 indicative of immunosuppressive cancer-associated fibroblasts (CAFs). Novel approaches to ameliorate this immunosuppressive TME are required to realise the full benefit of immunotherapy in SCCHN.NG-641 is a next-generation blood-stable and transgene-armed Tumour-Specific Immuno Gene Therapy (T-SIGn) adenoviral vector that selectively replicates in epithelial tumour cells. NG-641 encodes four immunostimulatory transgenes: a FAP-directed bi-specific T-cell activator antibody to target CAFs, interferon alpha 2 to promote innate and adaptive immune responses, and C-X-C motif chemokine ligands 9 and 10 to induce T cell infiltration.4 Together, these transgenes are designed to locally re-programme the immunosuppressive TME and promote functional anti-cancer immune responses while minimising systemic immune-related toxicities. This mechanism of action is particularly suited to SCCHN and should complement anti–PD-1 inhibitors. We, therefore, designed a study to assess neoadjuvant treatment with NG-641 and pembrolizumab in locally advanced SCCHN.MethodsThe mode-of-action transgene (MOAT) study is a multicentre, open-label, dose-escalating, phase 1b study of NG-641 as monotherapy or with pembrolizumab. Patients are eligible if they have newly diagnosed or recurrent locally advanced SCCHN and have definitive surgery planned within 8 weeks of screening. In Part A, patients will receive three doses of intravenous NG-641 monotherapy prior to surgery (figure 1). Once NG-641 transgene expression is confirmed in excised tumour tissues, Part A will close and NG-641 dose-escalation can continue in Part B. Patients will then also receive a single dose of pembrolizumab given ~5 days after NG-641 to minimize toxicity and take advantage of the mechanism of NG-641 prior to PD-1 blockade. The primary objective is to characterise the safety and tolerability of NG-641 ± pembrolizumab in SCCHN; secondary objectives are to identify a recommended dose of NG-641 plus pembrolizumab and to assess treatment outcomes, including pathological tumour responses and overall survival. Pharmacodynamic outcomes will be assessed following NG-641 ± pembrolizumab, including characterising immune/inflammatory biomarkers in both tumour and blood. The study is to be conducted at 4 sites in the UK; up to 36 patients will be enrolled.Abstract 437 Figure 1MOAT study schematicAcknowledgementsThis study was funded by PsiOxus Therapeutics Ltd.Trial RegistrationThis trial is registered as NCT04830592 on clinicaltrials.gov.ReferencesUppaluri R, Campbell KM, Egloff AM, et al. Neoadjuvant and Adjuvant Pembrolizumab in Resectable Locally Advanced, Human Papillomavirus-Unrelated Head and Neck Cancer: A Multicenter, Phase II Trial. Clin Cancer Res 2020;26:5140–52.Cristescu R, Mogg R, Ayers M, et al. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science 2018;362:eaar3593.Dolznig H, Schweifer N, Puri C, et al. Characterization of cancer stroma markers: In silico analysis of an mRNA expression database for fibroblast activation protein and endosialin Cancer Immun 2005;5:10.Champion BR, Besneux M, Patsalidou M, et al. NG-641: An oncolytic T-SIGn virus targeting cancer-associated fibroblasts in the stromal microenvironment of human carcinomas. Cancer Res 2019;79:5013.Ethics ApprovalThis study was approved by a central United Kingdom Research Ethics Committee (South Central - Oxford A Research Ethics Committee); approval reference 20/SC/0425, Integrated Research Application System ID 290504. All participants must provide informed consent prior to enrolment.

Prostate cancer currently stands as the most frequently diagnosed solid tumor in men, and remains one of the leading causes of cancer mortality in men in the Western world, accounting for an estimated 32,050 deaths in the United States in 2010 (Jemal et al., 2010). With the wellknown use of serum prostate-specific antigen (PSA) as a screening tool, men are being diagnosed with earlier stage disease at younger ages. However, a significant number of men continue to be diagnosed with high-risk localized prostate cancer. Radical prostatectomy, radiotherapy, cryotherapy, high-intensity focused ultrasound, radiation therapy, and androgen deprivation as well as androgen receptor blockade have been the mainstays of treatment for cancer patients with localized and androgen-dependent prostate cancer. As prostate cancer cell growth is androgen dependent, its deprivation is an important therapeutic strategy. However, long-term androgen-ablation results in androgenindependent cancer cell growth in metastatic patients, leading to hormone refractory prostate cancer (HRPC) (Sonpavde et al., 2006). Prostate cancer tends to invade the pelvic lymph nodes and spread to distant organs, mainly via the blood stream, showing a strong predilection for bones (Koutsilieris, 1993;Sourla et al., 1996). This disease frequently metastasizes to bone and almost invariably progresses from an androgen-sensitive to an androgen-independent status, greatly limiting therapeutic options and significantly reducing life expectancy in patients. Skeletal metastases occur in more than 80% of cases of advanced-stage prostate cancer and they confer a high level of morbidity. Metastasis of prostate cancer, like that of other solid tumors, involves multiple steps, including angiogenesis, local migration, invasion, intravasation, circulation and extravasation of tumor cells and then angiogenesis and colonization in the new site. Treatment-naive metastatic prostate cancer is largely sensitive to androgen-deprivation therapy (ADT), but the effectiveness of ADT is temporary, and tumors in the majority of patients eventually relapse and evolve into castration-resistant prostate cancer (CRPC), from which most patients die (Eisenberger and Walsh, 1999). These tumors eventually become incurable or resistant to antihormonal therapy. Indeed, there is an association between ADT and high risk of cardiovascular disease and mortality, and men with a history of recent or active cardiac disease are particularly at risk (Saigal et al., 2007). In men with a history of coronary artery disease, chronic heart failure, or myocardial infarction, ADT was associated with an increased risk of mortality (Nguyen et al., 2011). Continuous ADT use for at least 6 months in older men is also associated with an increased risk of diabetes and fragility fracture (Alibhai et al., 2009). For this reason, new agents and therapeutic modalities are needed,

Ineffectiveness of immune checkpoint inhibitors in patients with castration- resistant prostate cancer (CRPC) suggests that CRPC may harbor a profound immunosuppressive tumor microenvironment. However, immune tumor microenvironment of CRPC has never been well investigated due to limited availability of castration-resistant tumor tissue. To characterize the changes in immune tumor microenvironment during CRPC progression and identify disease stage which is potentially favorable for immunotherapy, we studied the densities of tumor-infiltrating immune cells by using the immunohistochemical method and manual counting in paired castration-naive (CN) and castration-resistant (CR) tumors. We identified 11 metastatic prostate cancer patients who had received palliative transurethral resection of prostate both before androgen deprivation therapy (ADT) and at the time when castration resistance emerged from the hospital database during 2006.1~2017.3. We also used prostatic tissue from 5 patients with benign prostate hyperplasia as the normal prostate control. The median age at diagnosis of PC patients was 74.7 (range: 62-85) year-old. The numbers of tumors with Gleason score 7, 8, 9 and 10 were 1, 1, 6, and 2, respectively. The median PSA level at diagnosis was 96.6 (range: 3.3-847.7) ng/ml. The median overall survival after initiation of ADT was 48.8 months. The median density of CD4+ T cells (no./mm2) was 182.3 (45.0-363.5) for normal prostate, 160.9 (range: 12.6-240.6) for CNPC and 69.4 (range: 31-499.6) for CRPC (non-statistically significant; n.s.). The median density of CD8+ T cells (no./mm2) was 12.5 (range: 32.5-220.7) for normal prostate, 65.7 (range: 3.7-195.6) for CNPC and 53.8 (range: 4.4-190.4) for CRPC (n.s.). The median density of CD20+ B cells (no./mm2) was 132.1 (range: 54.6-514.4) for normal prostate, 112.2 (range: 3.7-298.9) for CNPC and 47.6 (range: 7.0-137.3) for CRPC (n.s.). The median density of CD68+ macrophages (no./mm2) was 31 (range: 0.4-248.7) for normal prostate, 77.5 (range: 3.7-403.7) for CNPC and 31.7 (range: 2.2-180.8) for CRPC (n.s.). The tumor-infiltrating immune cell densities in CNPC did not correlate with PSA level, Gleason score or ADT response. Only high B cell density in CNPC was prognostic for overall survival (median: 23.9 months for patients with high tumor-infiltrating B cell density vs. 64 months for patients with low tumor-infiltrating B cell density; P=0.0463). In conclusion, immune tumor microenvironment of CNPC and CRPC is very similar and is not different from normal prostate. It suggests that immune checkpoint inhibitors may not be effective against CNPC unless combining with other treatment, such as ADT or radiotherapy, which can reprogram the tumor microenvironment toward more immunosupportive. Citation Format: Ying-Chun Shen, Chia-Tung Shun, Ching-Ping Yeh, Jhe-Cyuang Kuo, Yu-Chieh Tsai, Chung-Hsin Chen, Chao-Yuan Huang, Yeong-Shiau Pu. Immune cell infiltration and its clinical correlations in paired castration-naive and castration-resistant prostate cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4697.

Objectives Immune checkpoint inhibitors (ICIs) are shown to improve cancer treatment effectiveness by boosting the immune system of the patient. Nevertheless, the unique and highly suppressive TME poses a significant challenge, causing heterogeneity of response or resistance in a considerable number of patients. This review aims to explore the challenges posed by the immunosuppressive tumor microenvironment (TME) in response to immune checkpoint inhibitors (ICIs) and discusses potential strategies to overcome resistance. Material & Methods A comprehensive review of existing literature was conducted to analyze the immunosuppressive features of the TME, including the role of immunosuppressive cells, cytokine and chemokine signaling, metabolic alterations, and overexpression of immune checkpoint molecules (PD-1, CTLA-4, LAG-3, TIM-3, TIGIT, BTLA). Additionally, strategies to overcome resistance—such as targeting immunosuppressive cells, normalizing tumor vasculature, dual or triple checkpoint blockade, and combining ICIs with vaccines, oncolytic viruses, and metabolic inhibitors—are elaborated. The need for predictive biomarkers to stratify patients and assess treatment response was also discussed. Results The review highlights that the immunosuppressive TME contributes significantly to resistance against ICIs, mediated through various mechanisms. Potential strategies to overcome resistance include modulating the TME by targeting immunosuppressive components, combination therapies, and the identification of predictive biomarkers. Further research and innovative approaches are required to fully understand TME-ICI interactions and change the face of cancer treatment.

Immunotherapy in microsatellite-stable colorectal cancer: Strategies to overcome resistance.

Immune-Related Adverse Events and Outcomes in Patients with Advanced Non–Small Cell Lung Cancer: A Predictive Marker of Efficacy?

Ageism in the undertreatment of high-risk prostate cancer: how long will clinical practice patterns resist the weight of evidence?

Metastatic Burden in Hormone-Naive Prostate Cancer: A Tale of Two Subgroups

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide. HCC patients may benefit from liver transplantation, hepatic resection, radiofrequency ablation, transcatheter arterial chemoembolization, and targeted therapies. The increased infiltration of immunosuppressive immune cells and the elevated expression of immunosuppressive factors in the HCC microenvironment are the main culprits of the immunosuppressive nature of the HCC milieu. The immunosuppressive tumor microenvironment can substantially attenuate antitumoral immune responses and facilitate the immune evasion of tumoral cells. Immunotherapy is an innovative treatment method that has been promising in treating HCC. Immune checkpoint inhibitors (ICIs), adoptive cell transfer (ACT), and cell-based (primarily dendritic cells) and non-cell-based vaccines are the most common immunotherapeutic approaches for HCC treatment. However, these therapeutic approaches have not generally induced robust antitumoral responses in clinical settings. To answer to this, growing evidence has characterized immune cell populations and delineated intercellular cross-talk using single-cell RNA sequencing (scRNA-seq) technologies. This review aims to discuss the various types of tumor-infiltrating immune cells and highlight their roles in HCC development. Besides, we discuss the recent advances in immunotherapeutic approaches for treating HCC, e.g., ICIs, dendritic cell (DC)-based vaccines, non-cell-based vaccines, oncolytic viruses (OVs), and ACT. Finally, we discuss the potentiality of scRNA-seq to improve the response rate of HCC patients to immunotherapeutic approaches.