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A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: 31 May 2026 | Viewed by 14918

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Special Issue Editor

Dr. Yee Peng Phoon

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Guest Editor

Cleveland Clinic Foundation, Cleveland, OH, USA
Interests: immunotherapy; biomarkers; immuno-oncology

Special Issue Information

Dear Colleagues,

Cancer immunotherapy has evolved significantly over the past century, beginning with early theories and experimental treatments, and progressing to the modern era, which is marked by groundbreaking innovations like immune checkpoint inhibitors, CAR-T therapies, TIL therapy, and cancer vaccines. These advancements have fundamentally shifted the paradigm of cancer patient management. Today, immunotherapy stands at the forefront of cancer treatment, ushering in a new era that offers renewed hope to patients.

Despite these recent breakthroughs, cancer continues to pose a major global challenge. It is projected that by 2025, there will be approximately 26 million new cancer cases worldwide, along with 17 million cancer-related deaths. This stark reality underscores the need for more comprehensive treatment strategies that can bridge current gaps—specifically, the discovery and development of new modalities aimed at improving clinical outcomes and providing sustainable benefits for patients.

As research delves deeper into the mechanisms governing immune cell function and their interactions with the tumor microenvironment, even more promising therapeutic options are on the horizon. The field of neoadjuvant therapy has gained significant attention, with ongoing clinical trials and innovative approaches focused on improving clinical outcomes across a range of cancer types. Additionally, there has been a renewed interest in cytokine therapy and bispecific antibodies, which show great promise when used in combination therapies to enhance anti-tumor efficacy.

Another key area of focus is the development of predictive biomarkers to forecast treatment responses. Integrating these biomarkers into clinical practice has the potential to be one of the most transformative advancements in cancer care, reshaping diagnosis, treatment selection, and the timing of interventions.

In conclusion, the future of cancer treatment and management lies in the integration of combination therapies and predictive biomarkers to enable more personalized, targeted, and effective treatments, ultimately leading to better outcomes and advancing the overall quality of healthcare.

Dr. Yee Peng Phoon
Guest Editor

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Keywords

immunotherapy
CAR-T
TIL therapy
predictive biomarker
neoadjuvant
cytokine therapy
bispecific antibodies
personalized treatment
combination therapies
tumor microenvironment
immune modulation, interaction and mechanism

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Published Papers (8 papers)

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Research

Jump to: Review, Other

14 pages, 19811 KB

Open AccessArticle

Early Immune Signature Features, Including TLR2 and TLR4 Expression, Are Associated with Complete Remission After CD19 CAR-T Cell Therapy

by Serena Di Iasio, Chiara Di Nunzio, Elisabetta De Santis, Concetta Stella, Daniela Valente, Dalila Salvatore, Emanuela Merla, Grazia Dell’Olio, Costanzo Padovano, Mattia Colucci, Gaja Bruno, Barbara Pasculli, Mario Caldarelli, Paola Parrella, Giovanni Gambassi, Rossella Cianci, Angelo M. Carella and Vincenzo Giambra

Pharmaceuticals 2026, 19(5), 671; https://doi.org/10.3390/ph19050671 - 25 Apr 2026

Viewed by 530

Abstract

Background/Objectives: CD19-directed chimeric antigen receptor T (CAR-T) cell therapy induces profound immune remodeling. Nonetheless, biomarkers predicting complete remission (CR) remain poorly defined. We characterized longitudinal cytokine and immune-cell dynamics after CAR-T infusion and identified early immunological features associated with CR. Methods: Longitudinal immune profiling was performed in 18 patients with non-Hodgkin lymphoma, including 14 with relapsed/refractory diffuse large B-cell lymphoma treated with anti-CD19 CAR-T cells. Peripheral blood was collected at the baseline and days 7, 14, 21, 28, and 60 post-infusion. Multiparameter flow cytometry quantified lymphoid and myeloid subsets and Toll-like receptor (TLR)2 and TLR4 expression. Serum cytokines were measured by multiplex assays. Machine-learning-based feature selection identified variables associated with CR. Results: Two inflammatory waves were observed. The first, at day 7, featured elevated IL-6, IL-10, IFN-α, IFN-γ, and TNF-α, accompanied by increased CD4⁺ T cells, HLA-DR^high classical monocytes, and non-classical monocytes. The second, at days 21–28, showed increased IL-5, IL-6, IL-12, IFN-γ, and GM-CSF, with expansion of CD4⁺ and CD8⁺ T cells, regulatory T cells, NK-T cells, and non-classical monocytes. TLR2 expression was significantly upregulated at day 7 on T-cell subsets and on classical and intermediate monocytes. An exploratory feature-selection analysis identified baseline and day-7 TLR2 and TLR4 expression on lymphoid and myeloid cells, early IFN-γ levels, and monocyte frequencies as variables associated with CR. Conclusions: Together, these data show that anti-CD19 CAR-T therapy induces two coordinated waves of cytokine release and immune-cell activation. Moreover, the findings suggest that early modulation of innate immune features, particularly TLR2 expression, is associated with complete remission, although these biomarker relationships remain exploratory and require validation in larger cohorts. Full article

(This article belongs to the Special Issue Comprehensive Strategies in Cancer Immunotherapy)

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17 pages, 1233 KB

Open AccessArticle

Combined Lung Immune Prognostic Index (LIPI)-Glasgow Prognostic Score (GPS) as a Prognostic Tool in Extensive-Stage Small-Cell Lung Cancer Treated with First-Line Chemo-Immunotherapy

by Maral Martin Mıldanoğlu, Fatih Kemik, Melisa Eryaşar, Hakan Özçelik, Erdem Sünger, Mehmet Haluk Yücel, Ebru Engin Delipoyraz, Sena Fidan, Harun Muğlu, Burçin Çakan Demirel, Jamshid Hamdard, Yasin Kutlu, Özgür Açıkgöz, Fatih Selcukbiricik, Mesut Şeker and Ahmet Bilici

Pharmaceuticals 2026, 19(4), 587; https://doi.org/10.3390/ph19040587 - 7 Apr 2026

Viewed by 491

Abstract

Introduction: Inflammatory and immune-based prognostic markers such as the Lung Immune Prognostic Index (LIPI) and the Glasgow Prognostic Score (GPS) have gained increasing attention in ES-SCLC, particularly in patients receiving first-line chemoimmunotherapy. However, no prior study has explored a broader, integrated inflammatory framework that evaluates these parameters collectively. Methods: We retrospectively evaluated 166 patients with ES-SCLC treated with first-line platinum–etoposide plus atezolizumab or durvalumab between 2019 and 2025. LIPI could be calculated in 123 patients based on available dNLR and LDH values, while GPS and the Combined Inflammatory Prognostic Score (CIPS) could be assessed in 120 patients with accessible CRP and albumin data. Results: Median PFS and OS were 8.16 and 15.96 months, respectively. In univariate analyses, poor ECOG PS, liver and bone metastases, poor LIPI, poor GPS, and high-risk CIPS were associated with shorter PFS and OS. In multivariate analysis, only LIPI and GPS remained independent predictors of both PFS and OS, while ECOG PS was independently associated with OS. Although CIPS demonstrated clear prognostic separation in univariate analysis, it did not retain independent significance, likely due to sample size limitations and overlap with LIPI and GPS components. Conclusions: LIPI and GPS are strong independent prognostic markers in ES-SCLC receiving chemoimmunotherapy. While CIPS did not demonstrate independent prognostic value in multivariate analysis, its simplicity, balanced two-tier design, and use of routinely available biomarkers highlight its potential clinical utility. To our knowledge, this is the first study to assess a combined inflammatory prognostic model in this population. Prospective multicenter validation is warranted. Full article

(This article belongs to the Special Issue Comprehensive Strategies in Cancer Immunotherapy)

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Review

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21 pages, 1868 KB

Open AccessReview

Broad-Spectrum RAS Inhibition in Pancreatic Ductal Adenocarcinoma: Mechanistic Advances and Therapeutic Promise

by Fawaz E. Alanazi, Yasser Alatawi, Abdullah Alattar, Reem Alshaman, Ahmed A. Kotb and Helal F. Hetta

Pharmaceuticals 2025, 18(12), 1788; https://doi.org/10.3390/ph18121788 - 24 Nov 2025

Cited by 2 | Viewed by 3347

Abstract

The RAS family of oncoproteins (KRAS, HRAS, and NRAS) drive aggressive cancers like pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC), yet targeting mutant RAS has historically been challenging due to its “undruggable” structure. Recent advances in mutation-specific inhibitors (e.g., sotorasib for KRAS^G12C) have demonstrated clinical efficacy but face limitations in tumor types like PDAC, where KRAS^G12C mutations are rare. Broad-spectrum pan-RAS inhibitors (e.g., RMC-7977, RMC-6236, ADT-007/ADT-1004) now offer promise by targeting active GTP-bound or nucleotide-free RAS across isoforms and mutations. Preclinical studies show these agents induce deep tumor regressions, overcome resistance to allele-specific inhibitors, and remodel the tumor microenvironment (TME) by enhancing T-cell infiltration and reducing immunosuppressive myeloid cells. Early clinical data for RMC-6236 report disease control rates of 85–87% in NSCLC and PDAC, with manageable toxicity. This review shows that pan-RAS inhibitors represent a promising new class of therapeutics capable of overcoming many historical challenges associated with the “undruggable” nature of RAS proteins and demonstrating encouraging preclinical and early clinical results, particularly in difficult-to-treat tumor types such as PDAC and NSCLC. Challenges remain in achieving a therapeutic index due to RAS’s role in normal tissue homeostasis, but tumor-specific drug accumulation and rapid normal tissue recovery may mitigate risks. Ongoing trials are evaluating combination strategies with immunotherapy and chemotherapy, positioning pan-RAS inhibitors as transformative agents for RAS-driven cancers. Full article

(This article belongs to the Special Issue Comprehensive Strategies in Cancer Immunotherapy)

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26 pages, 3289 KB

Open AccessReview

BTLA: An Emerging Immune Checkpoint Target in Cancer Immunotherapy

by Ming-Cheng Chang, Wan-Chi Lee, Yi-Jou Tai and Ying-Cheng Chiang

Pharmaceuticals 2025, 18(12), 1784; https://doi.org/10.3390/ph18121784 - 24 Nov 2025

Cited by 2 | Viewed by 2148

Abstract

B and T lymphocyte attenuator (BTLA) is a unique co-inhibitory receptor of the CD28 immunoglobulin superfamily that exhibits dual regulatory functions in immune activation and tolerance. Unlike PD-1 or CTLA-4, BTLA interacts bidirectionally with its ligand HVEM, forming a complex signaling network that shapes immune homeostasis within the tumor microenvironment. Dysregulated BTLA expression has been associated with tumor immune evasion and poor prognosis in several cancers. Owing to its distinctive molecular features and multifaceted immunoregulatory roles, BTLA represents an emerging therapeutic target, particularly in tumors unresponsive to conventional immune checkpoint inhibitors. This review provides a comprehensive overview of BTLA’s structure, signaling mechanisms, and functional implications in tumor immunity and discusses current advances and challenges in BTLA-targeted therapy. Finally, we outline future perspectives on leveraging BTLA modulation to enhance cancer immunotherapy outcomes. Full article

(This article belongs to the Special Issue Comprehensive Strategies in Cancer Immunotherapy)

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27 pages, 2047 KB

Open AccessReview

Harnessing Single-Cell RNA-Seq for Computational Drug Repurposing in Cancer Immunotherapy

by Olivia J. Cheng, T.T.T. Tran, Y. Ann Chen and Aik Choon Tan

Pharmaceuticals 2025, 18(11), 1769; https://doi.org/10.3390/ph18111769 - 20 Nov 2025

Viewed by 2582

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment and show notable success in some cancer types such as non-small cell lung cancer, melanoma and colorectal cancers, while they demonstrate relatively low response rate in others, such as esophageal cancers. Due to the heterogeneous nature of the tumor microenvironment and patient-to-patient variability, there remains a need to improve ICI response rates. Combining ICIs with therapies that can overcome resistance is a promising strategy. Compared to de novo drug development, drug repurposing offers a faster and more cost-effective approach to identifying such combination candidates. A variety of computational drug repurposing tools leverage genomics and/or transcriptomic data. As single-cell RNA sequencing (scRNA-seq) technology becomes available, it enables precise targeting of cancer-driving cellular components. In this review, we highlight current computational drug repurposing tools utilizing scRNA-seq data and demonstrate the application of two such tools, scDrug and scDrugPrio, on an esophageal squamous cell carcinoma dataset to identify potential drug candidates for combination with ICI therapy to enhance treatment response. scDrug focuses on predicting tumor cell-specific cytotoxicity, while scDrugPrio prioritizes drugs by reversing gene signatures associated with ICI non-responsiveness across diverse tumor microenvironment cell types. Together, this review underscores the importance of a multi-faceted approach in computational drug repurposing and highlights its potential for identifying drugs that enhance ICI treatment. Future work can expand the application of these strategies to multi-omics and spatial transcriptomics datasets, as well as personalized patient samples, to further refine drug repurposing involving ICI therapy. Full article

(This article belongs to the Special Issue Comprehensive Strategies in Cancer Immunotherapy)

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19 pages, 2143 KB

Open AccessSystematic Review

Is Brukinsa (Zanubrutinib) a Safer Bruton’s Tyrosine Kinase (BTK) Inhibitor in Relapsed or Refractory Chronic Lymphocytic Leukemia? A Systematic Review and Meta-Analysis

by Helal F. Hetta, Ayman Salama, Turki A. Aljuaid, Yazan T. Mojmami, Riyadh S. Alotibi, Ahmed M. Alqabaly, Nawaf A. Aldosari, Sami A. Alshahri, Walid I. A. Asiri, Raed S. Alamri, Fayez A. Alanazi, Malek S. A. Alenazi, Mohammed H. Albuhayri, Yasmin N. Ramadan and Reem Sayad

Pharmaceuticals 2026, 19(3), 467; https://doi.org/10.3390/ph19030467 - 12 Mar 2026

Cited by 1 | Viewed by 1350

Abstract

Background/Objectives: Zanubrutinib (Brukinsa) is a next-generation Bruton’s tyrosine kinase inhibitor approved for the treatment of relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL); however, a comprehensive quantitative assessment of its safety profile remains limited. Methods: A systematic search of PubMed, Scopus, Web of Science, and MEDLINE was conducted to identify clinical trials published up to August 2025 that reported treatment-emergent adverse events (TEAEs) associated with zanubrutinib in patients with R/R CLL/SLL. Pooled incidence estimates were calculated using a random-effects model (DerSimonian and Laird method). Results: Four studies comprising 508 patients were included, with median follow-up durations ranging from 15.1 to 34.5 months. The pooled incidence of any-grade adverse events was 98.5% (95% CI, 97.1–99.9), while grade ≥3 adverse events occurred in 67.0% (95% CI, 55.4–78.7). Serious adverse events were reported in 32.2% of patients (95% CI, 25.1–39.3), treatment discontinuation due to toxicity occurred in 7.2% (95% CI, 2.5–11.8), and adverse event-related mortality was observed in 7.1% (95% CI, 0.2–13.9). The most frequently reported hematological adverse events were neutropenia (32.1%) and anemia (26.7%), while common non-hematological adverse events included bleeding events (51.9%), upper respiratory tract infections (27.2%), pneumonia (19.4%), and hypertension (16.4%). Atrial fibrillation occurred in 2.9% of patients. Conclusions: Zanubrutinib was associated with a high incidence of adverse events, although rates of treatment discontinuation and atrial fibrillation were relatively low, supporting its tolerability in R/R CLL/SLL within clinical trial settings while highlighting the need for continued long-term and real-world safety monitoring. Full article

(This article belongs to the Special Issue Comprehensive Strategies in Cancer Immunotherapy)

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21 pages, 3209 KB

Open AccessSystematic Review

Therapeutic Impact of Zanubrutinib in Chronic Lymphocytic Leukemia: Evidence from a Systematic Review and Single-Arm Meta-Analysis

by Yasser Alatawi, Fawaz E. Alanazi, Abdullah Alattar, Reem Alshaman, Yasmin N. Ramadan, Reem Sayad and Helal F. Hetta

Pharmaceuticals 2025, 18(11), 1674; https://doi.org/10.3390/ph18111674 - 5 Nov 2025

Cited by 2 | Viewed by 1514

Abstract

Background and Objective: Zanubrutinib, a next-generation Bruton’s tyrosine kinase inhibitor (BTKi), has demonstrated promising efficacy in chronic lymphocytic leukemia (CLL), including treatment-naïve (TN) and relapsed/refractory (R/R) patients. However, evidence synthesis across clinical trials remains limited. We conducted a systematic review and single-arm meta-analysis to evaluate the efficacy of zanubrutinib in CLL. Methods: This study was performed in accordance with PRISMA guidelines and Cochrane recommendations. PubMed, Medline, Scopus, and Web of Science were searched up to August 2025 using terms related to zanubrutinib and CLL/SLL. Eligible studies included clinical trials of zanubrutinib in TN or R/R CLL/SLL patients. Risk of bias was assessed using the JBI tool for non-randomized studies and for RCTs. Pooled estimates of efficacy outcomes were calculated using a random-effects model. Pooled estimates were calculated using the DerSimonian–Laird random-effects model, which accounts for both within- and between-study variability. Results: Seven studies (n > 1000) were included, enrolling both TN and R/R patients across diverse global populations. The pooled overall response rate (ORR) was 93.3% (95% CI, 86.7–99.8%) in mixed TN and R/R populations, 94.4% (95% CI, 91.6–97.3%) in TN patients, and 83.9% (95% CI, 75.0–92.8%) in R/R patients. Complete response (CR) rates were 12.2% (95% CI, 0.3–24.2%) overall, 13.8% (95% CI, 1.5–26.2%) in TN patients, and 5.0% (95% CI, 0.3–9.8%) in R/R patients. Partial response (PR) rates reached 86.0% (95% CI, 82.6–89.5%) in TN and 63.2% (95% CI, 53.5–73.0%) in R/R patients. Progressive disease was rare (≤1% in R/R cohorts). Heterogeneity was moderate to high across several outcomes. Conclusions: Zanubrutinib demonstrates favorable efficacy in CLL, achieving high ORR in both TN and R/R patients, with particularly durable responses in TN populations. Although complete response rates remain modest, especially among R/R patients, overall disease control appears consistent. These findings support zanubrutinib as an effective treatment option across CLL settings; however, variability among studies and the modest CR rates highlight the need for longer follow-up and direct comparative trials to further define its clinical role. Full article

(This article belongs to the Special Issue Comprehensive Strategies in Cancer Immunotherapy)

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17 pages, 758 KB

Open AccessSystematic Review

Evaluating the Safety and Efficacy of PD-1 Inhibitors in HIV Patients Diagnosed with Lung Cancer: A Systematic Review

by Helal F. Hetta, Yasser Alatawi, Fawaz E. Alanazi, Abdullah Alattar, Reem Alshaman, Hanan Alshareef, Zinab Alatawi, Majd S. Alatawi, Jumana H. Albalawi, Ghadeer A. Alosaimi, Reem Sayad and Wedad M. Nageeb

Pharmaceuticals 2025, 18(11), 1654; https://doi.org/10.3390/ph18111654 - 1 Nov 2025

Cited by 2 | Viewed by 1679

Abstract

Background and Aim: People with HIV (PWH) have historically been excluded from cancer immunotherapy trials due to concerns over immune dysregulation and safety. This systematic review evaluates the safety, efficacy, and immunologic outcomes of Programmed death-1 (PD-1) inhibitors in PWH diagnosed with non-small-cell lung cancer (NSCLC). Methods: Following PRISMA guidelines, a systematic search was conducted across PubMed, Scopus, Web of Science, and Medline through January 2025. Studies were included if they reported outcomes of ICIs in PWH with NSCLC. Data extraction included progression-free survival (PFS), overall survival (OS), immune-related adverse events (irAEs), antitumor response, HIV viral control, and immunologic parameters. Study quality was assessed using the Joanna Briggs Institute (JBI) checklist. Results: Six cohort studies (n = 762 patients) met inclusion criteria. ICIs used included nivolumab, pembrolizumab, atezolizumab, and durvalumab, with treatment durations ranging from 3.1 to 5.4 months. Median PFS ranged from 3.0 to 6.3 months, and OS ranged from 10.0 to 66.0 months. Overall response rates (ORRs) varied from 13% to 75%, and disease control rates (DCRs) ranged from 47% to 62.5%. irAEs occurred in 25% to 75% of patients, with 6–20% experiencing grade 3–4 events. Corticosteroids were required in 13–29% of patients, and treatment discontinuation due to toxicity occurred in up to 30%. Most patients had controlled HIV, with CD4 counts typically above 300 cells/μL and undetectable viral loads. Conclusions: ICIs appear safe and effective in PWH with NSCLC, with toxicity and efficacy outcomes comparable to the general population. While immunotherapy should not be withheld based solely on HIV status, better standardization in reporting HIV-related variables is needed to optimize patient selection and management. Full article

(This article belongs to the Special Issue Comprehensive Strategies in Cancer Immunotherapy)

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