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Clinical and Fundamental Research Progressions on Tumor-Infiltrating Lymphocytes Therapy in Cancer
No full textMalignant tumors represent a significant threat to human health. Among the various therapeutic strategies available, cancer immunotherapy-encompassing adoptive cell transfer (ACT) and immune checkpoint blockade therapy-has emerged as a particularly promising approach following surgical resection, radiotherapy, chemotherapy, and molecular targeted therapies. This form of treatment elicits substantial antigen-specific immune responses, enhances or restores anti-tumor immunity, thereby facilitating the control and destruction of tumor cells, and yielding durable responses across a range of cancers, which can lead to the eradication of tumor lesions and the prevention of recurrence. Tumor-infiltrating lymphocytes (TILs), a subset of ACT, are characterized by their heterogeneity and are found within tumor tissues, where they play a crucial role in mediating host antigen-specific immune responses against tumors. This review aims to explore recent advancements in the understanding of TILs biology, their prognostic implications, and their predictive value in therapeutic contexts
The Present and Future of Precision Oncology and Tumor-Agnostic Therapeutic Approaches
No full textPrecision oncology has transformed the treatment landscape for patients with advanced solid tumors. Tumor-agnostic therapies, those that have been approved based on genetic mutations or biomarkers across tumor histology types, are important examples of how the implementation of precision oncology can expand therapeutic options for patients, especially those with rare cancer types and treatment-refractory disease. In this review, we first discuss how advances in next-generation sequencing and molecular profiling have enabled the identification of shared actionable alterations. Subsequently, we explore the current landscape of tumor-agnostic therapies that have received approval from the Food and Drug Administration. We discuss the strengths and limitations of these therapies and evaluate the clinical trial data leading to their approval. In addition, we detail updated results from these clinical trials and additional observational studies reported after the approval. Several factors such as tumor histology, specific alteration types, and the presence of co-alterations are associated with the efficacy of these therapies. Also, challenges remain in understanding resistance mechanisms and predicting response. Looking ahead, we discuss how improved diagnostic tools, novel experimental strategies, and innovative trial designs may further advance the field of precision oncology and improve therapeutic options for patients
Bispecific Antibodies in Hematologic and Solid Tumors: Current Landscape and Therapeutic Advances
No full textBispecific antibodies (bsAbs) have emerged as a novel class of therapeutics, offering a dual-targeting strategy to enhance the therapeutic efficacy of monoclonal antibodies, which is often limited by tumor heterogeneity and the occurrence of resistance mechanisms. By simultaneously engaging two distinct antigens or pathways, bsAbs disrupt multiple signaling cascades simultaneously, preventing escape mechanisms and offering a more durable response. Furthermore, they can optimize immune activation, improving immune cell recruitment strategies. In particular, T-cell engager bsAbs facilitate immune cell-mediated tumor destruction by linking T cells to tumor antigens. Instead, dual immune checkpoint inhibitors (CPIs) enhance immune activation by blocking inhibitory signals. Additionally, bsAbs targeting tumor growth factors or receptor tyrosine kinases offer solutions for overcoming drug resistance in solid tumors. Although bsAbs have shown remarkable success in hematologic malignancies, their expansion into solid tumors faces key challenges, including tumor heterogeneity, limited tumor penetration, and the risk of on-target, off-tumor toxicities. Addressing these challenges requires innovative engineering strategies, optimized delivery mechanisms, and careful patient selection to maximize therapeutic benefit while mitigating adverse effects. The efficacy of bsAbs in clinical trials has led to their approval for both hematologic and solid malignancies, with numerous agents in development. Combination strategies with chemotherapy, targeted agents, and immune CPIs could represent a promising strategy to further expand their potential. As research progresses, bsAbs are expected to play a role in reshaping the future of precision oncology, offering more effective and tailored treatment options
Excellent Response Following Palliative Radiation for Locally Advanced Epidemic/AIDS-Associated Kaposi Sarcoma of the Lower Extremity: A Case Report
No full textImage-Based Mandibular and Maxillary Parcellation and Annotation Using Computed Tomography (IMPACT): A Deep Learning-Based Clinical Tool for Orodental Dose Estimation and Osteoradionecrosis Assessment
No full textBackground and purpose: Accurate delineation of orodental structures on radiotherapy computed tomography (CT) images is essential for dosimetric assessment and dental decisions. We propose a deep-learning (DL) auto-segmentation framework for individual teeth and mandible/maxilla sub-volumes aligned with the ClinRad osteoradionecrosis staging system.
Materials and methods: Mandible and maxilla sub-volumes were manually defined on simulation CT images from 60 clinical cases, differentiating alveolar from basal regions; teeth were labelled individually. For each task, a DL segmentation model was independently trained. A Swin UNETR-based model was used for mandible sub-volumes. For smaller structures (e.g., teeth and maxilla sub-volumes) a two-stage model first used the ResUNet to segment the entire teeth and maxilla regions as a single ROI used to crop the image input for Swin UNETR. In addition to segmentation accuracy and geometric precision, a dose-volume comparison was made between manual and model-predicted segmentations.
Results: Segmentation performance varied across sub-volumes - mean Dice values of 0.85 (mandible basal), 0.82 (mandible alveolar), 0.78 (maxilla alveolar), 0.80 (upper central teeth), 0.69 (upper premolars), 0.76 (upper molars), 0.76 (lower central teeth), 0.70 (lower premolars), 0.71 (lower molars) - with limited applicability in segmenting sub-volumes absent in the data. The maxilla alveolar central sub-volume showed a statistically significant dose-volume difference in both Dmean and D2%.
Conclusions: We present a novel DL-based auto-segmentation framework of orodental structures, enabling spatial localization of dose-related differences. This tool may enhance image-based bone injury detection and improve clinical decision-making in radiation oncology and dental care for head and neck cancer patients
Safety and Antitumor Activity of a Novel aCD25 Treg Depleter RG6292 as a Single Agent and in Combination with Atezolizumab in Patients with Solid Tumors
No full textPurpose: Therapeutic depletion of immunosuppressive regulatory T cells (Treg) may overcome resistance to cancer immunotherapies. RG6292 is an anti-CD25 antibody that preferentially depletes Tregs while preserving effector T-cell functions in preclinical models. The safety, pharmacokinetics, pharmacodynamics, and antitumor efficacy of selective Treg depletion by RG6292 administered as monotherapy or in combination with atezolizumab were evaluated in two phase I studies.
Patients and methods: Adult patients with advanced solid tumors were administered intravenous RG6292, given every 3 weeks alone (study 1: NCT04158583, n = 76) or with 1,200 mg atezolizumab every 3 weeks (study 2: NCT04642365, n = 49). Both studies included dose escalation and expansion parts to determine the maximum tolerated dose and recommended phase II dose.
Results: RG6292 was well tolerated. Pruritus and rash were the most frequent adverse events and were manageable with supportive treatment. Serum RG6292 levels increased dose proportionally, independent of the atezolizumab combination. RG6292 induced a sustained dose-dependent depletion of peripheral Tregs with no apparent effect on other immune cells. Evidence of intratumoral Treg reduction (≥50% vs. baseline) was observed at RG6292 doses of 35 to 100 mg. The maximum tolerated dose was 165 mg every 3 weeks, and the recommended phase II dose was proposed as 70 mg every 3 weeks. Objective responses were limited to three partial responses in patients receiving RG6292 combined with atezolizumab.
Conclusions: RG6292 induced a dose-dependent peripheral blood and measurable intratumoral Treg depletion in concordance with the proposed mode of action; however, clinical efficacy as a single agent or combined with atezolizumab was insufficient to warrant further exploration in this population.
Significance: RG6292 (vopikitug) targets CD25 (IL-2Rα) and mediates regulatory T-cell depletion while not interfering with IL-2 signaling. Peripheral and intratumoral Treg depletion was shown in two phase I studies. However, RG6292 alone or in combination with atezolizumab was insufficient to reverse and rescue from established resistance mechanisms in solid tumors
Longitudinal Analysis of Gut Microbiome and Metabolome Correlates of Response and Toxicity With Idecabtagene Vicleucel
No full textIncreasing evidence suggests that the gut microbiome may influence the responses and toxicities associated with chimeric antigen receptor T-cell (CAR-T) therapy. We conducted whole-genome shotgun sequencing on stool samples (N = 117) collected at various times from patients with multiple myeloma (n = 33) who underwent idecabtagene vicleucel (ide-cel) anti-B-cell maturation antigen CAR-T therapy. We observed a significant decrease in bacterial diversity after ide-cel infusion, along with significant differences in the bacterial composition linked to therapy response and toxicities. Specifically, we found significant enrichment of Flavonifractor plautii, Bacteroides thetaiotaomicron, Blautia fecis, and Dysosmobacter species in ide-cel responders. A notable finding was the link of major microbiome disruption, defined as the presence of dominant specific taxa (\u3e35% prevalence), and increased facultative pathobionts, like Enterococcus, with ide-cel toxicities, especially cytokine release syndrome (CRS). Patients with genus dominance in baseline samples had a higher incidence of grade 2 or higher CRS at 46.2% than those without genus dominance (11.1%; P = .043). In addition, network analysis and mass spectrometric assessment of stool metabolites revealed important associations and pathways, such as F plautii being linked to increased indole metabolites and pathways in responders. Our findings uncovered novel microbiome associations between ide-cel responses and toxicities that may be useful for developing modalities to improve CAR-T outcomes
Conformal Predictive Intervals in Survival Analysis: A Resampling Approach
No full textThe distribution-free method of conformal prediction has gained considerable attention in computer science, machine learning, and statistics. Candès et al. extended this method to right-censored survival data, addressing right-censoring complexity by creating a covariate shift setting, extracting a subcohort of subjects with censoring times exceeding a fixed threshold. Their approach only estimates the lower prediction bound for type I censoring, where all subjects have available censoring times regardless of their failure status. In medical applications, we often encounter more general right-censored data, observing only the minimum of failure time and censoring time. Subjects with observed failure times have unavailable censoring times. To address this, we propose a bootstrap method to construct 1- as well as 2-sided conformal predictive intervals for general right-censored survival data under different working regression models. Through simulations, our method demonstrates excellent average coverage for the lower bound and good coverage for the 2-sided predictive interval, regardless of working model is correctly specified or not, particularly under moderate censoring. We further extend the proposed method to several directions in medical applications. We apply this method to predict breast cancer patients\u27 future survival times based on tumor characteristics and treatment
Systematic Literature Review of Intravenous Versus Subcutaneous Administration of Oncology Therapies: A Clinical, Economic and Patient Perspective
No full textSubcutaneous (SC) formulations of oncology therapies offer a potentially less time-consuming and more convenient alternative to intravenous (IV) administration. However, exploring the potential benefits of SC over IV administration from a broader perspective is necessary to understand the larger-scale impact. In this systematic literature review (SLR), we evaluated the efficacy, pharmacokinetics/pharmacodynamics (PK/PD), safety, and patient and healthcare provider (HCP) preference for SC/IV oncology therapies, along with differences in patient outcomes, costs, and time requirements. The SLR was conducted in January 2019 and updated in May 2023, and included 169 publications. Studies providing comparative results between IV and SC formulations regarding clinical, economic, and patient outcomes were included. The focus was anticancer therapies for which both IV and SC formulations are being developed in phase 3 clinical trials, or are regulatory approved. SC administration was associated with savings in HCP time and patient chair time. Direct and indirect cost-savings were also observed. Increased treatment satisfaction and patient/HCP preference was reported with SC administration, as was improved caregiver productivity. The relative tolerability of SC and IV formulations for oncology drugs was similar; however, a higher incidence of injection-site reactions was reported with SC administration. Overall survival, PK/PD, and overall response rate results were comparable between IV and SC administration. This SLR demonstrates that SC and IV administration had comparable efficacy, PK/PD, and tolerability profiles, with SC administration associated with cost and time savings, and generally preferred by patients and HCPs. Therefore, SC administration of oncology therapies may offer advantages over IV administration
Integrating Priorities at the Intersection of Cancer and Neuroscience
No full textCancer neuroscience is a rapidly growing multidisciplinary field that conceptualizes tumors as tissues fully integrated into the nervous system. Recognizing the complexity and challenges in this field is of fundamental importance to achieving the goal of translational impact for cancer patients. Our commentary highlights key scientific priorities, optimal training settings, and roadblocks to translating scientific findings to the clinic in this emerging field, aiming to formulate a transformative and cohesive path forward