Examining and addressing unmet care needs is integral to improving the provision and quality of cancer services. This review explored the prevalence of unmet supportive care needs, and factors ...associated with unmet need, in adults with advanced cancers (solid and hematological malignancies) and their caregivers. Electronic databases (PubMed, CINAHL, EMBASE) were searched, producing 85 papers representing 81 included studies. People with advanced cancer reported the highest unmet needs in financial, health system and information, psychological, and physical and daily living domains, whereas caregivers reported the highest unmet needs in psychological, and patient care and support domains. Distress, depression, and anxiety were associated with higher unmet needs across all unmet need domains for people with advanced cancer and their caregivers. Substantial heterogeneity in study populations and methods was observed. Findings from this review can inform targeted strategies and interventions to address these unmet needs in people with advanced cancer.
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•Distress, depression, and anxiety are associated with unmet needs across domains.•Patients and carers share high unmet psychological needs as most prevalent.•Patients report unmet informational, financial, physical needs as most prevalent.•Carers report high unmet care and support needs of patients as most prevalent.•There was substantial heterogeneity, warranting further research with validated tools.
The Italian Register of Actionable Mutations (RATIONAL) is a multicentric, observational study collecting next-generation sequencing (NGS)-based tumour profiling data of patients with advanced solid ...tumours.
The study enrols patients who had available an NGS-based tumour profiling (Pathway-A) or undergo comprehensive genomic profiling (CGP) with FoundationOne CDx assays within the trial (Pathway-B). The primary endpoint was the rate of actionable mutations identified.
Sequencing data were available for 738 patients in Pathway-A (218) and -B (520). In Pathway-A, 154/218 (70.6%) tests were performed using NGS panels ≤52 genes, and genomic alterations (GAs) were found in 164/218 (75.2%) patients. In Pathway-B, CGP revealed GAs in 512/520 (98.5%) patients. Levels I/II/III actionable GAs according to the European Society of Medical Oncology Scale for Clinical Actionability of molecular Targets (ESCAT) were identified in 254/554 (45.8%) patients with non-small-cell lung cancer, cholangiocarcinoma, colorectal, gastric, pancreatic and breast cancer. The rate of patients with level I GAs was similar in Pathways A and B (69 versus 102). CGP in Pathway-B revealed a higher number of patients with level II/III GAs (99 versus 20) and potentially germline pathogenic/likely pathogenic variants (58 versus 15) as compared with standard testing in Pathway-A. In patients with cancer of unknown primary, CGP detected OncoKB levels 3B/4 GAs in 31/58 (53.4%) cases. Overall, 67/573 (11.7%) of patients received targeted therapy based on genomic testing.
The Italian Register of Actionable Mutations represents the first overview of genomic profiling in Italian current clinical practice and highlights the utility of CGP for identifying therapeutic targets in selected cancer patients.
•Comprehensive genomic profiling (CGP) is limited to selected cases in Italy.•European Society of Medical Oncology Scale for Clinical Actionability of molecular Targets level I alterations are equally identified by small and large next-generation sequencing panels.•CGP identifies more level II/III alterations and potentially germline variants.•The rate of patients receiving a therapy matched to the genomic profile is low.
Neoantigens arise from mutations in cancer cells and are important targets of T cell-mediated anti-tumor immunity. Here, we report the first open-label, phase Ib clinical trial of a personalized ...neoantigen-based vaccine, NEO-PV-01, in combination with PD-1 blockade in patients with advanced melanoma, non-small cell lung cancer, or bladder cancer. This analysis of 82 patients demonstrated that the regimen was safe, with no treatment-related serious adverse events observed. De novo neoantigen-specific CD4+ and CD8+ T cell responses were observed post-vaccination in all of the patients. The vaccine-induced T cells had a cytotoxic phenotype and were capable of trafficking to the tumor and mediating cell killing. In addition, epitope spread to neoantigens not included in the vaccine was detected post-vaccination. These data support the safety and immunogenicity of this regimen in patients with advanced solid tumors (Clinicaltrials.gov: NCT02897765).
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•The personalized neoantigen vaccine Neo-PV-01 plus nivolumab is feasible and safe•NEO-PV-01 plus nivolumab stimulates durable neoantigen-specific T cell reactivity•NEO-PV-01-specific T cells have cytotoxic potential and can traffic to the tumor•NEO-PV-01 induces epitope spreading consistent with vaccine-mediated tumor cytotoxicity
In a phase Ib clinical trial, Ott et al. demonstrate feasibility, safety, and immunogenicity of the combination of personalized neoantigen vaccines and PD-1 inhibition in patients with advanced solid tumors. Vaccine-induced T cells persist over time, exhibit cytotoxic potential, and can migrate to tumors. Epitope spread and major pathologic tumor responses were detected following vaccination.
•HD-RT ± LD-RT to separate lesions can be safely delivered for IO refractory patients.•HD-RT + LD-RT safely improved lesion-specific response for IO refractory patients.•LD-RT may be a consideration ...for large tumors or multiple isocenters.•T- and NK cell infiltration was enhanced in lesions treated with LD-RT.
To report early findings from a phase II trial of high-dose radiotherapy (HD-RT) with or without low-dose RT (LD-RT) for metastatic cancer.
Eligible patients had metastatic disease that progressed on immunotherapy within 6 months. Patients were given either HD-RT (20–70 Gy total; 3–12.5 Gy/f), or HD-RT + LD-RT (0.5–2 Gy/f up to 1–10 Gy total) to separate lesions, with continued immunotherapy. Radiographic response was assessed per RECIST 1.1 and Immune-Related Response Criteria (irRC). Primary endpoints: (1) 4-month disease control (DCR, complete/partial response CR/PR or stable disease SD) or an overall response (ORR, CR/PR) at any point in ≥10% of patients, per RECIST 1.1; (2) dose-limiting toxicity within 3 months not exceeding 30%. Secondary endpoint was lesion-specific response.
Seventy-four patients (NSCLC, n = 38; melanoma n = 21) were analyzed (39 HD-RT and 35 HD-RT + LD-RT). The median follow-up time was 13.6 months. The primary endpoint was met for 72 evaluable patients, with a 4-month DCR of 42% (47% 16/34 vs. 37% 14/38 in HD-RT + LD-RT vs. HD-RT, P = 0.38), and 19% ORR at any time (26% 9/34 vs. 13% 5/38 in HD-RT + LD-RT vs. HD-RT, P = 0.27). Three patients had toxicity ≥grade 3. LD-RT lesion response (53%) was improved compared to nonirradiated lesions in HD-RT + LD-RT (23%, P = 0.002) and HD-RT (11%, P < 0.001). T- and NK cell infiltration was enhanced in lesions treated with LD-RT.
HD-RT plus LD-RT safely improved lesion-specific response in patients with immune resistant solid tumors by promoting infiltration of effector immune cells into the tumor microenvironment.
•Development of a novel mutli-stimuli-responsive fucoidan/protamine nanoparticle.•P-selectin targeting, charge conversion, and stimuli-responsive properties.•Drug release was triggred by enzymatic ...digestion and acidic intracellular pH.•DOX-loaded nanoparticles improved inhibitory effect against MDA-MB-468 cancer cells.
Fucoidan, a sulfated marine polysaccharide, has many potential biological functions, including anticancer activity. Recently, fucoidan has been reported to target P-selectin expressed on metastatic cancer cells. Increasing research attention has been devoted to the developments of fucoidan-based nanomedicine. However, the application of traditional chitosan/fucoidan nanoparticles in anticancer drug delivery may be limited due to the deprotonation of chitosan at a pH greater than 6.5. In this study, a mutli-stimuli-responsive nanoparticle self-assembled by fucoidan and a cationic polypeptide (protamine) was developed, and their pH-/enzyme-responsive properties were characterized by circular dichroism (CD) spectroscopy, dynamic light scattering (DLS), and zeta potential analysis. Enzymatic digestion and acidic intracellular microenvironment (pH 4.5–5.5) in cancer cells triggered the release of an anticancer drug (doxorubicin) from the nanoparticles. The protamine/fucoidan complex nanoparticles with P-selectin mediated endocytosis, charge conversion and stimuli-tunable release properties showed an improved inhibitory effect against a metastatic breast cancer cell line (MDA-MB-231).
Studies suggest that tunicamycin may work as a therapeutic drug to cancer cells by inducing stress in the endoplasmic reticulum (ER) through unfolded protein response (UPR) and thereby promoting ...apoptosis. However, mechanisms of the prolonged activation of the UPR under sustained ER stress in the regulation of cell apoptosis are largely unknown. To delineate the role of candidate genes in the apoptotic process under ER stress and to search for new therapeutic strategies to treat metastatic castration resistant prostate cancer, we performed whole genome expression microarray analysis in tunicamycin treated metastatic androgen-insensitive prostate cancer cells, PC-3. Among several induced genes, the expression of eNOS (
) gene was remarkably high. The increased expression of eNOS activates mTORC1 through RagC. This results into an accumulation of p62 (SQSTM1) which facilitates aggregation of ubiquitinated protein thus compromising clearance of misfolded toxic protein aggregates. Lastly, association of p62 proteins and misfolded proteins promote reactive oxygen species (ROS) mediated mitochondrial apoptosis. Overall, our data demonstrate that tunicamycin induced ER stress promotes prostate cancer cell death by activating mTORC1 through eNOS-RagC pathway.
The development of 3D in vitro models capable of recapitulating native tumor microenvironments could improve the translatability of potential anticancer drugs and treatments. Here, 3D bioprinting ...techniques are used to build tumor constructs via precise placement of living cells, functional biomaterials, and programmable release capsules. This enables the spatiotemporal control of signaling molecular gradients, thereby dynamically modulating cellular behaviors at a local level. Vascularized tumor models are created to mimic key steps of cancer dissemination (invasion, intravasation, and angiogenesis), based on guided migration of tumor cells and endothelial cells in the context of stromal cells and growth factors. The utility of the metastatic models for drug screening is demonstrated by evaluating the anticancer efficacy of immunotoxins. These 3D vascularized tumor tissues provide a proof‐of‐concept platform to i) fundamentally explore the molecular mechanisms of tumor progression and metastasis, and ii) preclinically identify therapeutic agents and screen anticancer drugs.
A migration‐inducing, vascularized tumor model platform is created via 3D bioprinting of cells, natural hydrogels, and programmable release capsules. These cell‐laden architectures are designed to recapitulate the primary characteristics of metastasis. The 3D models both physically and chemically reconstruct the tumor microenvironments with high spatiotemporal resolution, offering a tool to bridge the gap between monolayer cell culture and animal models.
Checkpoint inhibitors, such as antibodies blocking the PD-1/PD-L1 pathway, are among the most promising immunotherapies to treat metastatic cancers, but their response rate remains low. In addition, ...the usage of monoclonal antibodies as checkpoint inhibitors is associated with a series of drawbacks. Herein, an all synthetic nanoparticle with PD-L1 blockade capability is developed for cancer photothermal-immunotherapy. The polymeric nanoparticle integrates photothermal treatment, antitumor vaccination, and PD-1/PD-L1 blockade in a single system to augment the antitumor efficacy. In a CT26 bilateral tumor model, intravenously injected nanoparticles accumulate in tumor sites and mediate strong photothermal effects, eradicate the NIR treated primary tumors and elicit strong antitumor immunity by inducing immunogenic cell death (ICD). Growth of the untreated distant tumors is also suppressed due to the synergies of systemic antitumor immune activation and PD-L1 blockade. Our strategy offers a simple but promising approach for the treatment of metastatic cancer.
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A vast majority of cancer deaths occur as a result of metastasis. Unfortunately, effective treatments for metastases are currently lacking due to the difficulty of selectively targeting these small, ...delocalized tumors distributed across a variety of organs. However, nanotechnology holds tremendous promise for improving immunotherapeutic outcomes in patients with metastatic cancer. In contrast to conventional cancer immunotherapies, rationally designed nanomaterials can trigger specific tumoricidal effects, thereby improving immune cell access to major sites of metastasis such as bone, lungs, and lymph nodes, optimizing antigen presentation, and inducing a persistent immune response. This paper reviews the cutting-edge trends in nano-immunoengineering for metastatic cancers with an emphasis on different nano-immunotherapeutic strategies. Specifically, it discusses directly reversing the immunological status of the primary tumor, harnessing the potential of peripheral immune cells, preventing the formation of a pre-metastatic niche, and inhibiting the tumor recurrence through postoperative immunotherapy. Finally, we describe the challenges facing the integration of nanoscale immunomodulators and provide a forward-looking perspective on the innovative nanotechnology-based tools that may ultimately prove effective at eradicating metastatic diseases.
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•The state of the art for nanotechnology-enabled cancer immunotherapy and the emerging concepts in nano-based immunomodulation are summarized•The cutting-edge trends in nano-immunoengineering for metastatic cancers with an emphasis on different nano-immunotherapeutic strategies are highlighted•Benefits, challenges, and opportunities of nanoscale immunomodulators and a forward-looking perspective on the innovative nanotechnology-based tools that may ultimately prove effective at eradicating metastatic diseases are presented
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