This review article focuses on the current local therapies mediated by implanted macroscaled biomaterials available or proposed for fighting cancer and also highlights the upcoming research in this ...field. Several authoritative review articles have collected and discussed the state-of-the-art as well as the advancements in using biomaterial-based micro- and nano-particle systems for drug delivery in cancer therapy. On the other hand, implantable biomaterial devices are emerging as highly versatile therapeutic platforms, which deserve an increased attention by the healthcare scientific community, as they are able to offer innovative, more effective and creative strategies against tumors. This review summarizes the current approaches which exploit biomaterial-based devices as implantable tools for locally administrating drugs and describes their specific medical applications, which mainly target resected brain tumors or brain metastases for the inaccessibility of conventional chemotherapies. Moreover, a special focus in this review is given to innovative approaches, such as combined delivery therapies, as well as to alternative approaches, such as scaffolds for gene therapy, cancer immunotherapy and metastatic cell capture, the later as promising future trends in implantable biomaterials for cancer applications.
Somatic missense mutations in the substrate-binding pocket of the E3 ubiquitin ligase adaptor SPOP are present in up to 15% of human prostate adenocarcinomas, but are rare in other malignancies, ...suggesting a prostate-specific mechanism of action. SPOP promotes ubiquitination and degradation of several protein substrates, including the androgen receptor (AR) coactivator SRC-3. However, the relative contributions that SPOP substrates may make to the pathophysiology of SPOP-mutant (mt) prostate adenocarcinomas are unknown. Using an unbiased bioinformatics approach, we determined that the gene expression profile of prostate adenocarcinoma cells engineered to express mt-SPOP overlaps greatly with the gene signature of both SRC-3 and AR transcriptional output, with a stronger similarity to AR than SRC-3. This finding suggests that in addition to its SRC-3-mediated effects, SPOP also exerts SRC-3-independent effects that are AR-mediated. Indeed, we found that wild-type (wt) but not prostate adenocarcinoma-associated mutants of SPOP promoted AR ubiquitination and degradation, acting directly through a SPOP-binding motif in the hinge region of AR. In support of these results, tumor xenografts composed of prostate adenocarcinoma cells expressing mt-SPOP exhibited higher AR protein levels and grew faster than tumors composed of prostate adenocarcinoma cells expressing wt-SPOP. Furthermore, genetic ablation of SPOP was sufficient to increase AR protein levels in mouse prostate. Examination of public human prostate adenocarcinoma datasets confirmed a strong link between transcriptomic profiles of mt-SPOP and AR. Overall, our studies highlight the AR axis as the key transcriptional output of SPOP in prostate adenocarcinoma and provide an explanation for the prostate-specific tumor suppressor role of wt-SPOP.
The p160 steroid receptor coactivators (SRCs) SRC-1, SRC-2 nuclear receptor coactivator (NCOA)2, and SRC-3 amplified in breast cancer 1 (AIB1)/NCOA3 are key pleiotropic “master regulators” of ...transcription factor activity necessary for cancer cell proliferation, survival, metabolism, and metastasis. SRC overexpression and overactivation occur in numerous human cancers and are associated with poor clinical outcomes and resistance to therapy. In prostate cancer (PC), the p160 SRCs play critical roles in androgen receptor transcriptional activity, cell proliferation, and resistance to androgen deprivation therapy. We recently demonstrated that the E3 ubiquitin ligase adaptor speckle-type poxvirus and zinc finger (POZ) domain protein (SPOP) interacts directly with SRC-3 and promotes its cullin 3-dependent ubiquitination and proteolysis in breast cancer, thus functioning as a potential tumor suppressor. Interestingly, somatic heterozygous missense mutations in the SPOP substrate-binding cleft recently were identified in up to 15% of human PCs (making SPOP the gene most commonly affected by nonsynonymous point mutations in PC), but their contribution to PC pathophysiology remains unknown. We now report that PC-associated SPOP mutants cannot interact with SRC-3 protein or promote its ubiquitination and degradation. Our data suggest that wild-type SPOP plays a critical tumor suppressor role in PC cells, promoting the turnover of SRC-3 protein and suppressing androgen receptor transcriptional activity. This tumor suppressor effect is abrogated by the PC-associated SPOP mutations. These studies provide a possible explanation for the role of SPOP mutations in PC, and highlight the potential of SRC-3 as a therapeutic target in PC.
Hepatocellular carcinoma (HCC) is the fifth most common type of cancer diagnosed and the second leading cause of death worldwide. Despite advancement in current treatments for HCC, the prognosis for ...this cancer is still unfavorable. This comprehensive review article focuses on all the current technology that applies biomaterials to treat and study liver cancer, thus showing the versatility of biomaterials to be used as smart tools in this complex pathologic scenario. Specifically, after introducing the liver anatomy and pathology by focusing on the available treatments for HCC, this review summarizes the current biomaterial-based approaches for systemic delivery and implantable tools for locally administrating bioactive factors and provides a comprehensive discussion of the specific therapies and targeting agents to efficiently deliver those factors. This review also highlights the novel application of biomaterials to study HCC, which includes hydrogels and scaffolds to tissue engineer 3D in vitro models representative of the tumor environment. Such models will serve to better understand the tumor biology and investigate new therapies for HCC. Special focus is given to innovative approaches, e.g., combined delivery therapies, and to alternative approaches-e.g., cell capture-as promising future trends in the application of biomaterials to treat HCC.
The use of lentiviral vectors in cell and gene therapy is steadily increasing, both in commercial and investigational therapies. Although existing data increasingly support the usefulness and safety ...of clinical-grade lentiviral vectors used in cell manufacturing, comprehensive studies specifically addressing their long-term stability are currently lacking. This is significant considering the high cost of producing and testing GMP-grade vectors, the limited number of production facilities, and lengthy queue for production slots. Therefore, an extended shelf life is a critical attribute to justify the investment in large vector lots for investigational cell therapies. This study offers a thorough examination of essential stability attributes, including vector titer, transduction efficiency, and potency for a series of clinical-grade vector lots, each assessed at a minimum of 36 months following their date of manufacture. The 13 vector lots included in this study were used for cell product manufacturing in 16 different clinical trials, and at the time of the analysis had a maximum storage time at −80°C of up to 8 years. The results emphasize the long-term durability and efficacy of GMP-grade lentiviral vectors for use in ex vivo cell therapy manufacturing.
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As the use of GMP-grade lentiviral vectors for clinical cell therapy manufacturing increases, the high cost, limited production facilities, and long queues necessitate that vector lots remain stable in long-term storage for extended use. This comprehensive analysis demonstrates long-term stability by titer, product transduction efficiency, and potency.
Variation within genes has important implications for all biological traits. We identified 3899 single nucleotide polymorphisms (SNPs) that were present within 313 genes from 82 unrelated individuals ...of diverse ancestry, and we organized the SNPs into 4304 different haplotypes. Each gene had several variable SNPs and haplotypes that were present in all populations, as well as a number that were population-specific. Pairs of SNPs exhibited variability in the degree of linkage disequilibrium that was a function of their location within a gene, distance from each other, population distribution, and population frequency. Haplotypes generally had more information content (heterozygosity) than did individual SNPs. Our analysis of the pattern of variation strongly supports the recent expansion of the human population.
The androgen receptor (AR) is a key driver of prostate cancer (PC), even in the state of castration-resistant PC (CRPC) and frequently even after treatment with second-line hormonal therapies such as ...abiraterone and enzalutamide. The persistence of AR activity via both ligand-dependent and ligand-independent mechanisms (including constitutively active AR splice variants) highlights the unmet need for alternative approaches to block AR signaling in CRPC. We investigated the transcription factor GATA-binding protein 2 (GATA2) as a regulator of AR signaling and an actionable therapeutic target in PC. We demonstrate that GATA2 directly promotes expression of both full-length and splice-variant AR, resulting in a strong positive correlation between GATA2 and AR expression in both PC cell lines and patient specimens. Conversely, GATA2 expression is repressed by androgen and AR, suggesting a negative feedback regulatory loop that, upon androgen deprivation, derepresses GATA2 to contribute to AR overexpression in CRPC. Simultaneously, GATA2 is necessary for optimal transcriptional activity of both full-length and splice-variant AR. GATA2 colocalizes with AR and Forkhead box protein A1 on chromatin to enhance recruitment of steroid receptor coactivators and formation of the transcriptional holocomplex. In agreement with these important functions, high GATA2 expression and transcriptional activity predicted worse clinical outcome in PC patients. A GATA2 small molecule inhibitor suppressed the expression and transcriptional function of both full-length and splice-variant AR and exerted potent anticancer activity against PC cell lines. We propose pharmacological inhibition of GATA2 as a first-in-field approach to target AR expression and function and improve outcomes in CRPC.
Significance Androgen receptor (AR) signaling is a key driver of prostate cancer (PC), even in the context of resistance to current therapies, creating an unmet need for novel approaches to inhibit AR. We demonstrate that the transcription factor GATA-binding protein 2 (GATA2) is critical for both AR expression and optimal transcriptional activity. GATA2 colocalizes with AR and Forkhead box protein A1 on chromatin to enhance recruitment of steroid receptor coactivators and formation of the transcriptional holocomplex. A GATA2 inhibitor suppressed the expression and transcriptional function of AR (including the constitutively active splice variants) and exerted potent anticancer activity against PC cells. We propose GATA2 inhibition as a previously unexplored approach to extinguish both ligand-dependent and ligand-independent AR transcriptional activity and to improve clinical outcomes for PC patients.
BackgroundPreclinical combinations of CAR-T therapies with oncolytic viruses have shown promise,1 2 but thus far no clinical data are available. Here we report interim results for three patients with ...epithelial ovarian- and pancreatic cancer treated with an intravenous infusion of VCN-01, an investigational PH20 hyaluronidase-armed oncolytic virus3 followed by autologous T cells transduced to express a chimeric antigen receptor directed against mesothelin (huCART-meso) from an ongoing Phase I study.MethodsVCN-01 is a genetically modified, oncolytic adenovirus with tumor tropism enhanced by an integrin-binding motif and selective replication in pRB-defective cells.4 It encodes, PH20 hyaluronidase to degrade tumor hyaluronan and might thereby increase tumor penetrance of coadministered therapies.4–6 HuCART-meso are autologous T cells transduced with a fully humanized chimeric antigen receptor composed of anti-mesothelin ‘M5’ ScFv fused to 4–1BB and TCRzeta signaling domains.7 This is a phase I trial to establish safety and feasibility of the combination of VCN-01 and huCART-meso (table 1).ResultsThree patients (table 2) received combination therapy at their assigned dose and no dose limiting toxicities observed. One subject experienced cytokine release syndrome (CRS), grade 2 in severity and lasting 2 days. No neurotoxicity was observed. Transient grade 3 anemia and lymphopenia were observed, and AST elevation, as expected from VCN-01. There was no grade 4 or higher adverse events. All three patients were retreated with huCART-meso cells via IV infusion post-Month 2. VCN-01 and huCART-meso were detected in the peripheral blood for extended periods (figure 1). The two patients with measurable disease (both with ovarian cancer) showed SD up to 150 and 300 days with the biggest decrease of disease volume 15% and 29.1% respectively by RECIST criteria (figure 2 and table 3).ConclusionsA regimen of IV delivery of 3.3 x 1012 VP VCN-01 followed 14 d later by 5 x 107 huCART-meso T cells is feasible and appears safe. Repeat dosing with huCART-meso post-Month 2 is also feasible. VCN-01 persistence suggests tumor infection and active replication. The peak and duration of huCART-meso T cells in the peripheral blood as well as duration of stable disease in evaluable patients show encouraging trends. The study will test higher doses of VCN-01 and will interrogate tumor biopsies to gain further insights. The results will inform and guide optimization of the combination of CAR T cells with oncolytic virus.AcknowledgementsWe wish to acknowledge the clinical trial patients and their families, Theriva Biologics for providing VCN-01, and the members of the Clinical Trials Unit at the Abramson Cancer Center. Funding – UPenn private funds.Trial RegistrationNCT05057715 (trial in progress)ReferencesGuedan S, Alemany R. CAR-T Cells and Oncolytic Viruses: Joining Forces to Overcome the Solid Tumor Challenge. Front Immunol. 2018;9:2460.McGrath K, Dotti G. Combining Oncolytic Viruses with Chimeric Antigen Receptor T Cell Therapy. Hum Gene Ther. 2021;32(3–4):150–157.Garcia-Carbonero R, Bazan-Peregrino M, Gil-Martin M, et al. Phase I, multicenter, open-label study of intravenous VCN-01 oncolytic adenovirus with or without nab-paclitaxel plus gemcitabine in patients with advanced solid tumors. J Immunother Cancer. 2022;10(3).Rodriguez-Garcia A, Gimenez-Alejandre M, Rojas JJ, et al. Safety and efficacy of VCN-01, an oncolytic adenovirus combining fiber HSG-binding domain replacement with RGD and hyaluronidase expression. Clin Cancer Res. 2015;21(6):1406–1418.Bazan-Peregrino M, Garcia-Carbonero R, Laquente B, et al. VCN-01 disrupts pancreatic cancer stroma and exerts antitumor effects. J Immunother Cancer. 2021;9(11).Farrera-Sal M, Moreno R, Mato-Berciano A, Maliandi MV, Bazan-Peregrino M, Alemany R. Hyaluronidase expression within tumors increases virotherapy efficacy and T cell accumulation. Mol Ther Oncolytics. 2021;22:27–35.Haas AR, Golden RJ, Litzky LA, et al. Two Cases of Severe Pulmonary Toxicity from Highly Active Mesothelin-Directed CAR T Cells. Mol Ther. 2023.Ethics ApprovalUniversity of Pennsylvania, Institutional Review Board, Federalwide Assurance: 00004028; Confirmation #: dgjegcid; Protocol Number: 849937\28-September 2022ConsentPC4b-03821-VCN-01=M5 Main IFC V3.12.03.2021Abstract 671 Figure 1Pharmacokinetics of VCN-01 and huCART-meso in the peripheral blood.Abstract 671 Figure 2Response to Combination Therapy. Change in tumor volume from baseline (%) is shown for the two patients with disease measurable by RECIST. Timepoints for infusion of VCN-01, huCART-meso (first dose) and huCART-meso retreatment are shown.Abstract 671 Table 1Study DesignAbstract 671 Table 2Patient Demographics and Disease CharacteristicsAbstract 671 Table 3Response to Combination Therapy
Previously, we showed that adoptive transfer of in vivo vaccine-primed and ex vivo (anti-CD3/anti-CD28) costimulated autologous T cells (ex-T) at day +12 after transplant increased CD4 and CD8 T-cell ...counts at day +42 and augmented vaccine-specific immune responses in patients with myeloma. Here, we investigated the safety and kinetics of T-cell recovery after infusing ex-T at day +2 after transplant.
In this phase I/II two-arm clinical trial, 50 patients with myeloma received autografts after high-dose melphalan followed by infusions of ex-T at day +2 after transplant. Patients also received pretransplant and posttransplant immunizations using a pneumococcal conjugate vaccine only (arm B; n = 24) or the pneumococcal conjugate vaccine plus an HLA-A2-restricted microltipeptide vaccine for HLA-A2(+) patients (arm A; n = 26).
The mean number of T cells infused was 4.26 x 10(10) (range, 1.59-5.0). At day 14 after transplant, the median CD3, CD4, and CD8 counts were 4,198, 1,545, and 2,858 cells/microL, respectively. Interleukin (IL)-6 and IL-15 levels increased early after transplant and IL-15 levels correlated significantly to day 14 T-cell counts. Robust vaccine-specific B- and T-cell responses were generated. T-cell infusions were well tolerated with no effect on hematopoietic recovery. Eight patients (16%) developed a T-cell "engraftment syndrome" characterized by diarrhea and fever that was clinically and histopathologically indistinguishable from grade 1 to 3 acute graft-versus-host disease (GVHD) of the gastrointestinal tract (seven patients) and/or grade 1 to 2 cutaneous GVHD (four patients).
Adoptive T-cell transfers achieve robust T-cell recovery early after transplant and induce moderate-to-severe autologous GVHD in a subset of patients.
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