Recent evidence suggests that mesenchymal stem cells (MSC) selectively home to tumors, where they contribute to the formation of tumor-associated stroma. This effect can be opposed by genetically ...modifying MSC to produce high levels of anti-cancer agents that blunt tumor growth kinetics and inhibit the growth of tumors in situ. In this review article, we describe the biological properties of MSC within the tumor microenvironment and discuss the potential use of MSC and other bone marrow-derived cell populations as delivery vehicles for antitumor proteins.
Background: High concentrations of interferon beta (IFN-β) inhibit malignant cell growth in vitro. However, the therapeutic utility of IFN-β in vivo is limited by its excessive toxicity when ...administered systemically at high doses. Mesenchymal stem cells (MSC) can be used to target delivery of agents to tumor cells. We tested whether MSC can deliver IFN-β to tumors, reducing toxicity. Methods: Human MSC were transduced with an adenoviral expression vector carrying the human IFN-β gene (MSC-IFN-β cells). Flow cytometry was used to measure tumor cell proliferation among in vitro co-cultures of MSC-IFN-β cells and human MDA 231 breast carcinoma cells or A375SM melanoma cells. We used a severe combined immunodeficiency mouse xenograft model (4–10 mice per group) to examine the effects of injected MSC-IFN-β cells and human recombinant IFN-β on the growth of MDA 231- and A375SM-derived pulmonary metastases in vivo and on survival. All statistical tests were two-sided. Results: Co-culture of MSC-IFN-β cells with A375SM cells or MDA 231 cells inhibited tumor cell growth as compared with growth of the tumor cells cultured alone (differences in mean percentage of control cell growth: −94.0% 95% confidence interval {CI} = −81.2% to −106.8%; P<.001 and −104.8% 95% CI = −82.1% to −127.5%; P<.001, respectively). Intravenous injection of MSC-IFN-β cells into mice with established MDA 231 or A375SM pulmonary metastases led to incorporation of MSC in the tumor architecture and, compared with untreated control mice, to prolonged mouse survival (median survival for MDA 231–injected mice: 60 and 37 days for MSC-injected and control mice, respectively difference = 23.0 days (95% CI = 14.5 to 34.0 days; P<.001; median survival for A375SM-injected mice: 73.5 and 30.0 days for MSC-injected and control mice, respectively difference = 43.5 days (95% CI = 37.0 to 57.5 days; P<.001). By contrast, intravenous injection of recombinant IFN-β did not prolong survival in the same models (median survival for MDA 231–injected mice: 41.0 and 37.0 days for IFN-β–injected and control mice, respectively difference = 4 days, 95% CI = −5 to 10 days; P = .308; median survival for A375SM-injected mice: 32.0 and 30.0 days for IFN-β–injected and control mice, respectively difference = 2 days, 95% CI = 0 to 4.5 days; P = .059). Conclusions: Injected MSC-IFN-β cells suppressed the growth of pulmonary metastases, presumably through the local production of IFN-β in the tumor microenvironment. MSC may be an effective platform for the targeted delivery of therapeutic proteins to cancer sites.
The poor survival of patients with human malignant gliomas relates partly to the inability to deliver therapeutic agents to the tumor. Because it has been suggested that circulating bone ...marrow-derived stem cells can be recruited into solid organs in response to tissue stresses, we hypothesized that human bone marrow-derived mesenchymal stem cells (hMSC) may have a tropism for brain tumors and thus could be used as delivery vehicles for glioma therapy. To test this, we isolated hMSCs from bone marrow of normal volunteers, fluorescently labeled the cells, and injected them into the carotid artery of mice bearing human glioma intracranial xenografts (U87, U251, and LN229). hMSCs were seen exclusively within the brain tumors regardless of whether the cells were injected into the ipsilateral or contralateral carotid artery. In contrast, intracarotid injections of fibroblasts or U87 glioma cells resulted in widespread distribution of delivered cells without tumor specificity. To assess the potential of hMSCs to track human gliomas, we injected hMSCs directly into the cerebral hemisphere opposite an established human glioma and showed that the hMSCs were capable of migrating into the xenograft in vivo. Likewise, in vitro Matrigel invasion assays showed that conditioned medium from gliomas, but not from fibroblasts or astrocytes, supported the migration of hMSCs and that platelet-derived growth factor, epidermal growth factor, or stromal cell-derived factor-1alpha, but not basic fibroblast growth factor or vascular endothelial growth factor, enhanced hMSC migration. To test the potential of hMSCs to deliver a therapeutic agent, hMSCs were engineered to release IFN-beta (hMSC-IFN-beta). In vitro coculture and Transwell experiments showed the efficacy of hMSC-IFN-beta against human gliomas. In vivo experiments showed that treatment of human U87 intracranial glioma xenografts with hMSC-IFN-beta significantly increase animal survival compared with controls (P < 0.05). We conclude that hMSCs can integrate into human gliomas after intravascular or local delivery, that this engraftment may be mediated by growth factors, and that this tropism of hMSCs for human gliomas can be exploited to therapeutic advantage.
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Background: The inhibitory Notch ligand, DLL3, is highly expressed on the cell surface of SCLC and NEC tumors and is a promising drug target. BI 764532 is a DLL3/CD3 T cell engaging bispecific ...antibody that has shown potent preclinical anti-tumor activity in DLL3+ cells and xenograft models. NCT04429087 is an ongoing phase I first-in-human, open-label, dose-escalation trial of BI 764532 in adults with locally advanced/metastatic DLL3+ (confirmed centrally) SCLC, NEC or small cell carcinoma of any other origin (grouped as NEC), or large cell NEC (LCNEC). Methods: BI 764532 was administered intravenously using three different regimens: Regimen (R) A (fixed iv dose q3w); RB1 (fixed iv dose qw); RB2 (step-in doses followed by a fixed dose). Treatment (Tx) continued until progressive disease (PD), unacceptable toxicity, other withdrawal criteria, or maximum Tx duration (36 mos). The main objective was to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion of BI 764532, based on dose-limiting toxicities (DLTs) during the MTD evaluation period. Further objectives were safety, tolerability, PK/PD and preliminary efficacy based on investigator review (RECIST v1.1). Results: As of 28th Dec 2022, 90 pts received ≥1 dose of BI 764532 (RA: n = 24, 8 dose levels; RB1: n = 10, 3 dose levels; RB2: n = 56, 6 dose levels; starting dose: 0.03 µg/kg). Median age: 60 years (32–78); ECOG PS 0/1: 24/74%; prior PD1/PD-L1 Tx: 40%; ≥2 prior lines of Tx: 69%. SCLC/NEC/LCNEC: 52/41/4%. Median Tx duration: 43 days (range 1–443); 25 pts are ongoing. DLTs were seen in 1 pt on RA (Grade 3 confusion) and 4 pts on RB2 (Grade 4 cytokine release syndrome CRS; Grade 3 CRS, Grade 3 nervous system disorder, Grade 2 infusion-related reaction). MTD has not been reached and dose escalation is ongoing. Overall, the most common treatment-related AEs were (any/Grade 3+): CRS (58/2%); pyrexia (19/0%); decreased lymphocytes (18/14%); asthenia (17/1%); dysgeusia (14/0%). CRS was managed with supportive care, corticosteroids, and/or anti-IL-6R antibodies. With RB2, most CRS and neurological events occurred early, and were reversable. Tumor response data were available for 70 pts (RA/RB1/RB2: n = 19/8/43). In pts with SCLC (n = 24) or NEC (n = 23) who received ≥ target dose of BI 764532, ORR was 33% and 22% across all regimens, respectively. One pt with LCNEC was also evaluable for response and achieved PR. Conclusions: BI 764532 showed clinically manageable tolerability and MTD has not been reached at the doses administered to date. Promising efficacy has been observed, not only in SCLC but also in difficult to treat entities such as NEC and LCNEC. The study is ongoing; updated data will be presented. Clinical trial information: NCT04429087 .
Abstract only
TPS8588
Background: First-line standard of care for pts with metastatic SCLC and neuroendocrine carcinoma (NEC) is platinum-based chemotherapy ± immunotherapy. While the addition of ...anti-PD1 antibodies has improved outcomes, nearly all pts relapse and prognosis is poor. There is a major unmet need for additional treatment (tx) options. BI 764532 is a delta-like ligand 3 (DLL3)/CD3 T cell engaging bispecific antibody. DLL3 is expressed on the cell surface of many SCLC and NEC tumors, but not on normal cells. In preclinical studies, BI 764532 induced cytotoxicity of DLL3-positive cells and showed anti-tumor activity in animal models. Methods: NCT04429087 is a first-in-human, open-label, dose-escalation trial of BI 764532 in adults with locally advanced/metastatic SCLC, large cell neuroendocrine lung carcinoma, NEC or small cell carcinoma of any other origin. Pts must have failed on or be ineligible for available standard therapies (including ≥1 line of platinum-based chemotherapy). Tumors must be positive for DLL3 expression (archived tissue/in-study fresh biopsy) according to central review. Pts must have ≥1 evaluable lesion (modified RECIST 1.1) outside of CNS and adequate liver, bone marrow and renal organ function. Main exclusion criteria: previous tx with T cell engagers or DLL3-targeted therapies; persistent toxicity from previous tx that has not resolved to ≤ CTCAE grade 1; immunodeficiency or receiving immunosuppressive therapy ≤7 days, prior anti-cancer therapy ≤3 wks/5 half-life periods or extensive field radiotherapy ≤2 wks of first dose of BI 764532. The main objective of phase Ia is to determine the maximum tolerated dose (MTD) or recommended dose for expansion of BI 764532, based on dose-limiting toxicities during the MTD evaluation period. Further objectives are to evaluate safety, tolerability, PK/PD and preliminary efficacy. The phase Ib objectives, endpoints and design will be specified after availability of phase Ia results. The trial will assess ≤3 dosing regimens: Regimen A (fixed iv dose once every 3 wks); Regimen B1 (fixed iv dose once every wk); Regimen B2 (step-in doses followed by fixed-dose weekly doses; optional). Tx will continue until confirmed progressive disease, unacceptable toxicity, other withdrawal criteria or a maximum tx duration of 36 mos, whichever occurs first. For Phase Ia, ̃160 pts will be screened and 110 pts accrued. As of Feb 2021, pts are being recruited and treated in early dose escalation cohorts. Clinical trial information: NCT04429087.
Poorly differentiated neuroendocrine carcinomas such as small-cell lung cancer (SCLC) have poor survival and high relapse rates. DLL3 is found on these carcinomas and has become a target of ...increasing interest in recent years. The bispecific DLL3/CD3 T-cell engager BI 764532 has been shown to induce complete tumor regression in a human T cell-engrafted mouse model. Here, we describe the study design of a first-in-human, phase I, multicenter, open-label, non-randomized, dose-escalation study in patients with SCLC or other DLL3-positive neuroendocrine carcinomas. The study will determine the maximum tolerated dose and evaluate safety, tolerability, pharmacokinetics and preliminary efficacy of BI 764532 monotherapy.
Abstract
BACKGROUND
Patients with progressive diffuse gliomas have limited treatment options. DLL3, a Notch ligand, is expressed on most diffuse gliomas. BI 764532, a humanized IgG-like T cell ...engager, binds selectively to DLL3-positive cells and promotes T cell-mediated cytotoxicity. Preclinical data showed activity of BI 764532 against intracranial tumors. In an ongoing first-in-human trial in patients with DLL3-positive small-cell lung carcinoma and other neuroendocrine carcinomas (NECs) including extrapulmonary NECs and large-cell NECs of the lung (NCT04429087), BI 764532 exhibited promising efficacy and manageable tolerability. Here we describe a planned Phase Ib dose-escalation/expansion trial of BI 764532 monotherapy in patients with DLL3-positive refractory/relapsed diffuse glioma.
METHODS
The dose-escalation part will include ~12–20 patients (≥3 patients per dose level) from 12 sites across Europe/USA. Dose escalation will be guided by Bayesian logistic regression model with overdose control. BI 764532 will be administered intravenously. Treatment will continue until disease progression, undue toxicity, informed consent withdrawn, or other reasons requiring treatment discontinuation. Once a recommended dose for expansion is established, ~15 patients from Europe will be treated in a dose-expansion phase. Key inclusion criteria: ≥18 years old; histologically confirmed primary progressive diffuse glioma who have failed on standard-of-care therapies; DLL3-positivity by IHC on archived tumor tissue by central pathology review. Key exclusion criteria: extracranial metastatic or leptomeningeal disease; previous treatment with DLL3-targeting therapies; prior treatment with bevacizumab/other anti-VEGF/anti-angiogenic treatment ≤6 months prior to first administration of BI 764532; persistent toxicity from previous treatments that has not resolved to ≤CTCAE Grade 1; diagnosis of immunodeficiency, or intake of immunosuppressive therapy ≤7 days prior to first administration of BI 764532. Primary endpoints: dose-limiting toxicities (DLTs) during the maximum tolerated dose evaluation period (escalation phase); DLTs during the entire treatment period (expansion phase). Other objectives include pharmacokinetics, pharmacodynamics, preliminary efficacy and evaluation of DLL3 as a potential biomarker.
Studeny, Marini, and Andreeff respond to the concerns of Wolf et al. about their research on mesenchymal stem cells and lung cancer. They think the data presented by Wolf et al. in their letter do ...not undermine the concept or conclusions presented in their article.
Nintedanib is a potent, oral angiokinase inhibitor that targets VEGF, PDGF and FGF signalling, as well as RET and Flt3. The maximum tolerated dose of nintedanib was evaluated in a phase I study of ...treatment-refractory patients with advanced solid tumours. In this preplanned subanalysis, the effect of nintedanib on the tumour vasculature, along with efficacy and safety, was assessed in 30 patients with colorectal cancer (CRC).
Patients with advanced CRC who had failed conventional treatment, or for whom no therapy of proven efficacy existed, were treated with nintedanib ranging from 50-450 mg once-daily (n = 14) or 150-250 mg twice-daily (n = 16) for 28 days. After a 1-week rest, further courses were permitted in the absence of progression or undue toxicity. The primary objective was the effect on the tumour vasculature using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and expressed as the initial area under the DCE-MRI contrast agent concentration-time curve after 60 seconds (iAUC60) or the volume transfer constant between blood plasma and extravascular extracellular space (Ktrans).
Patients received a median of 4.0 courses (range: 1-13). Among 21 evaluable patients, 14 (67%) had a ≥40% reduction from baseline in Ktrans and 13 (62%) had a ≥40% decrease from baseline in iAUC60, representing clinically relevant effects on tumour blood flow and permeability, respectively. A ≥40% reduction from baseline in Ktrans was positively associated with non-progressive tumour status (Fisher's exact: p = 0.0032). One patient achieved a partial response at 250 mg twice-daily and 24 (80%) achieved stable disease lasting ≥8 weeks. Time to tumour progression (TTP) at 4 months was 26% and median TTP was 72.5 days (95% confidence interval: 65-114). Common drug-related adverse events (AEs) included nausea (67%), vomiting (53%) and diarrhoea (40%); three patients experienced drug-related AEs ≥ grade 3. Four patients treated with nintedanib once-daily had an alanine aminotransferase and/or aspartate aminotransferase increase ≥ grade 3. No increases > grade 2 were seen in the twice-daily group.
Nintedanib modulates tumour blood flow and permeability in patients with advanced, refractory CRC, while achieving antitumour activity and maintaining an acceptable safety profile.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Molecules that physiologically control cell proliferation are often produced locally in tissues and are rapidly destroyed when they enter circulation. This allows local effects while avoiding ...interference with other systems. Unfortunately, it also limits the therapeutic use of these molecules via systemic delivery. We here demonstrate that, for the purpose of anticancer therapy, bone marrow-derived mesenchymal stem cells (MSCs) can produce biological agents locally at tumor sites. We show that the tumor microenvironment preferentially promotes the engraftment of MSCs as compared with other tissues. MSCs with forced expression of IFN-beta inhibited the growth of malignant cells in vivo. Importantly, this effect required the integration of MSCs into the tumors and could not be achieved by systemically delivered IFN-beta or by IFN-beta produced by MSCs at a site distant from the tumors. Our results indicate that MSCs may serve as a platform for delivery of biological agents in tumors.
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