Evaluation of safety and efficacy of colon cancer stem cell target immunotherapy
Ontology highlight
ABSTRACT:
DISEASE(S): Colorectal Cancer
PROVIDER: 2649618 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:ImportanceSeveral immune checkpoint inhibitors (ICIs) are approved for use in patients with metastatic renal cell carcinoma (mRCC), but the efficacy and safety of ICI rechallenge in mRCC is unknown.ObjectiveTo evaluate the safety and efficacy of ICI rechallenge in patients with mRCC.Design, setting, and participantsThis multicenter, retrospective cohort study included consecutive patients with mRCC from 9 institutions in the US who received at least 2 separate lines of ICI (ICI-1, ICI-2) between January 2012 and December 2019.ExposureReceipt of an ICI (anticytotoxic T-lymphocyte-associated protein 4, anti-programmed cell death protein 1, or anti-programmed cell death ligand 1), alone or in combination with other therapies, in at least 2 separate lines of therapy for mRCC.Main outcomes and measuresInvestigator-assessed best overall response and immune-related adverse events.ResultsA total of 69 patients were included. Median (range) age at diagnosis of mRCC was 61 (36-86) years. Of these, 50 were men and 19 were women. The most common therapies received at ICI-1 were single-agent ICI (n = 27 [39%]) or ICI in combination with targeted therapy (n = 29 [42%]), while at ICI-2, the most common therapies were single-agent ICI (n = 26 [38%]) or dual ICI (n = 22 [32%]). Most patients discontinued ICI-1 owing to disease progression (n = 50 [72%]) or toxic effects (n = 16 [23%]). The overall response rates at ICI-1 and ICI-2 were 37% and 23%, respectively. The likelihood of a response at ICI-2 was greatest among patients who had previously responded to ICI-1 (7 of 24 [29%]), although responses at ICI-2 were seen in those who had progressive disease as their best response following ICI-1 (3 of 14 [21%]) as well as in those who received single-agent ICI at ICI-2 (7 of 23 [30%]). Grade 3 or higher immune-related adverse events were seen in 18 patients (26%) and 11 patients (16%) at ICI-1 and ICI-2, respectively. There were no treatment-related deaths.Conclusions and relevanceThe findings of this multicenter cohort study suggest that ICI rechallenge in patients with mRCC may be safe and reasonably efficacious, with an overall response rate of 23%. Data from prospective studies are needed to validate these findings and determine the role of sequential ICI regimens in treatment of mRCC.
| S-EPMC7260689 | biostudies-literature
Project description:Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by thymidine phosphorylase (TP) deficiency resulting in systemic accumulation of thymidine (d-Thd) and deoxyuridine (d-Urd) and characterized by early-onset neurological and gastrointestinal symptoms. Long-term effective and safe treatment is not available. Allogeneic bone marrow transplantation may improve clinical manifestations but carries disease and transplant-related risks. In this study, lentiviral vector-based hematopoietic stem cell gene therapy (HSCGT) was performed in Tymp-/-Upp1-/- mice with the human phosphoglycerate kinase (PGK) promoter driving TYMP. Supranormal blood TP activity reduced intestinal nucleoside levels significantly at low vector copy number (median, 1.3; range, 0.2-3.6). Furthermore, we covered two major issues not addressed before. First, we demonstrate aberrant morphology of brain astrocytes in areas of spongy degeneration, which was reversed by HSCGT. Second, long-term follow-up and vector integration site analysis were performed to assess safety of the therapeutic LV vectors in depth. This report confirms and supplements previous work on the efficacy of HSCGT in reducing the toxic metabolites in Tymp-/-Upp1-/- mice, using a clinically applicable gene transfer vector and a highly efficient gene transfer method, and importantly demonstrates phenotypic correction with a favorable risk profile, warranting further development toward clinical implementation.
| S-EPMC5908387 | biostudies-literature
Project description:BackgroundGenerally, oral immunotherapy (OIT) aims for daily administration. Recently, the efficacy of treatment with OIT at a low dose has been reported. However, the optimal dose and the evaluation of dose-dependent OIT outcome have not been described.MethodsA multicenter, parallel, open-labeled, prospective, non-placebo controlled, randomized study enrolled 101 Japanese patients for treatment with OIT. We hypothesized that target dose OIT would induce short-term unresponsiveness (StU) earlier than reduced dose OIT. StU was defined as no response to 6200 mg whole egg, 3400 mg milk, and 2600 mg wheat protein, as evaluated by oral food challenge after 2-week ingestion cessation. To compare the two doses of OIT efficacy, the maximum ingestion doses during the maintenance phase of OIT were divided into 100%-dose or 25%-dose groups against their target StU dose, respectively. A total of 51 patients were assigned to the 100%-dose group [hen's egg (HE) = 26, cow's milk (CM) = 13, wheat = 12] and 50 to the 25%-dose group (HE = 25, CM = 13, wheat = 12). Primary outcome was established by comparing StU at 1 year. Secondary outcome was StU at 2 years and established by comparing allergic symptoms and immunological changes.ResultsThe year 1 StU rates (%) for the 100%- and 25%-dose groups were 26.9 vs. 20.0 (HE), 7.7 vs. 15.4 (CM), and 50.0 vs. 16.7 (wheat), respectively. The year 2 StU rates were 30.8 vs. 36.0 (HE), 7.7 vs. 23.1 (CM), and 58.3 vs. 58.3 (wheat), respectively. There were no statistically significant differences in StU between years 1 and 2. The total allergic symptom rate in the 25%-dose group was lower than that in the 100%-dose group for egg, milk, and wheat. Antigen-specific IgE levels for egg-white, milk, and wheat decreased at 12 months.ConclusionsReduced maintenance dose of egg OIT showed similar therapeutic efficacy to the target dose. However, we were not able to clearly demonstrate the efficacy, particularly for milk and wheat. Reducing the maintenance dose for eggs, milk, and wheat may effectively lower the symptoms associated with their consumption compared to the target OIT dose. Furthermore, aggressive reduction of the maintenance dose might be important for milk and wheat, compared to the 25%-dose OIT.Trial registrationUMIN000009373, Multicenter Oral Immunotherapy for Hen's Egg, Cow's Milk, and Wheat-Allergic Children at Outpatient Clinic.
| S-EPMC7527748 | biostudies-literature
Project description:POISED (Peanut Oral Immunotherapy: Safety, Efficacy, and Discovery)
| PRJNA886099 | ENA
Project description:POISED (Peanut Oral Immunotherapy: Safety, Efficacy, and Discovery)
| PRJNA886098 | ENA
Project description:The tumorigenicity and toxicity of induced pluripotent stem cells (iPSCs) and their derivatives are major safety concerns in their clinical application. Recently, we developed granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing proliferating myeloid cells (GM-pMCs) from mouse iPSCs as a source of unlimited antigen-presenting cells for use in cancer immunotherapy. As GM-pMCs are generated by introducing c-Myc and Csf2 into iPSC-derived MCs and are dependent on self-produced GM-CSF for proliferation, methods to control their proliferation after administration should be introduced to improve safety. In this study, we compared the efficacy of two promising suicide gene systems, herpes simplex virus-thymidine kinase (HSV-TK)/ganciclovir (GCV) and inducible caspase-9 (iCasp9)/AP1903, for safeguarding GM-pMCs in cancer immunotherapy. The expression of HSV-TK or iCasp9 did not impair the fundamental properties of GM-pMCs. Both of these suicide gene-expressing cells selectively underwent apoptosis after treatment with the corresponding apoptosis-inducing drug, and they were promptly eliminated in vivo. iCasp9/AP1903 induced apoptosis more efficiently than HSV-TK/GCV. Furthermore, high concentrations of GCV were toxic to cells not expressing HSV-TK, whereas AP1903 was bioinert. These results suggest that iCasp9/AP1903 is superior to HSV-TK/GCV in terms of both safety and efficacy when controlling the fate of GM-pMCs after priming antitumor immunity.
| S-EPMC7994724 | biostudies-literature
Project description:Islet engraftment after transplantation is impaired by high rates of islet/? cell death caused by cellular stressors and poor graft vascularization. We studied whether cotransplantation of ex vivo expanded autologous bone marrow-derived mesenchymal stem cells (MSCs) with islets is safe and beneficial in chronic pancreatitis patients undergoing total pancreatectomy with islet autotransplantation. MSCs were harvested from the bone marrow of three islet autotransplantation patients and expanded at our current Good Manufacturing Practices (cGMP) facility. On the day of islet transplantation, an average dose of 20.0?±?2.6 ×106 MSCs was infused with islets via the portal vein. Adverse events and glycemic control at baseline, 6, and 12 months after transplantation were compared with data from 101 historical control patients. No adverse events directly related to the MSC infusions were observed. MSC patients required lower amounts of insulin during the peritransplantation period (p?=?.02 vs. controls) and had lower 12-month fasting blood glucose levels (p?=?.02 vs. controls), smaller C-peptide declines over 6 months (p?=?.01 vs. controls), and better quality of life compared with controls. In conclusion, our pilot study demonstrates that autologous MSC and islet cotransplantation may be a safe and potential strategy to improve islet engraftment after transplantation. (Clinicaltrials.gov registration number: NCT02384018). Stem Cells Translational Medicine 2018;7:11-19.
| S-EPMC5746145 | biostudies-literature
Project description:Chordoma is a rare tumor derived from notochord remnants that has a propensity to recur and metastasize despite conventional multimodal treatment. Cancer stem cells (CSC) are implicated in chordoma's resistant and recurrent behavior; thus strategies that target CSCs are of particular interest. Using in vitro cytotoxicity models, we demonstrated that anti-programmed death-ligand 1 (N-601) and anti-epidermal growth factor receptor (cetuximab) antibodies enhanced lysis of chordoma cells by healthy donor and chordoma patient NK cells through antibody-dependent cellular cytotoxicity (ADCC). Treatment of NK cells with an IL-15 superagonist complex (N-803) increased their cytotoxicity against chordoma cells, which was further enhanced by treatment with N-601 and/or cetuximab. PD-L1-targeted chimeric antigen receptor NK cells (PD-L1 t-haNKs) were also effective against chordoma cells. CSCs were preferentially vulnerable to NK cell killing in the presence of N-601 and N-803. Flow cytometric analysis of a chordoma CSC population showed that CSCs expressed significantly more NK activating ligand B7-H6 and PD-L1 than non-CSCs, thus explaining a potential mechanism of selective targeting. These data suggest that chordoma may be effectively targeted by combinatorial NK cell-mediated immunotherapeutic approaches and that the efficacy of these approaches in chordoma and other CSC-driven tumor types should be investigated further in clinical studies.
| S-EPMC9236084 | biostudies-literature
Project description:Colon adenocarcinoma (COAD) is one of the leading causes of cancer-associated deaths worldwide. Patients with microsatellite instability-high (MSI-H) tumors were shown to highly benefit from immune checkpoint inhibitors (ICIs) than patients with microsatellite stable (MSS) tumors. Furthermore, the infiltration of immune cells and the expression of cancer stem cells (CSCs) in COAD were associated with the anti-tumor immune response. However, the potential mechanisms showing the relationship between microsatellite instability and CSCs or tumor-infiltrating immune cells (TIICs) have not been elucidated. Accumulating evidence reveals that achaete-scute family bHLH transcription factor 2 (ASCL2) plays a crucial role in the initiation and progression of COAD and drug resistance. However, the specific biological functions of ASCL2 in COAD remain unknown. In this study, we performed weighted gene co-expression network analysis (WGCNA) between MSS and MSI-H subsets of COAD. The results revealed that ASCL2 was a potential key candidate in COAD. Subsequently, the single-cell RNA-seq revealed that ASCL2 was positively associated with CSCs. Further, ASCL2 was shown to indirectly affect tumor immune cell infiltration by negatively regulating the expression of DUSP4. Finally, we inferred that the immunotherapy-sensitive role of ASCL2/DUSP4 axis on COAD is partly attributed to the activation of WNT/β-catenin pathway. In conclusion, this study revealed that ASCL2 was positively correlated to CSCs and tumor immune infiltration in COAD. Therefore, ASCL2 is a promising predictor of clinical responsiveness to anti-PD-1/PD-L1 therapy in COAD.
| S-EPMC9237783 | biostudies-literature
Project description:Single-agent immunotherapy, such as immune checkpoint inhibition, has shown remarkable efficacy in selected cancer entities and individual patients. However, most patients fail to respond. This is likely due to diverse immunosuppressive mechanisms acting in a concerted way to suppress the host anti-tumor immune response reducing the efficacy of single-agent immunotherapy. Combination immunotherapy approaches that are effective in such poorly immunogenic tumors mostly rely on precise knowledge of immunological targets on tumor cells by vaccinations or antibodies engineered to directly target those. Thus, creating a target-agnostic combination immunotherapy that is effective in poorly immunogenic tumors for which an immunological target is not known is a major challenge. We show that combined adoptive cellular therapy (ACT) with lymphokine-activated killer cells (LAKs), cytokine-induced killer cells (CIKs), Vγ9Vδ2-T-cells (γδ-T-cells) and adaptive, tumor-specific T-cells (CTLs) display synergistic anti-tumor treatment effects, which is further enhanced by co-treatment with anti-PD1 antibodies. Most strikingly, combination of this ACT with anti-PD1 antibodies, local immunotherapy of agonists against Toll-like receptor 3, 7 and 9 and pre-ACT lymphodepletion, a protocol we named TRI-IT, eradicates established, poorly immunogenic tumors and induces durable anti-tumor immunity in a variety of poorly immunogenic syngeneic, autochthonous, as well as autologous humanized patient-derived models. Mechanistically, we show that TRI-IT co-activates adaptive cellular and humoral, as well as innate anti-tumor immune responses to mediate its anti-tumor effect without inducing off-target toxicity. Our data demonstrate the efficacy of a target-agnostic combination immunotherapy that eradicates and potentially cures established poorly immunogenic tumors.
2022-10-28 | GSE173107 | GEO