A Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients With Metastatic Colorectal Cancer (Morpheus-CRC)
Ontology highlight
ABSTRACT:
DISEASE(S): Metastatic Colorectal Cancer,Colorectal Cancer (crc),Colorectal Cancer,Colorectal Neoplasms
PROVIDER: 2275230 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
Similar Datasets
Project description:Genomic imbalance refers to the more severe phenotypic consequences of changing a single chromosome compared to changing the whole genome set. Previous genome imbalance studies in maize have identified gene expression modulation in aneuploids of single chromosome arms. Here, the modulation of gene expression in more complex aneuploids, e.g. monosomy of one chromosome arm and trisomy of another. To determine the extent that combination aneuploids were additive, multiplicative, or rebalanced in terms of their effect on gene expression. A series of genetic crosses was performed to produce one, two, and three copies of one arm with independent one, two, and three copies of the other arm in each of the three genotypes for the opposite arm. In total, 31 combinations were analyzed. By examining RNA modulation, we discovered that cis genes on varied chromosome arms are generally more dosage-compensated in aneuploid combinations than in single aneuploidy even though some showed a clear dosage effect. For genes on the unvaried chromosomes (trans), there is greater modulation in most of the aneuploidy combinations. Finally, 22 of the 31 combinations were found to have an altered transcriptome size, suggesting that extensive stoichiometric changes of genomic regions upsets global mRNA transcription. Overall, these results have important implications for understanding the role of genomic stoichiometry for mechanisms of gene expression, the evolution of dosage-sensitive duplicated genes, the evolution of sex chromosomes, the rapid growth adaptation of aneuploid cancer cells, and the diploid of quantitative traits.
2025-04-27 | GSE284999 | GEO
Project description:Immunotherapy provides an alternative approach for cancer treatment. However, in-depth analyses of the effects of immunotherapy on the tumor microenvironment (TME) have not been conducted in non-melanoma tumors. Here we describe changes in the pancreatic ductal adenocarcinoma (PDAC) TME following immunotherapy treatment, and show for the first time that vaccine-based immunotherapy directly alters the TME, inducing neogenesis of tertiary lymphoid structures that convert immunologically quiescent tumors into immunologically active tumors. Alterations in five pathways important for immune modulation and lymphoid structure development (TH17/Treg, NFkB, Ubiquitin-proteasome, Chemokines/chemokine receptors, and Integrins/adhesion molecules) in vaccine-induced intratumoral lymphoid aggregates were associated with improved post-vaccination responses. Additional studies in other cancers and patients treated with other forms of immunotherapy are warranted to further develop signatures defined in intratumoral lymphoid structures into biomarkers that predict effective anti-tumor immune responses. These signatures may also expose therapeutic targets for promoting more robust antitumor immune responses in the TME. Between July 2008 and September 2012, 59 patients were enrolled into an ongoing study of an irradiated, allogeneic GM-CSF-secreting pancreatic tumor vaccine (GVAX) administered intradermally either alone or in combination with immune modulatory doses of cyclophophamide (Cy) as neoadjuvant and adjuvant treatment for patients with resectable pancreatic ductal adenocarcinoma (PDAC). Patients were randomized 1:1:1 to 3 treatment arms. In Arm A, patients received GVAX alone; in Arm B, patients received GVAX plus a single intravenous dose of Cy at 200 mg/m2 1 day prior to each vaccination; in Arm C, patients received GVAX plus oral Cy at 100 mg once daily for 1 week on and 1 week off. Up to 6 GVAX treatments were administered and all of the patients remained in their initial treatment arms throughout the duration of the study. All 59 of the patients received the 1st GVAX treatment 2 weeks +/-4 days prior to surgery. Formalin-fixed paraffin-embedded (FFPE) tissue blocks of surgically resected PDAC were obtained from the pathology archive. FFPE tissue blocks from each subject were stained by H&E immediately before the vaccine therapy-induced lymphoid aggregates were microdissected . To better understand the functional status of these vaccine therapy induced lymphoid aggregate structures, gene microarray analysis on RNA isolated from microdissected lymphoid aggregates was performed. Gene expression was compared among samples grouped according to patient overall survival, post-vaccination induction of enhanced mesothelin-specific T cell responses in peripheral blood lymphocytes (PBL), and the intratumoral CD8+ T effector to FoxP3+ Treg ratio. Post-vaccination induction of enhanced mesothelin-specific T cell responses has been reported to correlate with longer survival in patients treated with Panc GVAX.
2014-08-05 | E-GEOD-52171 | biostudies-arrayexpress
Project description:<p>Cancer immunotherapy utilizing cytotoxic T lymphocytes (CTLs) has demonstrated significant promise in clinical applications, but cancer immunosuppressive mechanisms hamper further progress in T cell immunotherapy. Here we show a correlation between cancer cell mitochondria content and their resistance to immunotherapy. Observing that cancer cells with higher mitochondrial content show increased resistance to CD8+ T cells, we developed mitochondrial nanoinducers designed to selectively target and degrade mitochondria within autophagosomes. The direct degradation of mitochondria not only enhances the recognition and activation of CD8+ T cells but also increases the susceptibility of cancer cells to CD8+ T cell-mediated cytotoxicity. We demonstrated the feasibility and efficacy of this strategy in multiple in vitro and in vivo tumor therapeutic models. This nanoinducer, designed to manipulate cellular mitochondrial degradation, holds promise as a versatile tool for enhancing adoptive T-cell therapy, CAR T-cell therapy and tumor vaccine-based immunotherapy.</p>
2025-03-13 | MTBLS12284 | MetaboLights
Project description:Multiple myeloma (MM) is a neoplasia of bone marrow (BM) plasma cells that remains largely incurable with current treatment. Advancing therapeutic discoveries has been hampered by the lack of genetically heterogeneous models of MM. To circumvent this limitation, we engineered fifteen mouse models carrying combinations of eight MM genetic drivers, which fulfilled the pathogenesis of human disease including progression from premalignant states under immune surveillance. Integrative analyses of ⁓500 mice and ⁓1,000 patients revealed a MAPK-MYC genetic pathway that regulates time to progression and immune escape mechanisms across genetically heterogeneous tumors. During progression, MYC-dependent and independent remodeling of the BM microenvironment divided MM into immune categories with predominance of selected T-cell subpopulations, which dictated immunotherapy responses. Experimental targeting of the cytotoxic or immunosuppressive T-cell states observed in refractory MM patients enhanced immunotherapy effectiveness. Our resource enabled characterization of MM cell-intrinsic and immunological traits at unprecedented levels, which will accelerate the translation of personalized immunotherapy.
2023-01-31 | GSE220997 | GEO
Project description:Background: Combinations of dendritic and cytokine-induced killer cell (D-CIK) based adoptive immunotherapy and anti-PD-1 antibody may enhance the immune response and stop cancer cells from growing.
Objective: Phase II clinical trial to investigate the safety, clinical activity and toxicity of combinations of D-CIK and anti-PD-1 antibody in patients with treatment-refractory solid tumors.
Methodology: Phase II clinical trial in patients with advanced metastatic hepatocellular carcinoma, renal cell carcinoma,bladder cancer,colorectal cancer,non-small-cell lung cancer,breast cancer and other solid cancers. The D-CIK was isolated from peripheral blood of participants,then activated,expanded and incubated with anti-PD-1 antibody before infusion. The enough number (1.0-1.5 *10^10 cells) of D-CIK were infused back into participants.
| 2223938 | ecrin-mdr-crc
Project description: Not available
| S-EPMC11029554 | biostudies-literature
Project description:Radiotherapy (RT) destroys tumor cells, which may lead to release of antigens and immune-activating signals. In this way, RT may act as an in situ vaccine and kick-start a T-cell response against the tumor. Immunotherapy enhances tumor-specific T-cell responses. Combination of radiotherapy and immunotherapy (radio-immunotherapy (RIT)) can therefore be expected to synergize in inducing and sustaining systemic anti-tumor T-cell responses. However, in the clinic, systemic combined responses between radiotherapy and immunotherapy are rarely observed, as the effect of RIT combinations on ‘abscopal’ tumors outside the radiotherapy field are not (yet) greater than the effect of immunotherapy alone. In order to define potential bottlenecks in the tumor micro-environment that impede CD8 T cell activity, we harvested irradiated and non-irradiated tumors from the same mice that were treated with RIT (10 Gy RT, anti-CD137 and anti-PD1). From these tumors, effector (CD43+) CD8 T cells, ‘other’ hematopoietic (CD45+) cells and tumor/stromal (CD45-) were sorted and RNA sequencing was performed to identify differences between these cell populations in the irradiated and non-irradiated tumors that could explain the lack of T cell activity in the non-irradiated tumor.
2019-02-12 | E-MTAB-6914 | biostudies-arrayexpress
Project description:This open-label, exploratory study is designed to evaluate the safety and efficacy of targeted therapies or immunotherapy as single agents or combinations, in participants with metastatic colorectal cancer (mCRC) whose tumors are biomarker positive as per treatment arm-specific definition. Eligible participants with mCRC will be enrolled into specific treatment arms based on their biomarker assay results.
| 2380789 | ecrin-mdr-crc
Project description:A Randomized, Placebo-Controlled Trial of Intradermal Allergen Immunotherapy for Grass Pollen Allergy Background: Repeated intradermal injection of grass pollen (nanograms of allergen) suppresses allergen-induced cutaneous late phase responses, in keeping with effects of conventional high dose subcutaneous and sublingual immunotherapy. We evaluated the efficacy and safety of grass pollen intradermal immunotherapy for treatment of allergic rhinitis.Methods: We randomly assigned 93 adults with grass pollen allergic rhinitis to receive 7 pre-seasonal Intradermal allergen immunotherapy injections (containing 7 ng of Phl p 5 major allergen) or histamine control. The primary end point was daily combined symptom-medication scores during the 2013 pollen season. Skin biopsies were taken after the pollen season following an intradermal allergen challenge. Cutaneous late phase responses were measured 4 and either 7, 10 or 13 months post-treatment. Results No difference in the primary endpoint was observed between treatment arms (median difference, 14; 95% confidence interval [CI], -172.5 to 215.1; P=0.80). Amongst secondary endpoints, nasal symptoms measured with daily scores (median difference, 35; 95% CI, 4.0 to 67.5; P=0.03) and visual-analogue scales (median difference, 53; 95% CI, -11.6 to 125.2; P=0.05) were higher in the intradermal treatment group. Intradermal immunotherapy increased serum Phl p-specific IgE (P=0.001) compared to the control arm and T cells cultured from biopsies showed higher and lower surface of surface markers for Type 2 (P=0.04) and Type 1 (P=0.01) T-helper cells, respectively, Interleukin-5 was differentially expressed by microarray (P=0.03). Late phase responses were still inhibited 7 months after treatment (P=0.03) but not at 10-13 months. Conclusions Grass pollen intradermal allergen immunotherapy was not clinically effective but resulted in immunological priming and worsening of allergic rhinitis symptoms.
2017-06-23 | GSE72324 | GEO
Project description:A phase Ib, open-label platform study of select drug combinations chosen in order to characterize safety and tolerability of each treatment arm tested and to identify recommended doses and regimens for future studies.
| 2331996 | ecrin-mdr-crc