scholarly journals Rationalizing the pathway to personalized neoadjuvant immunotherapy: the Lombard Street Approach

2020 ◽  
Vol 8 (2) ◽  
pp. e001352
Author(s):  
Judith M Versluis ◽  
Daniela S Thommen ◽  
Christian U Blank
Keyword(s):  
Ex Vivo ◽  
Human Tumor ◽  
Direct Determination ◽  
Easy Access ◽  
New Combinations ◽  
Human Patient ◽  
Additional Tool ◽  
Neoadjuvant Immunotherapy ◽  
Radio Therapy ◽  
Tumor Fragment

Neoadjuvant chemo(radio)therapy is part of the established standard of care in cancer treatment; neoadjuvant application of immunotherapy, however, is only performed within recent trials. Combination of programmed cell death protein 1 and cytotoxic T lymphocyte antigen 4 blockade shows promising results with high pathologic response rates in the neoadjuvant setting and a very low relapse rate in the responding patients. In addition, neoadjuvant administration allows direct determination of treatment efficacy within the individual patient, and offers easy access to paired tumor material, both pretherapy and post-therapy, thus facilitates the rational development of new combinations driven by preclinical analyses. Patient-derived human tumor explant systems such as a recently developed human patient-derived tumor fragment platform can provide an additional tool to further rationalize the development of new treatment combinations. We will discuss neoadjuvant immunotherapy as a unique opportunity for rational trial design, the development of immune signatures for non-responding patients to steer clinical trial development, and the use of patient-derived ex vivo models to identify new personalized immunotherapy combinations. In this context, we propose the ‘Lombard Street Approach’, a back and forth approach of characterizing non-responders on neoadjuvant immunotherapy combinations, identifying promising new combinations for this group in the tumor fragment platform, and performing subsequently signature-driven small proof-of-concept combination trials. Repeating this approach with smaller and smaller groups of non-responders will step by step increase the percentage of patients benefiting from neoadjuvant immunotherapy in a rational and fast manner.

An ex vivo tumor fragment platform to dissect response to PD-1 blockade in cancer

2021 ◽  
Author(s):  
Paula Voabil ◽  
Marjolein de Bruijn ◽  
Lisanne M. Roelofsen ◽  
Sanne H. Hendriks ◽  
Simone Brokamp ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Tumor Fragment

IMMU-14. REVEALING THE MANY MYELOID STATES IN HUMAN BRAIN TUMORS AND WAYS TO PERTURB THEM

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi94-vi95
Author(s):  
Tyler Miller ◽  
Chadi El Farran ◽  
Julia Verga ◽  
Charles Couturier ◽  
Zeyu Chen ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Tumor Microenvironment ◽  
Immune Cells ◽  
Ex Vivo ◽  
Myeloid Cells ◽  
Human Tumor ◽  
Myeloid Cell ◽  
Low Grade ◽  
Tumor Patients ◽  
The Many

Abstract Recent breakthroughs in immunotherapy have revolutionized treatment for many types of cancer, but unfortunately trials of these therapies have failed to provide meaningful life-prolonging benefit for brain tumor patients, potentially due to abundant immunosuppressive myeloid cells in the tumor. Our ultimate goal is to reprogram immunosuppressive tumor associated myeloid cells to an antitumor state to enable effective immunotherapy. Towards this goal, we have deeply characterized the immune microenvironment of more than 50 primary high and low grade gliomas using high-throughput single-cell RNA-sequencing to reveal recurrent myeloid cell states and immunosuppressive programs across IDH1 wild-type and mutant tumors. We have also established a brain tumor organoid model from primary patient tissue that maintains all of the tumor microenvironment, including myeloid and other immune cells. We utilize the this model to functionally test data-driven reprogramming strategies and understand how they impact the states of tumor and immune cells in the ex vivo human tumor microenvironment.

Aptamers against mouse and human tumor-infiltrating myeloid cells as reagents for targeted chemotherapy

2020 ◽  
Vol 12 (548) ◽  
pp. eaav9760
Author(s):  
Adriana De La Fuente ◽  
Serena Zilio ◽  
Jimmy Caroli ◽  
Dimitri Van Simaeys ◽  
Emilia M. C. Mazza ◽  
...  
Keyword(s):  
Mouse Models ◽  
Anticancer Agents ◽  
Targeted Delivery ◽  
Tumor Regression ◽  
Ex Vivo ◽  
Myeloid Cells ◽  
Human Tumor ◽  
Rna Aptamers ◽  
Targeted Chemotherapy

Local delivery of anticancer agents has the potential to maximize treatment efficacy and minimize the acute and long-term systemic toxicities. Here, we used unsupervised systematic evolution of ligands by exponential enrichment to identify four RNA aptamers that specifically recognized mouse and human myeloid cells infiltrating tumors but not their peripheral or circulating counterparts in multiple mouse models and from patients with head and neck squamous cell carcinoma (HNSCC). The use of these aptamers conjugated to doxorubicin enhanced the accumulation and bystander release of the chemotherapeutic drug in both primary and metastatic tumor sites in breast and fibrosarcoma mouse models. In the 4T1 mammary carcinoma model, these doxorubicin-conjugated aptamers outperformed Doxil, the first clinically approved highly optimized nanoparticle for targeted chemotherapy, promoting tumor regression after just three administrations with no detected changes in weight loss or blood chemistry. These RNA aptamers recognized tumor infiltrating myeloid cells in a variety of mouse tumors in vivo and from human HNSCC ex vivo. This work suggests the use of RNA aptamers for the detection of myeloid-derived suppressor cells in humans and for a targeted delivery of chemotherapy to the tumor microenvironment in multiple malignancies.

scholarly journals Mechanophenotyping of 3D multicellular clusters using displacement arrays of rendered tractions

2020 ◽  
Vol 117 (11) ◽  
pp. 5655-5663 ◽  
Author(s):  
Susan E. Leggett ◽  
Mohak Patel ◽  
Thomas M. Valentin ◽  
Lena Gamboa ◽  
Amanda S. Khoo ◽  
...  
Keyword(s):  
Tumor Invasion ◽  
Wound Repair ◽  
Epithelial Mesenchymal Transition ◽  
Ex Vivo ◽  
Three Dimensional ◽  
Human Patient ◽  
Mesenchymal Transition ◽  
Successive Loss ◽  
Surrounding Extracellular Matrix

Epithelial tissues mechanically deform the surrounding extracellular matrix during embryonic development, wound repair, and tumor invasion. Ex vivo measurements of such multicellular tractions within three-dimensional (3D) biomaterials could elucidate collective dissemination during disease progression and enable preclinical testing of targeted antimigration therapies. However, past 3D traction measurements have been low throughput due to the challenges of imaging and analyzing information-rich 3D material deformations. Here, we demonstrate a method to profile multicellular clusters in a 96-well-plate format based on spatially heterogeneous contractile, protrusive, and circumferential tractions. As a case study, we profile multicellular clusters across varying states of the epithelial–mesenchymal transition, revealing a successive loss of protrusive and circumferential tractions, as well as the formation of localized contractile tractions with elongated cluster morphologies. These cluster phenotypes were biochemically perturbed by using drugs, biasing toward traction signatures of different epithelial or mesenchymal states. This higher-throughput analysis is promising to systematically interrogate and perturb aberrant mechanobiology, which could be utilized with human-patient samples to guide personalized therapies.

scholarly journals Antitumoral Effect of Laurinterol on 3D Culture of Breast Cancer Explants

Marine Drugs ◽  
2019 ◽  
Vol 17 (4) ◽  
pp. 201 ◽  
Author(s):  
Sara García-Davis ◽  
Ezequiel Viveros-Valdez ◽  
Ana Díaz-Marrero ◽  
José Fernández ◽  
Daniel Valencia-Mercado ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Crude Extract ◽  
Human Breast Cancer ◽  
Ex Vivo ◽  
3D Culture ◽  
Human Tumor ◽  
Individual Response ◽  
Human Breast ◽  
Antitumoral Effect ◽  
Wide Range

Macroalgae represent an important source of bioactive compounds with a wide range of biotechnological applications. Overall, the discovery of effective cytotoxic compounds with pharmaceutical potential is a significant challenge, mostly because they are scarce in nature or their total synthesis is not efficient, while the bioprospecting models currently used do not predict clinical responses. Given this context, we used three-dimensional (3D) cultures of human breast cancer explants to evaluate the antitumoral effect of laurinterol, the major compound of an ethanolic extract of Laurencia johnstonii. To this end, we evaluated the metabolic and histopathological effects of the crude extract of L. johnstonii and laurinterol on Vero and MCF-7 cells, in addition to breast cancer explants. We observed a dose-dependent inhibition of the metabolic activity, as well as morphologic and nuclear changes characteristic of apoptosis. On the other hand, a reduced metabolic viability and marked necrosis areas were observed in breast cancer explants incubated with the crude extract, while explants treated with laurinterol exhibited a heterogeneous response which was associated with the individual response of each human tumor sample. This study supports the cytotoxic and antitumoral effects of laurinterol in in vitro cell cultures and in ex vivo organotypic cultures of human breast cancer explants.

scholarly journals Bortezomib Augments Natural Killer Cell Targeting of Stem-Like Tumor Cells

Cancers ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 85 ◽  
Author(s):  
Jesus Luna ◽  
Steven Grossenbacher ◽  
Ian Sturgill ◽  
Erik Ames ◽  
Sean Judge ◽  
...  
Keyword(s):  
Stem Cell ◽  
Natural Killer ◽  
Tumor Cells ◽  
Nk Cell ◽  
Ex Vivo ◽  
Killer Cell ◽  
Human Tumor ◽  
Growth Delay ◽  
Cell Targeting ◽  
Immunodeficient Mice

Tumor cells harboring stem-like/cancer stem cell (CSC) properties have been identified and isolated from numerous hematological and solid malignancies. These stem-like tumor cells can persist following conventional cytoreductive therapies, such as chemotherapy and radiotherapy, thereby repopulating the tumor and seeding relapse and/or metastasis. We have previously shown that natural killer (NK) cells preferentially target stem-like tumor cells via non- major histocompatibility complex (MHC) restricted mechanisms. Here, we demonstrated that the proteasome inhibitor, bortezomib, augments NK cell targeting of stem cell-like tumor cells against multiple solid human tumor-derived cancer lines and primary tissue samples. Mechanistically, this was mediated by the upregulation of cell surface NK ligands MHC class I chain-related protein A and B (MICA and MICB) on aldehyde dehydrogenases (ALDH)-positive CSCs. The increased expression of MICA and MICB on CSC targets thereby enhanced NK cell mediated killing in vitro and ex vivo from both human primary tumor and patient-derived xenograft samples. In vivo, the combination of bortezomib and allogeneic NK cell adoptive transfer in immunodeficient mice led to increased elimination of CSCs as well as tumor growth delay of orthotopic glioblastoma tumors. Taken together, our data support the combination bortezomib and NK transfer as a strategy for both CSC targeting and potentially improved outcomes in clinical cancer patients.

Optimal combination therapy for advanced colorectal cancer: An examination of synergy and antagonism with EGFR inhibition.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14075-e14075 ◽  
Author(s):  
Nilesh Vora ◽  
Steven Evans ◽  
Paula J Bernard ◽  
Federico Francisco ◽  
Robert Alan Nagourney
Keyword(s):  
Colorectal Cancer ◽  
Kras Mutation ◽  
Ex Vivo ◽  
Human Tumor ◽  
Relative Activity ◽  
Response Curves ◽  
Tissue Samples ◽  
Egfr Inhibition ◽  
Modes Of Interaction ◽  
The Impact

e14075 Background: While FOLFOX +/- Bevacizumab is the most widely used combination in colorectal cancer (CRC), the EGFr antagonists Cetuximab & Panitumumab have not further enhanced activity. On the contrary, the addition of EGFR inhibitors to Irinotecan-based regimens at 1st & 2nd line has improved response and both progression freel & overall survival (Van Cutsem. 2010; Peeters. 2010.) Methods: We applied the ex vivo analysis of programmed cell death (EVA-PCD) (Nagourney, Curr Treat Opt Onc 2006) to examine interactions between EGFr antagonists and Irinotecan or FOLFOX in 534 human tumor primary culture microspheroids isolated from CRC surgical specimens or cytologically (+) fluids. Gefitinib was used as a surrogate for Cetuxima/Panitumumab activity. Tissue samples exposed to Oxaliplatin, 5FU, Irinotecan, and Oxaliplatin & 5FU (FOLFOX) provided dose response curves with and without Gefitinib for formal synergy analysis by median effect (Chou & Talalay). Results: Shown in table below. Conclusions: Results indicate superiority for Irinotecan combination with the EGFr antagonist Gefitinib. The percentage of synergistic interactions for Irinotecan & Gefitinib (41%) is demonstrably higher than that associated with FOLFOX & Gefitinib (4%). This suggests distinct modes of interaction between these classes of agents favoring Irinotecan and could have an impact upon future clinical trial designs. Recognizing the importance of Kras mutation, additional studies are underway to examine the impact of Kras mutation upon synergy. However, as wild-type and mutant samples would be expected to be equally distributed, subset analyses may reveal quantitative (higher % synergy) rather than qualitative differences (relative activity of Irinotecan vs FOLFOX). Results of these analyses will be reported. Supported in part by the Vanguard Cancer Foundation. [Table: see text]

Development of drug resistance in colon cancer patients following chemotherapy, a contributing factor in the failure of oxaliplatin-based HIPEC to improve survival in the Prodige 7 trial.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4063-4063
Author(s):  
Robert Alan Nagourney ◽  
Steven Scott Evans ◽  
Paula J Bernard ◽  
Adam Nagourney ◽  
Peter Tran ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Drug Resistance ◽  
Cell Death ◽  
Cancer Patients ◽  
Drug Exposure ◽  
Residual Disease ◽  
Ex Vivo ◽  
Human Tumor ◽  
Cross Resistance ◽  
The Impact

4063 Background: Numerous studies suggest benefit for heated intra-peritoneal chemotherapy (HIPEC) in colon cancer but the Prodige 7 trial in 265 colon cancer patients randomized to HIPEC or observation after neo-adjuvant chemotherapy (NACT) didn't confirm benefit with median OS of 41.7 vs. 41.2 mos. (p = 0.99) (Proc. ASCO, 2018). One concern is that prior drug exposure selects for drug resistance blunting HIPEC effect. To test the hypothesis we examined the impact of prior chemotherapy on drug resistance in human tumor organoids isolated from colon cancer patients. Methods: Data query identified 111 colorectal cancers (87 colon & 24 rectal) tested for Oxaliplatin sensitivity by ex vivo analysis of programmed cell death (EVA/PCD), a primary culture platform that examines drug induced cell death (apoptotic & non-apoptotic) by morphology, metabolism & histology. Five-point dose response curves interpolated to provide lethal concentration 50% (LC50) were compared by Z score to distribute Oxaliplatin LC50 values around the mean using standard deviation units as the metric of sensitivity or resistance. Of 87 colon 54(62%) were untreated and 33 (38%) treated with 21/33 (64%) having received FOLFOX. To approximate Prodige 7, treated patients were separated by having received FOLFOX < 2 > months before EVA/PCD analysis and also compared Mitomycin (14 vs 41), Irinotecan (18 vs 47) & 5-FU (19 vs. 52) activity to assess cross-resistance. Results: Compared to chemo-naïve, FOLFOX-treated patients were significantly more resistant to Oxaliplatin (P < 0.01) with the degree of resistance increasing significantly for patients who received treatment < 2 months prior to EVA/PCD compared to those with chemotherapy > 2 months prior to EVA/PCD (P < 0.01). Activity for Mitomycin & Irinotecan was not significantly different for chemo-naïve vs. treated patients, but 5 FU was more resistant (P = 0.048) in previously treated. Conclusions: The failure of Prodige 7 to improve survival with HIPEC following NACT may reflect diminished Oxaliplatin activity in patients whose residual disease has been selected for Oxaliplatin & 5FU resistance. Resistance was not observed for Mitomycin or Irinotecan. This suggests that those using HIPEC may i) examine other classes of drugs or drug combinations for IP administration ii) improve the selection of candidates for HIPEC administration or iii) consider HIPEC administration earlier in the course of therapy when chemotherapy-induced drug resistance may be less evident.

scholarly journals CWR22 Xenograft as an Ex Vivo Human Tumor Model for Prostate Cancer Gene Therapy

1996 ◽  
Vol 88 (9) ◽  
pp. 607-611 ◽  
Author(s):  
L. Cheng ◽  
J. Sun ◽  
T. G. Pretlow ◽  
J. Culp ◽  
N.-S. Yang
Keyword(s):  
Prostate Cancer ◽  
Gene Therapy ◽  
Ex Vivo ◽  
Human Tumor ◽  
Tumor Model ◽  
Cancer Gene Therapy ◽  
Cancer Gene

scholarly journals Single Cell Analysis of Regions of Interest (SCARI) using a novel photoswitchable tag

2020 ◽  
Author(s):  
Anne M. van der Leun ◽  
Mirjam E. Hoekstra ◽  
Luuk Reinalda ◽  
Colinda L.G.J. Scheele ◽  
Mireille Toebes ◽  
...  
Keyword(s):  
Single Cell ◽  
Spatial Information ◽  
Ex Vivo ◽  
Environmental Influence ◽  
Human Tumor ◽  
Regions Of Interest ◽  
Live Cells ◽  
Clinical Samples ◽  
Differentiation Potential ◽  
Depth Analysis

AbstractThe functional activity and differentiation potential of cells is determined by their interaction with surrounding cells. Approaches that allow the unbiased characterization of cell states while at the same time providing spatial information are of major value to assess this environmental influence. However, most current techniques are hampered by a trade-off between spatial resolution and cell profiling depth. Here, we developed a photoswitch-based technology that allows the isolation and in-depth analysis of live cells from regions of interest in complex ex vivo systems, including human tissues. The use of a highly sensitive 4-nitrophenyl(benzofuran)-cage coupled to nanobodies allowed photoswitching of cells in areas of interest with low-intensity violet light and without detectable phototoxicity. Single cell RNA sequencing of spatially defined CD8+ T cells was used to exemplify the feasibility of identifying location-dependent cell states at the single cell level. Finally, we demonstrate the efficient labeling and photoswitching of cells in live primary human tumor tissue. The technology described here provides a valuable tool for the analysis of spatially defined cells in diverse biological systems, including clinical samples.

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