3042 Better Laid Plans of Mice and Men

Research in the field of humanized mice began in the late 1980s, a few years after the discovery of mice with severe combined immunodeficiency (SCID) resulting from a spontaneous mutation, specifically, Prkdcscid, (protein kinase, DNA activated, catalytic polypeptide; severe combined immunodeficiency allele) identified in a colony of C.B-17 mice. This functional inactivation then led to defective DNA repair and repair-dependent somatic V(D)J recombination of B and T cell receptor-encoding genes, resulting in the absence of mature B and T lymphocytes. Taking advantage of the severe immunodeficiency of these animals, several groups then successfully transplanted human PBMCs (peripheral blood mononuclear cells), human bone marrow cells, human fetal tissues, or human HSPCs (hematopoietic stem cells) into SCID or equivalent recipient mice models. These humanized mice can accept the xenografted elements of  the human immune system and as a result, the have an immune system that is part mouse part human.  Next, by xenografting cancer cell lines or patient tumor explants into such mice, the effect of an intervention such as a drug treatment on the xenograft in the context of an intact immune system can be investigated.  Thus, establishment of cell-line-derived xenograft (CDX) and patient-derived xenograft (PDX) into humanized mouse models has been a remarkable stride for facilitating diverse applications in the exploration of cancer pathogenesis, and the evaluation of therapeutic effects.

While CDX models are less time-consuming to generate, the in vitro culture step before engraftment typically leads to substantial loss of primary tumor features. PDX mice on the other hand, largely retain the key characteristics of the patient’s tumors, including histological features, genomic signatures, and the heterogeneity of cells in a tumor mass, particularly the tumor immune microenvironment (TiME), visualized using multiplexed immunofluorescence (mIF) techniques. Therefore, these mouse models can potentially serve as a more accurate platform for predicting therapeutic outcomes.

An area of active research is resistance mechanisms to immune checkpoint blockade therapy, and to identify therapeutic combination strategies to enhance effectiveness for treatment in these tumor types. For example, a recent publication (2) explored why most hepatocellular carcinoma (HCC) patients currently respond poorly to anti-PD1 therapy.

Hepatocellular carcinoma (HCC) remains one of the most prevalent and life-threatening malignancies globally.  Unfortunately, over 60% of HCC patients are diagnosed at advanced stages, and therefore cannot undergo curative surgery. While ICB (immune checkpoint blockade) therapies, especially with antibodies against the PD1/PD-L1 signaling axis, have made impressive breakthroughs in cancer treatment, clinical trials of HCC patients have not shown statistically significant improvements owing to primary or acquired anti-PD1 resistance. The group noted that the zinc finger protein, ZFP64 was frequently upregulated in HCC tissues of anti-PD1 resistant patients, with additional experiments indicating that a PKCα/ZFP64/CSF1 axis was critical for triggering immune evasion and anti-PD1 tolerance. Of interest, Gö6976, an inhibitor of PKCα, when introduced to both PDX and orthotopic xenograft tumor models, significantly suppressed tumor progression and altered the TiME via the PKCα/ZFP64/CSF1 axis in HCC, as measured using mIF techniques. Importantly, the group presented extensive evidence that the combined treatment of Gö6976 with anti-PD1 could synergistically improve the survival of tumor-bearing PDX mice, especially in the subset overexpressing ZFP64.

With the accumulating evidence from many publications (3,4), the use today of PDX and “better” improved humanized mouse model designs, as well as updated methods to visualize cell and spatial contexture, have become highly effective in predicting the efficacy of both conventional and novel anti-cancer therapeutics. Indeed, ongoing areas of research now afford “co-clinical trials,” in which pre-clinical investigations in vivo and clinical trials can be performed in parallel or sequentially to assess drug efficacy in mice (PDX) and men (patients).

Historically, detection of protein targets from different species in the same tissue section was difficult due to dependence on species-specific secondary antibodies (e.g. goat anti mouse secondary antibody to detect an mouse antibody made against a human protein).  Ultivue’s direct antibody labeling technology eliminates detection barriers due to species, allowing rapid creation of multiplex reagents against targets from multiple species in the same multiplex panel.  For more information on how to incorporate multiplexed immunofluorescence from your PDX or humanized mouse model and derive valuable spatial information from the tumor microenvironment, please visit www.ultivue.com or check out our latest brochure.

Categories: Uncategorized Tags: | Comments 945 Keen Eye and Ultivue announce collaborative agreement to propel multiplex and spatial analysis in clinical research

Ultivue develops unique solutions for use in mIF applications, imaging, and spatial phenomics. Its proprietary InSituPlex® technology enabling improved signal to noise data is designed for fast and comprehensive exploration of biologically relevant targets, up to 12-plex, with same slide-H&E analysis in tissue samples combines the power of computational pathology & spatial biology to guide translational science in immuno-oncology.

Ultivue recognizes the need for dedicated and custom AI models to analyze the complexity of mIF data at scale and to provide improved turn-around times and consistent readouts across large cohorts “We are looking forward to accelerating data generation for biopharma customers from mIF kits by partnering with Keen Eye. We can jointly support more scalable workflows which will allow us to meet increasing demand in clinical trials.” said Florian Leiss, Ph.D. Vice President Digital Health Strategies at Ultivue.

Keen Eye is an AI Platform company dedicated to deliver accurate, standardized, and undiscovered tissue insights in research and clinical development using Deep Learning histopathology digital image analysis. Its proprietary models dedicated for spatial exploration of tumor microenvironment give access to reliable tissue segmentation, biomarker quantification, cell population profiling, and morphological discovery.

Thanks to Ultivue’s pre-optimized assays, the high accuracy achieved for every biomarker will drastically reduce errors during quantification steps, as phenotypes combine several biomarkers. As Dr. Sylvain Berlemont, Keen Eye’s founder and CEO says, “We are thrilled to expand our application portfolio combined with best-in-class Ultivue mIF assays to biopharma companies and CROs. This partnership will undeniably support our customers to fully extend reproducibility and scalability throughout their clinical research.”

About Keen Eye


Keen Eye is a health technology company based in Paris, aiming to bring AI into every research laboratory, CRO and pharmaceutical company, for the benefit of biologists, pathologists, and patients. Keen Eye is building decision-support and GCLP-compliant image analysis solutions relying on Deep Learning technology through web-based platforms. Keen Eye strives to support the development of new therapies with better, faster, and accurate analytics. Learn more at keeneye.ai.

About Ultivue


Ultivue provides researchers and scientists in translational medicine with multiplex biomarker assays for tissue phenotyping and digital pathology. Its proprietary InSituPlex® technology enables advanced exploration and interrogation of tissue samples for precision medicine research. These highly customizable solutions coupled with our scientific consultative approach strengthen and accelerate biomarker discovery and drug development programs. Learn more at ultivue.com.

Keen Eye

Sylvain Berlemont, Ph.D

CEO and Founder

sylvain.berlemont@keeneye.ai

Ultivue

Florian Leiss Ph.D

Vice President Digital Health Strategies 

Florian.leiss@ultivue.com

Categories: News Tags: | Comments 788 The Much-Welcomed Return of In-Person Conferences

I was therefore thrilled to attend my first in-person event in 2022, in Brooklyn, New York: the 8th annual Immuno-Oncology 360 event, #IO360NY. The enthusiasm and excitement of researchers finally gathering to exchange scientific ideas and discourse was evident; we all missed the real, human connection to our peers. Scheduled over 3 days, the comprehensive program convenes stakeholders spanning the science, clinical, and business communities to report on the latest data-driven advancements in Immuno-Oncology in a wide variety of tumor types. It was a packed program, and for the sake of this summary, I’ll instead review my own highlights, but please feel free peruse the agenda herein, https://theconferenceforum.org/conferences/immuno-oncology-360/overview/.

Day one began with the keynote address by 2019 Nobel laureate Dr. Gregg Semenza, Johns Hopkins, discussing mechanisms of tumor immune evasion mediated by the hypoxia inducible factor (HIF) system and the impact targeting HIFs has had on cancer immunotherapeutic strategies. His discovery of HIFs has now been recognized as having far-reaching implications for understanding and treating a variety of conditions, such as cancer and ischemic cardiovascular disease, in which hypoxia plays an important role in disease pathogenesis.  Dr. Semenza showcased elegant, as yet unpublished work from his lab identifying several small molecule candidate drugs in a screening assay that potently inhibit HIF-1 and block cancer progression in mouse models of hepatocellular carcinoma yet avoid anemia as an on-target toxicity associated with HIF therapies to date.

Day two showcased highlights in imaging, operations, partnering, and biomarkers in the I/O field, with the annual top 10 I/O recommendations and what’s next on the IO radar from CITI analyst, Dr. Andrew Baum. With the wealth of public information, its often hard to keep up with the latest developments in the field, so I find his talks both insightful and very impactful in reviewing the past years “winners” and “losers” in the I/O drug development race as well as dynamics affecting the US biotechnology sector. I think many of us await with bated breath the outcome of some of phase 3 TIGIT data due this summer. The list of Top 10 drugs/therapy strategies to watch out for in 2023 didn’t change dramatically from 2022, top to bottom: TIGIT; ADC’s; ILT4/LILR2b; TGF-beta; Bi-specifics; IL2/15; DDR’s/PARP; TCR/CAR-T; oncolytic viruses, and rounding out the list, targeted CD28 therapies.

A highlight was the annual “great cancer immunotherapy debate” featuring Drs. Robert Valamehr from Fate Therapeutics vs.  Kristen Hege from Bristol Myers Squibb on the merits of different chimeric antigen receptor therapy (CARs) platforms, with newcomers to the fray natural killer (NK-)-CARs being challenged by T-cell-CARs of which there are now 6 FDA approved products.  Dr. Hege immediately launched into the undisputed success of CAR-T therapies, and why only T cells that are capable of directed cell killing; her quote that “this cell type is the culmination of many years of evolution to become powerful killing machines” isa strong argument indeed. Dr. Valamehr’s response was swift and to the point: NK cells instead have spontaneous cytotoxic activity and can generate target cell death independent of the tumor target antigen, while T lymphocytes only kill their targets by a CAR-target specific mechanism that is susceptible to resistance mechanisms. Dr. Hege pointed out that today, with hundreds of clinical trials in progress, CAR-T cells have shown astonishing results in the treatment of relapsed or refractory hematological malignancies, but she acknowledged the challenge in solid tumors where efficacy and toxic side effects were still issues, a concern that Dr. Valamehr seized upon in his rebuttal arguments. Ultimately, concluding her comments focused on cytoxicity, Dr. Hege argued that with the wealth of information now available, “we’ve learnt a lot about the side effects associated with CAR-T and can predict these, most side effects are low grade and reversible.”  Preclinical evidence thus far suggests NK-CARs are indeed less toxic, and her final comment was that patients want an effective proven therapy over a toxic one. The field of CAR-cellular therapies is still maturing, but preclinical and clinical studies have already shown remarkable results, and both researchers agreed that much of the data is profoundly promising, leading to the development of approved personalized therapeutic options in the future. I, for one, look forward to hearing more from these worthy opponents in future meetings.

Several of my esteemed colleagues at Ultivue were also in attendance at the meeting, our own VP Medical Director, Keith Wharton delivered a wonderful summary outlining the need for multiplexed tools in the era of cancer immunotherapeutics and the wealth of information that can be achieved from single whole slide imaging of tumor samples to better inform translational research efforts and clinical practice in Immunotherapy. If you missed our booth and/or would like more information on how our tissue-based solutions can help guide your research, please visit www.ultivue.com; specifically, our pre-optimized panels that are currently available www.ultivue.com/panels

It was overall a welcomed return to in-person meetings, having the opportunity to candidly discuss and follow up with each of the speakers in their respective fields of expertise.   Whilst I wholly recognize the benefits to democratizing science through virtual meetings, attending in person is key to networking, collaborating, sharing information, especially if it is over coffee or even a cocktail!

Categories: Uncategorized Tags: | Comments 948 Ultivue Announces Co-Marketing Agreement with Sirona DX for Multiplexed Tissue Biomarker Solutions for Precision Medicine

Ultivue, a leader in advancing precision medicine solutions by accelerating tissue biomarker discovery and validation, develops unique solutions for use in both multiplex immunofluorescence (mIF) imaging and spatial phenomics. Its proprietary InSituPlex® technology, designed for fast and comprehensive exploration of biologically relevant targets, up to 12-plex, with same slide-H&E analysis in precious tissue samples combines the power of computational pathology & spatial biology to guide translational science in immuno-oncology. “Our InSituPlex technology offers valuable profiling of the tissue and expands the depth of information possible from a single section that is complementary to the high-parameter capabilities offered by Sirona Dx. We believe this joint offering will now provide researchers a seamless workflow enabling a far more efficient biomarker discovery and drug development process.” said Mark Rees, Ph.D. Vice President Corporate Development at Ultivue.

Sirona Dx are original pioneers of spatial biology, having launched ultra-high parameter, multiplexed imaging services to Biopharma in 2018. Their technology agnostic, full service, spatial biology suite, contributed to their selection as a Top 10 CRO of 2021 by Medhealth Outlook.

“We are delighted to announce this partnership with Ultivue” said Andrew Brown, Ph.D. Chief Commercial Officer at Sirona Dx. “Since 2018, clients have relied on our leading expertise to develop and implement customized, high performance multiplexed imaging panels of up to 40 markers. Having cast a wide net to identify the most informative tissue biomarker signatures, we can now harness Ultivue’s powerful InSituPlex® technology to rapidly develop, robustly validated mid-plex panels of up to 12 markers enabling our clients to accelerate their drug development programs with transformative biomarker capabilities.

About Sirona Dx


Sirona Dx is a technical CRO, founded to accelerate the pace of immunotherapy and targeted therapy development. Bridging silos between diagnostics manufacturers and translational clinical research our laboratory offers specialized high complexity, single cell proteomics and genomics services supporting pharmaceutical companies with their drug discovery and development programs. Learn more at Sironadx.com.

About Ultivue


Ultivue provides researchers and scientists in translational medicine with multiplex biomarker assays for tissue phenotyping and digital pathology. Its proprietary InSituPlex® technology enables advanced exploration and interrogation of tissue samples for precision medicine research. These highly customizable solutions coupled with our scientific consultative approach strengthen and accelerate biomarker discovery and drug development programs. Learn more at Ultivue.com.

Ultivue

Mark Rees, Ph.D.
Vice President Corporate Development 
Mobile : (+1) 516-512-4977

ULTIVUE
USA: 763D Concord Ave. Cambridge, MA 02138-1044
Europe: Via Calabria, 15. 20090 Segrate. Milan. Italy
Website: www.ultivue.com
E. mail: mark.rees@ultivue.com

Sirona Dx

Andrew Brown, Ph.D.
Chief Commercial Officer
Mobile : (+1) 503-816-9692

SIRONA DX
USA: 4640 SW Macadam Ave, Suite 200 D, Portland, OR 97239
Website: www.sironadx.com
E. mail abrown@sironadx.com

Categories: News Tags: | Comments 943 Unique Spatial AI-Powered Imaging Solutions for Translational Medicine

The companies have already been working together since early 2021 to adapt Aignostics’ client platform to support visualization and analysis regrading some of Ultivue’s products and services, as well as provisioning of results and corresponding reports. The resulting co-developed platform will now be made available to joint clients.  Additionally, proof of concept work conducted on the Ultivue 12-plex Immunophenotyping biomarker panel in over 1,000 clinical NSCLC cases has demonstrated encouraging results for the capacity of AI-based analysis of multiplexed images for more consistent and reproducible readouts at scale. These results will be published later this year and respective AI models made available via the platform.

The companies are now expanding their relationship under a co-marketing agreement to offer the multiplex immunofluorescence (mIF) platform to their respective biotech and pharma clients, initially for research use, with a GCP-compliant version to follow later this year. Moreover, Ultivue and Aignostics will offer AI-powered image analysis services within the platform via Aignostics “Explainable AI” approach for the consistent and precise analysis of mIF cohorts at scale, for both translational research and clinical trial services in Ultivue’s CLIA accredited clinical research laboratory.  “We are excited to extend our workflow offering to include mIF AI for highly automated image analysis by partnering with Aignostics” says Florian Leiss, VP Digital Health at Ultivue. “Improved viewing capabilities enable us to interactively explore the interplay of mIF-labeled cell populations in the histological context of same-slide H&E.”

“We believe that development of Ultivue’s assays with our AI-powered image analysis will create insights from data at scale that are unprecedented in spatial biology today. We are excited to start offering this approach to our clients for translational science and clinical trials” said Viktor Matyas, CEO of Aignostics.

Besides offering research and development services to its clients, Ultivue and Aignostics will also develop and jointly certify products for the standardized analysis of certain Ultivue products in prospective clinical trials, that will become available in the future and are aimed at paving the way for more widespread use of these technologies in both clinical trials and into clinical routine.

About Ultivue


Ultivue provides researchers and scientists in translational medicine with multiplex biomarker assays for tissue phenotyping and digital pathology. Its proprietary InSituPlex® technology enables advanced exploration and interrogation of tissue samples for precision medicine research. These highly customizable solutions coupled with our scientific consultative approach strengthen and accelerate biomarker discovery and drug development programs. Learn more at Ultivue.com.

About Aignostics


Aignostics, a Berlin based company with offices in the US, is a digital pathology company dedicated to novel precision diagnostics through the use of a proprietary “Explainable AI” platform in pre-clinical and translational research and clinical trials. The use of such technology is expected to be crucial to implementation of AI-powered algorithms in routine diagnostics in order to verify (explain) the model’s decision outputs. Additionally, through its close alignment to Charité and TU Berlin amongst other collaborators, only Aignostics offers the combination of data access, sample testing and pathology expertise to develop digital pathology algorithms spanning multi-modal biomarker assay detection systems such as H&E, IHC and mIF, amongst others.

Ultivue

Florian Leiss, Ph.D.

Vice President Digital Health Strategies

E. mail: Florian.leiss@ultivue.com

Aignostics    

Jessica Riley, Ph.D. 

Chief Business Officer   

E.mail: jessica.riley@aignostics.com 

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