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Triple-Negative Breast Cancer (TNBC) cells interacting in the tumor microenvironment.

In the realm of oncology, few words instill as much uncertainty and trepidation as "triple negative breast cancer" (TNBC). With its resistance to many standard forms of therapy, TNBC demands a new generation of treatment innovation. Enter pembrolizumab—an immunotherapy designed to engage the body’s immune system in the fight against cancer. Its recent breakthroughs in clinical trials have charted a promising new course in the treatment of this aggressive form of breast cancer.

The Evolution of Treatment in TNBC: A Closer Look at Pembrolizumab

3/28/24 10:38 AM / by Champions Oncology posted in immunooncology, Solid Tumor Oncology, Triple-negative breast cancer, TNBC

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In the realm of oncology, few words instill as much uncertainty and trepidation as "triple negative breast cancer" (TNBC). With its resistance to many standard forms of therapy, TNBC demands a new generation of treatment innovation. Enter pembrolizumab—an immunotherapy designed to engage the body’s immune system in the fight against cancer. Its recent breakthroughs in clinical trials have charted a promising new course in the treatment of this aggressive form of breast cancer.

The TNBC challenge

Conventionally, breast cancer treatment plans are designed around the presence or absence of three receptors: estrogen, progesterone, and HER2/neu. TNBC, characterized by the absence of these receptors, compels a more bespoke approach, given the limitations it imposes on targeted treatments available for other forms of breast cancer. The lack of defined therapeutic targets has historically left TNBC patients with fewer options and a greater risk of disease progression and poor prognosis.[1]

The arrival of pembrolizumab: a precision tool in the TNBC arsenal

Pembrolizumab operates on a fundamentally different principle than traditional treatments. It is an immune checkpoint inhibitor that effectively releases the brakes on the immune system, allowing it to identify and combat cancer cells in a manner that is highly specific to a patient's tumor profile. This tailored approach has been nothing short of revolutionary in cancers with high mutational loads, such as TNBC, where the potential for an immune system response is significant.[2]

Groundbreaking trials: pembrolizumab's journey to TNBC approval

KEYNOTE-355

The KEYNOTE-355 study burst into the scientific limelight with its findings on the efficacy and safety of pembrolizumab in combination with chemotherapy in the treatment of locally recurrent inoperable or metastatic TNBC. The trial's incorporation of a diverse patient population, coupled with the comprehensive analysis of the drug's performance set a new precedent for the depth and breadth of oncology research.[3]

This landmark study, along with other trials such as KEYNOTE-012 and KEYNOTE-086, has served as evidence in the FDA's approval of pembrolizumab in combination with chemotherapy for the treatment of advanced TNBC expressing high levels of PD-L1. These studies have demonstrated not only the drug's ability to improve patient outcomes but also its potential to revolutionize the treatment landscape for this challenging form of breast cancer.[4]

The KEYNOTE-355 study has been a beacon of hope for those combating triple-negative breast cancer, illuminating the path forward with its groundbreaking results. Central to its findings is the remarkable improvement in overall survival (OS) rates for patients treated with pembrolizumab in conjunction with chemotherapy. Specifically, the study delineates a median OS of 23 months for these patients, significantly surpassing the 16.1 months median observed in those receiving chemotherapy alone. This stark contrast not only emphasizes pembrolizumab's efficacy but also marks a tangible advancement in extending the lives of individuals facing this formidable adversary.[4,5]

KEYNOTE-522

Similarly, the KEYNOTE-522 trial, which investigated pembrolizumab in the neoadjuvant setting, demonstrated a significant pathologic complete response (pCR) rate. This paradigm-shifting evidence supported the FDA's approval of pembrolizumab for high-risk early-stage TNBC, leading to a pivotal shift in the narrative around treating this formidable adversary.[6]

The results from KEYNOTE-522 have been nothing short of revolutionary, illustrating a marked improvement in both pCR (7.5% higher than in the control arm) and event-free survival (EFS). Patients on the pembrolizumab arm experienced EFS benefit regardless of tumor PD-L1 status.[6,7]

What makes these results particularly compelling is the implication for long-term survival outcomes. Early indications suggest that the increase in pathologic complete response rates correlates with longer overall survival, offering new hope that pembrolizumab could extend lives in a population historically challenged by high relapse and mortality rates. These outcomes underscore the importance of pembrolizumab in the TNBC treatment paradigm, highlighting its potential to significantly alter the prognostic outlook for patients facing this aggressive form of breast cancer.[6,7]

The future of the TNBC treatment landscape

The integration of pembrolizumab into TNBC treatment protocols is a landmark event that underscores the ongoing refinement of personalized oncology care. While the successes in clinical trials are incredibly encouraging, the implementation of these new standards into broader clinical practice requires deliberate consideration of patient selection, administration protocols, and the management of potential immune-related adverse events.[8]

Researchers and clinicians are now tasked with harnessing the full potential of this breakthrough treatment as well as identifying novel strategies to extend patient survival and improve quality of life. The future of TNBC treatment lies in leveraging emerging technologies and collaborative frameworks to uncover even more effective therapeutic solutions.

Preview of the breast cancer model cohort sheet to download by clicking on the image.

 

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Immune Checkpoint Blockade Strategies in Renal Cell Carcinoma

3/21/24 3:01 PM / by Champions Oncology posted in Solid Tumor Oncology, Immuno-Oncology, Renal Cell Carcinoma (RCC)

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Renal cell carcinoma (RCC) is a common cancer of the genitourinary tract that has very poor survival outcomes if metastatic. RCC is now understood to be composed of several different types of cancer with different genetic features and varied clinical responses. Histological diagnosis has been the primary method to diagnose RCC and has been used to define three major RCC subtypes, including the most common subtype, clear cell renal cell carcinoma (ccRCC), papillary renal cell carcinoma (PRCC; further divided into two subtypes), and chromophobe renal cell carcinoma (ChRCC)[1]. More recent comparative genomic and phenotypic analysis has identified mutations and epigenetic modifications associated with different histological subtypes[2]. Across all subtypes, increased DNA hypermethylation and gene alterations in CDKN2A were associated with a poor prognosis as was an increased Th2 immune gene signature. For ccRCC, increased levels of mRNA transcripts associated with ribose metabolism and the immune response were associated with poor survival. ccRCC is also defined by the early loss of chromosome 3p, which in turn causes a loss of heterozygosity for the VHL, PBRM1, SETD2, and BAP1 tumor suppressor genes and subsequent mutation of these genes that leads to tumorigenesis[3]. There is also a subset of ChRCC with a unique metabolic expression pattern that is associated with extremely poor survival[2]. PRCC can be classified as type 1, for which PBRM1 mutations are linked to poor survival but type 2 PRCC has increased expression of glycolysis and metabolism-related mRNA transcripts[2].

 

ccRCC tumors with VHL mutations show overexpression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factors (HIFs) can contribute to angiogenesis and cancer progression. Similarly, some RCCs show hyperactivation of the serine/threonine kinase mammalian target of rapamycin (mTOR), which can lead to the overproduction of VEGF. VEGFR inhibitors and anti-VEGF antibodies have been tested as therapies for RCC, and the anti-VEGF antibody bevacizumab has been approved for use in combination with IFN-α for metastatic RCC[4]. The mTOR inhibitors everolimus and temsirolimus have also been approved for the treatment of RCC, typically in combination with tyrosine kinase inhibitors (TKIs)[5]. Combination therapies that target VEGF and mTOR are considered more effective since they work in concert to target tumor growth and vascularization, whereas sequential treatments are typically associated with a greater likelihood of tumors developing resistance[6]. Unfortunately, these combination therapies are associated with undesirable toxicities and have not been linked with durable responses[7]. Notably, an HIF-2α inhibitor, belzutifan,  has shown good overall response rate and duration of response and has been approved by the FDA in 2021 for use in adults with VHL-associated RCC and in patients with advanced RCC who have been treated with anti-VEGF therapy and anti-PD-1/PD-L1 therapy[8]. Combination therapies with belzutifan and other targeted agents or ICB are currently being evaluated in clinical trials[9].

18Mar2021_InsideBlog

 

Advances in immunotherapy have led to transformative treatment options for RCC. Immune checkpoint blockade (ICB) has been one promising treatment strategy, and the FDA approved the use of anti-PD-1/PD-L1 (nivolumab) for the treatment of advanced ccRCC in 2015[10]. A follow-up study showed that anti-PD-1 was associated with the best clinical benefit in ccRCC carrying loss-of-function mutations in PBRM1, which appears to affect tumor expression profiles in such a way to maintain responsiveness to checkpoint blockade[11]. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is another checkpoint molecule targeted for checkpoint blockade with the monoclonal antibody ipilimumab. Similar to PD-L1 blockade, CTLA-4 blockade was associated with a partial response against metastatic RCC. Combination therapies have shown much more durable responses in patients with advanced RCC, and the FDA approved the use of nivolumab plus ipilimumab for the treatment of intermediate or high-risk metastatic RCC in 2018[12]. ICB in combination with TKI have also been approved for advanced disease [13,14,15,16]. Unfortunately, PD-1/PD-L1 blockade has been less successful for PRCC[17] and ChRCC[18], and further studies are needed to identify therapeutic targets in these forms of RCC. Clinical studies with other checkpoint blockade targets are currently underway and are likely to provide new treatment options to RCC patients[19].

 

The future of RCC therapies relies on the identification of new molecules or pathways in tumor cells that can be targeted therapeutically without causing toxicity or promoting resistance. Advances in single-cell omics are leading the way in terms of target identification and understanding how different forms of RCC progress.

 

Click here to download your renal cell carcinoma PDX model fact sheet.

 

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Choosing the RIGHT Model - Syngeneic versus Humanized Mouse Models

3/15/24 2:00 PM / by Champions Oncology posted in Syngeneic Models, Immuno-Oncology, Humanized Models

Immune T cell attacking cancer cell

Mouse models have been the workhorses of preclinical immuno-oncology (IO) research, and advances in mouse model development have expanded to applications for nearly all types of solid tumors and hematological malignancies. Preclinical evaluation of experimental immunotherapies has been advanced by syngeneic and humanized mouse models.

Syngeneic mice are one of the most established types of models used in cancer research, whereas humanized mice are a contemporary mouse model that has been critical to the screening of immunotherapeutic agents. Here we highlight features of syngeneic and humanized mouse models and define which models are most relevant to different phases of preclinical IO research.

Syngeneic Tumor Models

Syngeneic tumor models are created by transplantation of tumor cell lines into immunocompetent mice with the same genetic background as the cell line.[1] Tumors can be transplanted intravenously or subcutaneously into mice and typically grow rapidly over several weeks. Different types of tumor cell lines can be used in this type of model, including spontaneous, transgenic, or carcinogen-induced tumor cell lines. Syngeneic mouse models are best suited for screening novel IO agents or gaining insight into anti-tumor responses in the context of an intact immune system. Given the rapid growth of tumors in syngeneic mice, these models are less well suited to studying early events in tumor growth associated with cancer stem cells or understanding the contributions of heterogeneous tumor microenvironments, and these models typically do not recapitulate the mutational heterogeneity observed in human tumors.[2]

Tumor growth in a mouse

 

Humanized Tumor Models

Humanized tumor models are a more recent addition to preclinical IO research that provide valuable insight into how individual tumors from patients (xenografts) respond to experimental therapies. Prior to the development of humanized mouse models, human xenograft models were used for screening cytotoxic or immunotherapeutic agents like chimeric antigen receptor (CAR) T cells[3], and these models use human tumor cell lines or patient-derived specimens transplanted into immunocompromised host mice. Different immunocompromised models can be used, including athymic mice that lack T cells or severe combined immunodeficiency (SCID) models that lack all adaptive immune responses. Humanized mice have been engineered from immunocompromised mouse strains that include genetic mutations in other adaptive immune functions that allow for the engraftment of human hematopoietic cells. The NOD/SCID IL2rγ chain knockout (NSG) mouse (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ) is one of the most used combined immunodeficiency models that can be engrafted with human hematopoietic cells and primary human tumors.[4] These patient-derived xenograft (PDX) models are useful for evaluating experimental IO therapies in the context of the human immune system and can use human immune cells from the same or different donor as the tumor source. PDX models are suited to evaluating experimental therapies in the context of a genetically heterogeneous tumor and better recapitulate aspects of the tumor microenvironment. Tumors can be grafted either orthotopically or subcutaneously and this also impacts how tumors grow and respond to experimental treatments.[5] Given the heavily modified nature of the NSG immune system, these models do not always reflect responses observed in humans during clinical trials. Nonetheless, NSG mice and similarly modified humanized mice offer valuable insights into the efficacy of IO candidates.

 

Mouse models are constantly being refined and improved to better reflect human physiology. Both syngeneic and humanized mouse models serve as valuable tools for preclinical IO research and accelerate the screening and evaluation of novel therapeutics.

 

Click to download your infographic explaining when it is best to use syngeneic mouse models and when humanized mouse models.

 

 

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Advancing the Battle Against Mantle Cell Lymphoma

3/8/24 12:04 PM / by Champions Oncology posted in BTK inhibitors, Hematological Malignancies, lymphoma

MCL Blog Image 1

Mantle cell lymphoma (MCL) is a rare and aggressive non-Hodgkin’s lymphoma (NHL) that originates in B cells and occurs in secondary follicles of the lymph nodes.1 MCL accounts for roughly 6% of all lymphomas diagnosed annually, and despite its relatively low incidence, the aggressive course of MCL means it can quickly become a life-threatening disease. Understanding the origin and progression of MCL is crucial to identify new targets for drug development studies.

Understanding Mantle Cell Lymphoma Pathology

Over the last decade, our understanding of MCL pathogenesis has evolved from a single definition to a consensus that MCL development and progression is related to a range of molecular events. Early on MCL was defined as a pathognomonic chromosomal translocation t(11;14)(q13;q32) causing a mutation in the CCND1 gene, resulting in the over-expression of Cyclin D1.1, 2

Under normal conditions, Cyclin D1 is heavily regulated and modulates cell cycle transition from G1 phase to S phase.1 However, overexpression of Cyclin D1 activates cyclin-dependent kinases (CDK) 4 and 6 which later deactivate the retinoblastoma protein (Rb), a cell cycle inhibitor. This series of events accelerates cell cycle progression from G1 to S phase in many cell types, including B-cells.3 The progression of this process induces uncontrolled B-cell proliferation causing an enlargement of lymph nodes and immune system dysfunction that eventually spreads to critical organs.

Fewer Mutations Raise More Questions

Interestingly, Cyclin D1 mutations are not found in all MCL cells, suggesting other molecular actors, such as transcription factors, are involved. In 90% of MCL patients, transcription factor SOX11 is over-expressed in MCL cells with and without mutated CCND1. While SOX11’s role in MCL is not well understood, studies suggest that PAX-5, a transcription factor that regulates B-cell development and differentiation, is activated by SOX11.4 The overexpression of SOX11 that is commonly seen in MCL patients can therefore lead to reduced B-cell differentiation and increased B-cell antigen signaling.3, 5

Identifying Treatment Targets in Mantle Cell Lymphoma

B-cell proliferation and differentiation rely on B-cell receptor (BCR) signaling and are activated in response to antigen binding.6 Using the framework for CLL pathogenesis, preliminary MCL-BCR research has found that BCR signaling is highly active in MCL patients and intentional BCR activation resulted in an increase of BCR signaling in MCL cells.7 Additionally, murine studies have found SOX11-overexpressing B-cells have high levels of BTK, a key enzyme involved with BCR signaling, resulting in proliferation which suggests SOX11’s deeper role in MCL.7

MCL Blog Image 2

Initial MCL treatment includes R-CHOP therapy, however, many MCL patients are refractory or become resistant creating a need for additional therapies. As with CLL, BCR signaling plays a critical role in MCL progression shifting treatment protocols towards BTK inhibitors (BTKi) like ibrutinib, approved in 2013.1, 3 Ibrutinib is metabolized in the liver via CYP3A and CYPRD6 and irreversibly binds to cysteine residue 481 found on the active site of BTK.

While this targeting strategy effectively blocks BTK signaling limiting MCL cell development, ibrutinib has significant off-target consequences, namely IL-2 inducible kinase (ITK), which sparked the development of zanubrutinib.8 Zanubrutinib was approved for use in MCL patients and though it has a similar mechanism of action to ibrutinib, its reduced affinity for ITK, a major T-cell and natural killer (NK) cell regulator,9 makes it a highly selective and potent BTKi with improved overall response rate relative to ibrutinib.8

Resistant Mantle Cell Lymphoma and Future Therapeutic Strategies

Unfortunately, 32% of MCL patients become resistant to BTKi due to BTK mutations.10, 11 As a result, combination therapies such as ibrutinib combined with cirmtuzumab (a novel anti-ROR1 monoclonal antibody) or with obinutuzumab and venetoclax have been used to treat resistant MCL patients. 11 These therapeutic combinations have shown excellent remission results paving the way for other combination therapies, such as acalabrutinib, rituximab, and bendamustine. 11, 12 Notably, a phase 1 study investigating acalabrutinib, rituximab, and bendamustine achieved an 85% overall response rate which has led to a larger, ongoing Phase 2 study (NCT04115631). Additionally, novel MCL-1 inhibitors are under development in preclinical studies.13

Recently, the FDA has approved the first CAR T cell therapy for relapsed/refractory MCL, brexucabtagene autoleucel (Tecartus).14 Tecartus has shown durable response at the 3-year follow-up even in high-risk patients (NCT02601313), with sustained survival and a 67% complete response rate.15

Understanding the pathophysiology of naïve and BTKi resistant MCL is crucial to developing curative MCL therapies. While standard of care treatments like ibrutinib and zanubrutinib have had some success, additional studies investigating strategic combination therapies are underway providing hope for patients battling this disease.

Champions supports your in vivo preclinical studies with low passaged MCL PDX models available for subcutaneous modeling and fully characterized with NGS data in 4 models CTG-3771, CTG-3772, CTG-3776 (shown to be rituximab and ibrutinib resistant) and CTG-3808. Preclinical hematological scientists need to evaluate their pipeline of therapeutic candidates in robust hematological screening platforms; Champions' VitroScreen platform can advance potential next-generation therapies into the clinic, generating additional options for MCL patients.   

 

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Exploring DRUG-seq: Revolutionizing RNA-seq in Oncology Research

2/29/24 10:00 AM / by Champions Oncology posted in NGS, RNA Insights, DRUG-seq

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Oncology research is a field that continuously demands cutting-edge technologies to unravel the complexities of cancer. Among these innovations, RNA sequencing (RNA-seq) has emerged as a vital tool, enabling us to study the transcriptome with unprecedented depth. However, a new star is on the rise in the realm of RNA-seq — DRUG-seq. This application dazzles oncology researchers and genomics professionals with its cost-effective approach, reduced bias, and high sample efficiency, bringing with it a promise to redefine how we investigate cancer at a molecular level.[1]

In this comprehensive exploration, we'll dissect the advantages of DRUG-seq and map out its pivotal role in oncology research, shedding light on its unique applications and use cases in the fight against cancer.

Unveiling DRUG-seq: The New Era in RNA-Seq

RNA-seq, widely employed for quantifying gene expression, has been a game-changer in understanding the genetic mechanisms driving cancer. However, DRUG-seq takes this a step further, providing a powerful lens through which to examine the transcriptome under a spectrum of conditions, particularly those relevant to drug treatment responses.

While traditional RNA-seq methods offer insights into the steady state of gene expression, DRUG-seq provides a dynamic view that captures the immediate and prolonged gene expression changes following drug administration. This level of detail is especially critical in oncology, where the intricate interplay of genetics, environmental factors, and treatment response paints a highly complex picture of disease progression and therapy outcomes.

By enabling high-throughput profiling of the transcriptional response to drug compounds, DRUG-seq stands out as a catalyst for precision medicine, biomarker discovery, and the personalization of cancer treatment strategies.[1]

The Advantages of DRUG-seq in Comparative Analysis

Cost-Effectiveness

One of DRUG-seq's most touted benefits is its cost-effectiveness. The methodology uses a smaller number of sequences to cover the transcriptome, thanks to its selective enrichment of pre-existing reference indices. This focus on specific gene regions, associated with drug response or otherwise, lowers the overall sequencing cost per sample, making large-scale comparative studies feasible within more restrained budgets.

Sample Efficiency

With oncology often facing constraints of sample availability, the high efficiency of DRUG-seq is a game-changer. It requires smaller amounts of starting material, which not only conserves precious samples but also aligns with the trend toward microsampling in emerging clinical research practices.

DRUG-seq in Action: Enhancing Oncology Research and Development

Drug Response Profiling

An immediate application of DRUG-seq is in profiling the response of cancer cells to different compounds. By comparing the expression profiles pre- and post-treatment, researchers gain a comprehensive view of how drugs affect gene networks. This deep understanding underpins the development of more effective therapies by identifying compounds that selectively target critical pathways in specific cancer types.[2]

Identifying Novel Drug Targets

DRUG-seq empowers the hunt for new targets by revealing unsuspected links between gene expression patterns and drug effects. This insight into the cellular response can lead to the discovery of novel molecular targets that modulate sensitivity or resistance to treatment, providing fertile ground for the next generation of anti-cancer compounds.

Biomarker Discovery

Precision oncology heavily relies on the discovery and validation of biomarkers to predict patient outcomes and guide therapeutic decisions. DRUG-seq, with its ability to uncover gene signatures indicative of treatment response, plays a pivotal role in biomarker discovery, potentially leading to tests that can stratify patients for tailored treatment interventions.[1]

Tumor Heterogeneity

Cancer is not a single disease but a collection of disorders, each with its own molecular profile and behavior. DRUG-seq's power to unravel drug response within this context is invaluable, as it allows researchers to study how different cell populations within a tumor respond to treatment. This understanding of tumor heterogeneity can inform the development of combination therapies that target multiple facets of the disease.

Conclusion: The Bright Future of DRUG-seq in Oncology Research

From cost-effectiveness and reduced bias to sample efficiency and rich data, DRUG-seq provides a valuable addition to the oncologist's toolkit. Its applications span across drug and biomarker discovery, as well as understanding tumor heterogeneity, which is pivotal in the era of personalized medicine.

As we have navigated the many advantages, it's clear that DRUG-seq isn't just a new trend; it's a technological leap that can redefine the standard for RNA-seq applications in oncology research. By harnessing this tool, researchers can explore cancer treatments with unprecedented precision and efficacy, ultimately leading to improved patient outcomes and a more comprehensive arsenal against this formidable foe.

 

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Developing Flow Cytometry Assays in Non-Human Primates (NHPs)

2/22/24 11:46 AM / by champions posted in Preclinical Flow Cytometry

Scientist with pipette and samples

Non-human primates (NHPs) continue to be a valuable resource for preclinical research because of the similarities they share with humans. NHPs, especially rhesus macaques, are used in preclinical studies for evaluating new drugs or vaccines for safety and efficacy. Flow cytometry assays can be easily adapted to study cells from NHP. Consider these three factors if you are planning to adapt a flow cytometry assay for use with NHP samples.

  1. CellStaining panel prep: Like human subjects, PBMCs can be collected from Non-human primates and evaluated by flow cytometry. Many immune cell subsets, especially B and T cells, share similar phenotypes with their human counterparts. Human antibodies are most often used to stain NHP cells because of similarities shared between surface markers. Consider which cells of interest you may want to study and how existing antibodies used in flow cytometry may be used in your panel.
  2. Real-world variability: Many scientists are accustomed to working with an inbred mouse strain, which reduces background variability observed in experimental settings. In contrast, NHPs are outbred animals, and like humans, may display widely varying responses. As you develop your NHP protocols, consider how you will handle highly variable data, including flow cytometry data. These considerations will inform how many animals may be used in each group and how many cells are stained and evaluated in each sample.
  3. Metabolism and toxicity: NHPs share many physiological similarities to humans and are a valuable model for pharmacokinetic and pharmacodynamic measurements of experimental drugs and biologics. Toxicity testing can also be done in NHPs and together these data are critical to evaluating candidates in preclinical pipelines.

Developing NHP protocols from inception to sample analysis requires working with experts who have experience writing protocols that are compliant with appropriate oversight committees, such as institutional animal care and use committee offices. Working with experts, such as contract research organizations, also assures that any NHP flow cytometry studies will satisfy any necessary regulatory compliance determinations related to drug and biological development. 

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Triplet Therapy for IDH1-Mutant AML Tumors

2/15/24 11:32 AM / by Champions Oncology posted in Hematological Malignancies

blood cells

Acute myeloid leukemia (AML) is the most common leukemia among adults and has been challenging to treat with modern therapies.1, 2 This disease is highly heterogeneous and characterized by the rapid proliferation of undifferentiated myeloid cells that accumulate within the bone marrow. Several mutations and epigenetic abnormalities characteristic of AML have been targeted through chemotherapies or molecular inhibitors. Fortunately, the relentless pursuit of innovative, effective AML therapies has led to a deeper understanding of AML pathogenesis, such as the role of isocitrate dehydrogenase (IDH) mutations.3 IDH mutations have unique properties that, if properly targeted, may reshape AML patient outcomes and survival rates.

Unstable Gene Expression

The IDH family consists of three isoenzymes (IDH1, IDH2, and IDH3) and has an important role in the biosynthesis of metabolites involved in the tricarboxylic acid (TCA) cycle. Notably, IDH1 functions as a catalyst for reversible conversion of isocitrate to α-ketoglutarate in the cytosol as well as peroxisomes, yielding 1 NADPH. Downstream, α-ketoglutarate is reduced to D-2-hydroxyglutarate (D-2-HG) as part of the TCA cycle.3 Mutations in IDH1 are present in ~20% of AML patients and result from a single amino acid substitution at Arg132.4 This mutation induces an end-product shift that reduces α-ketoglutarate to R-2-HG instead. Unlike D-2-HG, R-2-HG competitively inhibits α-ketoglutarate-dependent enzymes, such as the TET family, and upon accumulation leads to impaired cellular differentiation and deregulation of DNA methylation. 3, 5 This alteration of DNA methylation and ultimately gene expression activates oncogenes and deactivates tumor-suppressor genes.6 The destabilizing features of IDH1 mutants have thus made this isoenzyme an interesting target for AML therapies.

IDH Focused Therapies

Since the identification of IDH mutations in 2008, the Food and Drug Administration (FDA) has approved two therapeutics for AML patients with IDH mutations, ivosidenib and enasidenib. Ivosidenib is a reversible, selective inhibitor that binds to the active site of mutated IDH1 to prevent the production of R-2-HG.7, 8, 9 Reduction in R-2-HG reportedly increases D-2-HG concentrations by 100x and restores DNA methylation and cellular differentiation in AML patients.10, 11 Though successful, resistance to ivosidenib and IDH inhibition has emerged, underlining the need for combination therapies that prevent IDH resistance.12

gloved fingers holding 2 pill capsules

Triplet Therapy

There are no triplet regimens currently approved for use in AML, however, clinical trial results have demonstrated successful remission in relapsed and naïve AML patients.13, 14 For instance, an ongoing phase Ib/II study examining ivosidenib and venetoclax with or without azacytidine has shown successful remission in patients with AML IDH1 mutations.13 The durable response to this therapy is especially promising, as the safety profile of this triplet therapy is similar to doublet therapies such as azacytidine + venetoclax and azacytidine + ivosidenib.13, 15 The median event-free-survival (EFS) for patients treated with this new triplet therapy was 36 months13, while previous azacytidine + ivosidenib combination treatments have achieved median EFS or 24 months.16

The Therapeutic Pipeline

Prolonged EFS in AML patients receiving ivosidenib in combination with AML standards of care, such as venetoclax and azacytidine, has recently gained the attention of the European Commission (EC). In 2023, the EC announced the approval of ivosidenib in combination with azacitidine for AML patients with an IDH1 R132 mutation.18 Further, clinical studies evaluating the side effects and appropriate dosages of ivosidenib and venetoclax with or without azacytidine are underway. As more clinical data is released, access to more robust therapeutic treatments will become available to improve AML patient outcomes.

 

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Providing Optimal Clinical Care for Cholangiocarcinoma Subtypes

2/5/24 2:00 PM / by Champions Oncology posted in Solid Tumor Oncology

3d rendered image, enhanced scanning electron micrograph (SEM) of cancer cellCholangiocarcinoma is a type of cancer that originates from cholangiocytes, the cells that constitute the bile ducts in the liver, which carry bile from the liver to the small intestine. It is a rare and aggressive cancer that can be categorized into different subtypes based on histological and molecular characteristics.

Histologically, cholangiocarcinoma can be classified as intrahepatic, perihilar, or distal. Intrahepatic cholangiocarcinoma originates within the liver, while perihilar and distal cholangiocarcinoma develop in the ducts outside the liver. These subtypes have distinct clinical presentations and treatment approaches [1,2].

In this blog, discover the diverse nature of cholangiocarcinoma subtypes and learn about the specific clinical care required for each subtype.

Histological Characteristics and Clinical Care

Histological characteristics play a significant role in guiding clinical care for cholangiocarcinoma subtypes. Intrahepatic cholangiocarcinoma often presents as a solitary mass within the liver, while perihilar cholangiocarcinoma typically involves the bifurcation of the bile ducts. Distal cholangiocarcinoma commonly manifests as a tumor in the lower part of the bile duct near the small intestine.

The histological features of each subtype influence the choice of diagnostic tests, surgical interventions, and other treatment modalities. For example, surgical resection is often the primary treatment option for intrahepatic cholangiocarcinoma, while perihilar cholangiocarcinoma may require a combination of surgery and liver transplantation. Distal cholangiocarcinoma may be treated with surgery, radiation therapy, or systemic chemotherapy.

By understanding the histological characteristics of cholangiocarcinoma subtypes, healthcare professionals can provide appropriate clinical care to improve patient outcomes.

 

Cholangiocarcinoma Subtype-Specific Therapies

Each cholangiocarcinoma subtype requires specific therapies tailored to its unique characteristics. For intrahepatic cholangiocarcinoma, surgical resection is often the primary treatment approach, followed by adjuvant therapy such as chemotherapy or radiation therapy. Liver transplantation may be considered in selected cases.

Perihilar cholangiocarcinoma, on the other hand, often requires more complex surgical interventions, such as liver resection combined with bile duct resection and reconstruction. Liver transplantation may be an option for patients with advanced disease or underlying liver disease.

Distal cholangiocarcinoma may be treated with surgical resection, radiation therapy, or systemic chemotherapy. The choice of treatment depends on the extent of the tumor and the patient's overall health.

By tailoring therapies to the specific cholangiocarcinoma subtype, healthcare professionals can optimize treatment outcomes and improve patient survival rates.

 

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Molecular Profiling and Treatment Strategies

In addition to histological characteristics, molecular profiling has emerged as an essential tool for understanding cholangiocarcinoma subtypes and guiding treatment strategies. Molecular profiling involves analyzing the genetic and molecular alterations in cancer cells to identify potential targets for therapy.

Advancements in molecular profiling techniques have allowed researchers to identify specific biomarkers and genetic mutations associated with cholangiocarcinoma subtypes. This information helps in developing targeted therapies that can effectively inhibit the growth and spread of cancer cells.

Two targeted therapies are currently available for patients presenting tumors with FGFR2 fusions/rearrangements (infigratinib) or IDH1 (ivosidenib) mutation [3,4].

In general, treatment strategies for cholangiocarcinoma subtypes may include targeted therapies, immunotherapy, chemotherapy, and radiation therapy. Molecular profiling enables healthcare professionals to select the most appropriate treatment options based on the molecular characteristics of the tumor and the patient's overall health [5].

 

Future Directions in Cholangiocarcinoma Care

The field of cholangiocarcinoma care is rapidly evolving, with ongoing research and advancements in treatment options.

Efforts are being made to improve early detection methods for cholangiocarcinoma. Early diagnosis allows for timely intervention and increases the chances of successful treatment. Additionally, advancements in precision medicine and molecular profiling techniques hold promise for tailoring treatment plans based on the unique molecular characteristics of each patient's tumor.

In conclusion, the diverse nature of cholangiocarcinoma subtypes necessitates specific clinical care for optimal treatment outcomes. Through a comprehensive understanding of histological and molecular characteristics, healthcare professionals can provide personalized therapies and contribute to ongoing research efforts aimed at improving cholangiocarcinoma care.

 

Click here to download your Biliary Tract Cancer Model Cohort fact sheet.

 

 


 

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A Needle in a Haystack: Finding Rare AML Populations by Flow Cytometry

2/1/24 11:00 AM / by Champions Oncology posted in Hematological Malignancies, Preclinical Flow Cytometry

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Hematologic malignancies include a wide array of lymphomas and leukemias that affect different immune cell subsets. Acute myelogenous leukemia (AML) is one of the most commonly occurring leukemias in adults and children. AML is a highly heterogeneous disease that can be caused by spontaneous gene mutations or chromosomal translocations, which result in the proliferation of dysfunctional myeloid cells. Cytogenetic and morphologic analyses have been the gold standard methods used in AML diagnosis. Still, flow cytometry-based protocols are becoming more widely used and validated as complementary diagnostic methods that can be coupled with these analyses to better guide treatment plans. Flow cytometry has also become an essential tool to understand AML progression and develop and evaluate novel therapeutics.

Consider these aspects of flow cytometry-based analysis of AML for exploratory or preclinical research:

Phenotype matters: Immunologists know a lot about what a normally developing myeloid cell should look like in terms of its immunophenotype. Changes in expression of different lineage markers correlate strongly with AML progression and are characterized by the presence of blasts (leukemic cells) in the bone marrow. Flow cytometry-based immunophenotyping offers researchers a rapid and sensitive method for detecting blasts at the onset of disease as well as monitoring changes in this population throughout an experimental therapy.

Rare cells from precious samples: A major consideration of following AML progression is the ability to detect relatively rare cells in bone marrow aspirates. This type of sample may be relatively small and is typically used fresh for morphologic evaluation, but even a small volume of remaining aspirate can be used for flow cytometry-based methods that are sensitive and robust enough to detect blasts.

Paired samples: Bone marrow cells can be analyzed along with peripheral blood using advanced flow cytometry methods that monitor the persistence of blasts and other leukemic subsets over time in these compartments. This type of analysis offers critical insight into the development of new therapeutics whether they are being evaluated in humanized mouse models or clinical trial participants.

Flow cytometry continues to advance immuno-oncology research, especially for diseases involving the detection of rare cell populations. Consider working with preclinical and clinical flow cytometry experts to develop protocols for future immuno-oncology studies.

 

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Enhancing CAR T Cell Therapy: Optimizing Preparation for Superior Results

1/25/24 11:10 AM / by Champions Oncology posted in Immuno-Oncology, Ex Vivo Platforms

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Chimeric antigen receptor-mediated T cell (CAR T cell) therapies have revolutionized the treatment of hematologic malignancies and solid tumors. This therapy uses T cells, typically harvested from patients, that are engineered to express chimeric antigen receptors (CAR) specific to tumor cell antigens. CD19-targeting CAR T cell therapy was the first immunotherapy shown to effectively treat acute lymphoblastic leukemia[1], but a subset of patients relapse due to loss or poor engraftment of CAR T cells. Here we highlight advances in CAR T cell therapy to improve the quality of the immunotherapy product ex vivo for more effective responses in vivo.

Culture Conditions

T cells from peripheral blood mononuclear cells (PBMCs) are the primary cellular product used for CAR T cell therapy, but several steps must be carried out ex vivo to ensure that enough cells are made for therapeutic efficacy. The best treatment outcomes have been linked to high levels of CAR T cell engraftment and persistence upon transfer into a patient[2]. Ex vivo culture methods have been optimized to expand T cells, and cultures using less differentiated T cells, like stem cell memory T cells or naïve-like T cells, have been linked to better persistence upon transfer[3]. Recent studies are characterizing phenotypic features of T cells that preserve “stemness” upon ex vivo culture but still allow for expansion and expression of CAR T receptors. Reduced culture time has been one of the most effective methods for improving engraftment and antitumor responses but is limited by the number of cells yielded by this minimal manipulation process[4].

 

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Biodistribution

The successful engraftment and persistence of CAR T cells depend greatly on where cells migrate upon transfer into patients. Preserving stem cell-like features correlates with better engraftment, especially if donor-derived cells are unavailable and autologous cell sources must be used[5]. In vivo imaging studies have been very helpful in understanding CAR T cell dynamics and anti-tumor responses. Studies in mouse models have indicated that CAR T cells can get trapped in tissues, including the lungs, which can limit access to tumor targets[6]. Analysis of CAR T cells with tumor cells also revealed extensive functional heterogeneity, including CAR-T cells that can interact with tumor cells but not exert cytotoxic effector functions. A recent first-in-human study examined the biodistribution of radioisotope-labeled CAR T cells and confirmed that these cells rapidly distribute to tumor tissue but are taken up by the liver and spleen and can persist systemically for up to two weeks[7]. As new in vivo imaging studies are carried out, these insights will inform how CAR T cell products are made and delivered and are likely to improve treatment outcomes.

 

Advances in ex vivo methods for CAR T cell preparation are already improving outcomes, and these methods are broadly applicable to donor-derived or autologous T cell products. In vivo imaging methods are also delineating characteristics of CAR T cells that improve tumor targeting or result in misdirected tissue homing. Future in vivo and ex vivo studies are well-poised to further advance CAR T cell applications.

 

Click to download your case study of preclinical evaluation of a novel CAR T cell therapy using Champions' DLBCL PDX models.

 

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