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Trends in Oncology

Renal cell carcinoma cells proliferating in the tumor microenvironment.

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].

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].

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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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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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UnTIL We Meet Again: Testing TIL Therapies in an Ex Vivo Platform

3/7/23 1:15 PM / by Champions Oncology posted in Immuno-Oncology, Ex Vivo Platforms

3D Rendering of a Natural Killer Cell (NK Cell) destroying a cancer cell

Tumor-infiltrating lymphocyte (TIL)-based immunotherapy is currently at the forefront of cutting-edge immuno-oncology treatments. TILs are a type of adoptive cellular therapy (ACT) using lymphocytes that are found within tumor tissues; most of these lymphocytes are T cells that can specifically target tumor cells. For TIL-based therapies, these T cells are harvested from a tumor biopsy, expanded ex vivo, and infused back into the patient. Advances in TIL-based therapies are driven by preclinical characterization and screening of TILs against a wide array of tumor types.

Consider these factors related to preclinical TIL therapy studies as you develop new research protocols:

  1. Wanted Alive, Not Dead: The development of plate-based TIL assays offers users flexibility and scalability, but it is critical to assess the viability of cultured TILs at the outset of any of these assays. Some TIL cultures are prone to high levels of cell death over time, and culture conditions may need to be optimized to include different cytokines and growth factors to promote viability as well as growth and expansion of tumor-specific T cells.

  2. Scientist injecting liquid into a microtiter plate Cell Selection: Optimal TIL culture conditions should enhance the expansion of tumor-specific T cells but may also involve a step to deplete other cells prior to expansion. This may involve the depletion of adherent cell subsets with immunosuppressive characteristics such as myeloid-derived suppressor cells (MDSCs). Removing these cells from ex vivo culture allows TILs to expand and differentiate into T cells with tumor-specific cytotoxic activity.

  3. TIL Test Drive: Ex vivo expansion of TILs must include functional assays in order to ascertain if these cells have anti-tumor properties. Analysis typically includes flow cytometry-based immunophenotyping and characterization of cytokine production and tumor-specific cytotoxicity. An ideal TIL product will show tumor-specific activity with limited off-target effects, and TILs will retain a phenotype that is predicted to be well-tolerated in a patient upon re-infusion.

 

Preclinical TIL studies are continuing to expand the usage of TIL-based therapies against a wide range of solid tumors, and this field of study will advance further as ex vivo culture and analysis techniques improve.

 

Get your copy of the Autologous TIL Platform - download now

 

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