The immune checkpoint molecule PD-1 and its ligand PD-L1 play a pivotal role in tumor immune evasion and progression by thwarting apoptosis induced by the immune system. Despite the significant efficacy of anti-PD-1/PD-L1 therapy against solid tumors, durable responses are observed in only a minority of patients. Many patients fail to experience the full benefits of therapy, with a notable proportion eventually developing acquired resistance. Therefore, establishing robust preclinical models of PD-1 resistance is crucial for unraveling resistance mechanisms and devising novel treatment strategies. Common mechanisms contributing to anti-PD-1/anti-PD-L1 resistance include the absence of suitable tumor antigens, tumor surface MHC molecules inactivation, dysregulated IFN-γ signaling pathways, and the immunosuppressive tumor microenvironment.

Interleukin-12 (IL-12) is a multifunctional cytokine predominantly produced by activated inflammatory cells. IL-12 plays a pivotal role in orchestrating the immune response of Th1 cells, promoting interferon (IFN-γ) production, and enhancing the activation of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Preclinical investigations have highlighted IL-12's ability to stimulate T cells and NK cells within the tumor microenvironment, leading to potent anti-tumor effects, thereby positioning IL-12 as a promising therapeutic target. GemPharmatech developed a novel mouse model expressing human IL-12RB1 and IL-12RB2 (BALB/c-hIL-12RB1/hIL-12RB2), providing a powerful tool to evaluate novel human IL-12 therapeutics.

Immuno-oncology (I-O) therapies have been extensively explored in recent years, particularly immune checkpoint inhibitors (ICIs) such as programmed cell death protein 1 (PD-1) and PD-ligand 1 (PD-L1) inhibitors. Robust and stable animal models are essential for advancing preclinical research and addressing challenges such as low response rates to anti-PD-1/PD-L1 therapies and drug resistance.
GemPharmatech has developed a human peripheral blood mononuclear cell (PBMC)-based humanized xenograft model. In this newly established model, human PBMCs are mixed with human tumor cell lines (including A-431 epidermoid carcinoma) and inoculated subcutaneously into the right flank of immunodeficient NCG mice. This PBMCs-cancer cell lines mixed injection model of NCG mice provides a valuable opportunity to evaluate the in vivo efficacy of immune checkpoint inhibitors.

Advances in immunology and hematopoietic stem cell (HSC) transplantation have led to the development of murine models that faithfully recapitulate human immune responses. GemPharmatech has developed the NCG-M/hIL15 model, which expresses human granulocyte-macrophage colony-stimulating factor 2 (GM-CSF), interleukin-3 (IL-3), stem cell factor (SCF), and interleukin-15 (IL-15) in the severely immunodeficient NCG mouse. The goal of developing this model is to support a broader reconstitution of the human immune system, including T cells, myeloid cells, and NK cells, following HSC engraftment.

Severely immunodeficient mice engrafted with human hematopoietic stem cells (HSCs) are widely used in immuno-oncology studies to evaluate cancer therapies. GemPharmatech has developed the NCG-XM model, which expresses human granulocyte-macrophage colony-stimulating factor 2 (GM-CSF), interleukin-3 (IL-3), and stem cell factor (SCF), along with a W41/W41 inactivation mutation in the Kit gene. The goal of this model is to support multilineage human immune cell differentiation without the need for irradiation. The HSC-NCG-XM model enables better reconstitution of human T cells, B cells, NK cells, and myeloid cells (such as granulocytes, monocytes, neutrophils, macrophages, and dendritic cells) without requiring murine myeloablation prior to HSC engraftment, typically achieved through sublethal radiation or chemoablation. Furthermore, HSC-NCG-XM mice can survive for over 22 weeks post-engraftment, making them ideal for long-term immuno-oncology studies.

Overexpression of the human epidermal growth factor receptor 2 (HER2) is increasingly recognized as a common molecular abnormality in gastric and gastroesophageal cancer. Drugs targeting the HER2 protein have shown promise in treating these cancers. Additionally, there is evidence to suggest that DS-8201a, a HER2-targeted antibody-drug conjugate (ADC), may be effective and safe in treating patients with heterogeneous or low HER2 expression. To aid in the design of personalized or precision drug treatment strategies for HER2-targeted therapies in clinical trials, GemPharmatech offers suitable patient-derived xenograft (PDX) gastric cancer models.