Why are many anti-cancer drugs effective in animals, but mediocre in humans?
|16.6.2021||Posted by tactical33 under Advertising & Marketing|
PDX model (full name: patient-derived tumor xenograft model) is a transplanted tumor model formed by implanting patient-derived tumor tissue and primary cells into the body of immunodeficient mice. It is usually used to assist with testing and developing anti-cancer drugs.
The PDX model has not been cultured in vitro, which maintains the genetic characteristics and heterogeneity of the primary tumor. Therefore, it is considered to truly represent the tumor growth microenvironment in vivo more than the tumor cells cultured in vitro, and is considered the best tumor animal model in current stage.
As of July 2020, there are already 4000 PDX models developed in the science community, with at least 19,242 research papers related to cancer mouse models in the Mouse Tumor Biology Database. Currently, 210 PDX-related research projects funded by the National Institutes of Health (NIH) are in progress, with a total budget of more than 116 million USD.
When testing or verifying a certain potential anti-cancer drug, which, if can kill or inhibit human tumors in the PDX model, is considered promising. However, anti-cancer drugs that are effective in the PDX model often do not function in human trials.
On April 1, 2021, a research team from the University of Texas Health Science Center published a research paper titled “Presence of complete murine viral genome sequences in patient-derived xenografts” in the Nature Communications, which re-analyzed the RNA-Seq data of the PDX samples in 184 experiments and found that murine virus sequences were widespread in these samples. 170 of the 184 PDX samples were infected with the mouse virus, which was further confirmed by single-cell sequencing.
It was also found that the expression levels of many genes related to cancer, immunity, and drug metabolism in PDX samples with high viral loads in mice had significant changes, which might affect the reliability of using the PDX model as an anti-cancer drug test. In other words, most anti-cancer drugs successfully killed human cancer cells in the PDX model, which, in fact, are human cancer cells infected with mouse viruses. This also explains why many anti-cancer drugs shown to be effective in the PDX model fail in human trials.
Humanized mice models could help.
A lack of an immunocompetent host is the major drawback of cell line-derived xenografts (CDX) and patient-derived xenografts models. Humanized mice models that are transplanted of human immune cells such as PBMC (human peripheral blood mononuclear cells) or HSC (hematopoietic stem cells) can generate functional human immune systems with expanding ability.
Advantages of the humanized PDX model
* Human-specific antibodies
* Compared with drug-targeted humanized models such as mouse immune system expressing human PD-1, using humanized PDX can evaluate multiple I/O targets with more accuracy meanwhile mimicking the diversity of human lymphocyte targets.
* Conduct humanized mouse clinical trials (MCT) by better capturing the diversity of the human immune system and tumors.
* Support combined treatment options, such as I/O+ targeted drugs or dual immunotherapy.
PBMC humanized mice
The PBMC transplantation mouse model rebuilds the human immune system by injecting human peripheral blood mononuclear cells into immunodeficient mice, which can obtain human CD3+ T cells efficiently, and is an excellent model for studying human T cell functions in vivo.
CD34+ humanized mice
Hematopoietic stem cells (HSC) from human bone marrow, umbilical cord blood, fetal liver, bone marrow, or peripheral blood cell colony stimulating factors are injected intravenously or intrafemorally into immunodeficient mice to develop into immune cells including T cells, B cells, myeloid cells, and NK cells. They can interact with transplanted tumors and can mimic the tumor microenvironment, which can be used to evaluate the efficacy of immune drugs and explore mechanisms.