Patient‐derived preclinical models to develop immunotherapies
Tumoroids Tumor cells from surgical samples are cultured in a special medium in the absence of serum. Tridimensional multicellular suspension spheres can be generated. These cultures can be passaged, frozen, and amplified for future experiments. They can be implanted in mice to generate tumors and can be infected with lentivirus expressing luciferase to monitor tumor growth. These cultures can be cocultured with leukocytes from the same patient that donated the tumor and the immune cell–tumor cell interactions can be analyzed. While these models recapitulate the complexity and heterogeneity of human cancer cells, they lack the tumor microenvironment, which can be crucial to the immune response to cancer. 

PDTTCs A fraction of the tumor is cut with a vibratom into 350‐μm‐thick slices and put into semidry culture conditions. These organotypic models allow the short‐term culture (7–10 days) of sections of tumors and maintain the tissue architecture and the stroma (infiltrating immune cells and endothelial cells among others) from the tumor of the patient. These models can be cocultured with autologous leukocytes, and the immune cell–tumor cell interactions can be analyzed. The viability of PDTTCs should be thoroughly monitored and should be higher than 80% for the experiment to proceed. These are therefore optimal models for the study of the tumor microenvironment in the context of the actual tumor of the patient, yet they lack the physiological aspects of in vivo models. 

PDX plus leukocytes Patient‐derived xenografts models are generated through the subcutaneous or orthotopic inoculation of small fresh tumor fragments in immune‐compromised mice (i.e., NOD SCID gamma (NSG) mice). The main limitation of this model is that NSG mice lack an immune system. In order to circumvent this problem, leukocytes can be implanted in mice (optimally from the same patient that donated the tumor). Although these procedures are known to cause graft‐versus‐host disease beginning 2–5 weeks after injection, short‐term experiments can be performed to address specific questions. 

Humanized PDX Patient‐derived xenografts models can be generated in CD34 + humanized mice. These humanized mouse models are generated first through the eradication of the mouse immune system to then reconstitute the human immune system by inoculating CD34 + hematopoietic stem cells. Yet, in this case, the immune cell reconstitution is not fully completed and, for example, the human myeloid compartment is not well re‐established. Moreover, the model does not present with the patient's autologous immune cells, and this limits the interpretation of the immune cell–tumor cell interactions. Moreover, the long coevolution of the tumor immune microenvironment that takes place in the human tumor is also missing. All these patient‐derived models have limitations but are complementary and when used in combination can allow the comprehensive study of the immune tumor microenvironment. In addition, each model should be used based on the question that is being addressed. Specific questions will require specific patient‐derived models or combined approaches to circumvent the limitations of each model and leverage complementary strengths. These models can be used for the preclinical testing of novel therapeutic compounds. Nowadays, many pharmaceutical companies are not usually using patient‐derived models. This challenges the translation of preclinical results into clinical studies, and without fully elucidating the mechanism of action of a compound, many trials may fail. The use of the right model or combination of patient‐derived models can advance insights into the biology of the immune response to cancer and help make clinical trials more successful. 

JS is a cofounder of Mosaic Biomedicals and has ownership interests from Mosaic Biomedicals and Northern Biologics. JS received grant/research support from Mosaic Biomedicals, Northern Biologics, Roche/Glycart, Hoffmann la Roche, and AstraZeneca. 

