Table 2.

Overcoming limitations of preclinical autologous models

Limitation	Potential solution	Future work	References
Access to autologous Lymphocytes and tumor cells	PBMC and TIL expansion protocols Use of alternative lymphocyte sources such as SPMCs 3D tumor organoids can be used as a substitute when tumor tissue is limited	Optimization of expansion protocols to allow for a greater lineage of lymphocyte populations Assessment of humanized PDO (hu-PDO) mouse models for the Preclinical study of immunotherapies	[10, 15, 16, 20, 21, 77]
Limited immune reconstitution	Preliminary colony-forming assay to assess repopulation capacity Use of patient bone marrow cells when possible Use of novel strains with transgenic expression of human Molecules that promote engraftment of human immune Compartments	Investigate and clarify benefits of novel strains in hu-PBL models Investigate and clarify disparities in tumor-immune interactions When using adult BM cells for immune reconstitution Explore methods of improving engraftment success for donors with low repopulation capacity	[10, 19, 81, 82]
Modeling the parental TME	Expanding PDXs orthotopically in already humanized mice Injection of PBMC derived MSCs to promote neovascularization Complimentary use organoid wholistic (ALI), reductionist (tumor-stromal/immune) and microfluidic (‘tumor-on-chip’) coculture systems	Further exploration of the implantation of tumor and stromal PDOs and PDO co-cultures in vivo	[44, 85–91]
Rapid onset of GvHD	Novel strains of immunocompromised mice with MHC class I and or II knockout (such as the NSG-dKO strain) can be used to lengthen experimental windows	More research needed using MHC knockout strains in preclinical study of immunotherapies Exploration of potential cross strains that can both improve immune engraftment and prolong the experimental window	[77, 92–95]