Cellular Therapies for the Treatment of Hematological Malignancies; Swine Are an Ideal Preclinical Model

Abstract

The absence of clinically relevant large animal tumor models has historically forced experimental cellular therapies for hematological malignancies to translate directly from murine models to clinical trials. However, recent advances highlight swine as an ideal large animal model to demonstrate the safety of murine proof of concept studies prior to their implementation clinically. The availability of the MHC defined MGH miniature swine herd has been key for the development of novel approaches for hematopoietic cell and solid organ transplantation. New spontaneously arising hematological malignancies in these swine, specifically myeloid leukemias and B cell lymphomas, resemble human malignancies, which has allowed for development of immortalized tumor cell lines and has implications for the development of a large animal transplantable tumor model. The novel development of a SCID swine model has further advanced the field of large animal cancer models, allowing for engraftment of human tumor cells in a large animal model. Here, we will highlight the advantages of the swine pre-clinical model for the study of hematological malignancies. Further, we will discuss our experience utilizing spontaneously arising tumors in MGH swine to create a transplantable tumor model, describe the potential of the immunodeficient swine model, and highlight several novel cellular and biological therapies for the treatment of hematological malignancies in swine as a large animal pre-clinical bridge.

Epstein-Barr Virus-Encoded BILF1 Orthologues From Porcine Lymphotropic Herpesviruses Display Common Molecular Functionality

“…Human PTLD samples are mostly limited to serum due to the technical challenges of conserving whole blood over time. The large size and long-life span of pigs enables greater ease of sample collection and monitoring over extended time periods (19,25,27,87,88), where the expression of BILF1 receptor can be determined from isolated B cells, as well as tissue material, such as spleen and lymph nodes, during PTLD development. Such a model would also enable use of genetically modified PLHV1-3 BILFs to study the importance of individual viral genes in PTLD development.…”

“…Immunodeficient mouse strains (NOG and NSG) reconstituted with human stem cells have been used to study the development of EBV-associated lymphoma or lymphoproliferative disease (12,(14)(15)(16) and limited features of primary EBV infection (17,18). However, major differences in genetics, immunologic and physiologic characteristics between mice and humans complicate direct translation of results from these models into human disease, especially cancer (19).…”

Lymphoma and the Microenvironmental Cross-Talk between Sex Hormone Receptors and Epstein-Barr Virus in Predicting Lymphoma Clinical Status

“…Preliminary EBV vaccination trials in patients with residual or low-mass EBV-related malignancies, or for the counteractive effect of EBV-PTLD in EBV-seronegative patients awaiting strong organ transplantation, are moving forward ( [52]). In many cases, the treatment of EBV-positive lymphomas is identical to that of EBV-negative lymphomas with similar histologies [53]. Special cases include experimental conventions and situations where a responsive immunotherapy method is available [54,55].…”

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“…Existing therapeutic approaches have made focus on interfering with biological aspects of EBV to target lymphomas associated with EBV as future therapeutic strategies. In many occasions, the way to deal with EBV-positive lymphomas doesn't contrast from EBV-negative lymphomas of a similar histology [13]. The special cases are with regards to investigational conventions or where a receptive immunotherapy approach is accessible [14,15].…”