In the Cellular Immunotherapy and Transplantation Program at Virginia Commonwealth University Massey Cancer Center, scientists are pursuing a cross-collaborative effort that could potentially change the way cellular immunotherapies such as stem cell transplantation and CAR T-cell therapies are performed.

This grassroots research is funded primarily through VCU Massey pilot grants, and it is culminating in a first-of-its-kind body of work that provides a detailed quantitative view of how the immune system responds to cellular therapies.

"We have developed the mathematical basis of the immune responses observed in stem cell transplantation and other forms of cancer therapy," said Massey hematologist-oncologist and lead researcher Amir Toor, MD.

"This has allowed us to understand the immune system What are the consequences? of transplantation and cancer immunotherapy as a deterministic, rather than random process," said Toor.

"In the future, we hope that such models will be used to facilitate treatment, which will improve the outcome of patients treated for cancers of the blood and lymphatic system," said Toor.

Toor has been pursuing the idea of modeling immune responses since I discovered fractal patterns in the development of T cells when I examined DNA sequencing data from stem cell six years ago. He gave TEDxRVA talk about their discoveries in 2013.

Human leucocyte antigen (HLA)

The first of the three studies, published in the journal   PLoS ONE , DNA sequencing samples from 27 HLA-matched related and 50 unrelated stem cell donors and transplant recipients, and it found substantial differences inprotein coding between the two.

The human leucocyte antigen (HLA) refers to the genes that encode for proteins on the surface of cells that are responsible for regulating the immune system. Doctors currently use HLA testing to match stem cell donors and recipients who have similar HLA makeup, and it identifies themajorHLA genes a person has inherited and their corresponding antigens.

The proteins produced by HLA genes help the body's immune system distinguish which cells are "self" and those that are foreign. The researchers looked at variation in minor histocompatibility antigens (mHA) of stem cell transplant donor-recipient pairs.

ThemHAare the protein fragments presented on HLA molecules, which interact with receptors on immune system T-cells. Using advanced computer-based analysis, the researchers examined potential interactions between the MHAs and the HLA and discovered a high level of FMAC in matched donor-related pairs.

This variation could contribute to graft-versus-host disease (GVHD), a potentially life-threatening complication in which the donor's immune cells attack healthy tissue in the recipient following transplantation.

Using the computer models they developed based on mHA interactions and protein-coding differences between the donors and recipients; the Scientists confirmed that the magnitude of the simulated T-cell response in their models correlated with cumulative GVHD incidence in the patients.

"We believe this type of modeling could be used to identify optimal donors for transplant recipients, reducing the risk of such graft-versus-host disease." Alternatively, it may also inform immunosuppression dosing following transplantation, "says Toor, who is also a member of the Developmental Therapeutics research program at Massey.