Immunomodulatory drugs (IMiDs) are a class of drugs, derived from the teratogenic compound thalidomide, that have made a major impact on treatment of many diseases, from multiple myeloma to assorted inflammatory diseases. From its dark beginnings as a teratogenic agent that caused phocomelia in newborn infants, thalidomide has resurged decades later as a potent immunomodulatory agent with widespread anti-inflammatory and anti-tumor effects. Research examining Thalidomide’s effects in vitro on malignant myeloma cells has led to the development of newer analogs, lenalidomide and pomalidomide, both of which are now available on the market. Clinically, these drugs have had a tremendous impact on patient progression-free survival, especially when administered in conjunction with other novel agents. Despite the numerous properties that have been reported for IMiDs, until recently, little was known about their mechanism of action. Knowledge of likely only one of IMiDs’ direct mechanism of action has not only opened up opportunities for additional discoveries, but also propelled research to better characterize genetic profiles of multiple myeloma patients and potential biomarkers of disease progression and response to treatment. This thesis will attempt to review the history and literature behind the biological mechanisms of IMiDs, the clinical risks and benefits of using such drugs as treatment for cancer, and future directions for areas of research.

Immunomodulatory drugs (IMiDs) could enhance both direct anti-tumour and graft-versus-tumour effects after allogeneic haematopoietic stem cell transplantation (AHSCT). However, clinical experience with IMiDs after AHSCT using adult peripheral blood (APB) as a stem-cell source has been limited by graft-versus-host disease. Characterization of the mechanisms by which IMIDs modulate alloresponses of T cells and identification of differential effects on T cells from different cell sources could facilitate more effective use of these drugs in the setting of AHSCT. Using in vitro modelling, multi-parameter flow cytometry and gene expression analysis, I have determined the impact of the widely used IMiD lenalidomide on alloresponses of APB and umbilical cord blood (UCB)-derived T cells. Lenalidomide-treatment potentiates net alloproliferation of APB-derived T cells by selectively enhancing proliferation of CD8+ T cells. These CD8+ T cells have enhanced effector memory differentiation, are enriched for polyfunctional effectors, have enhanced direct-cytotoxicity against heamatopoietic target-cells and have a distinct gene expression profile with altered expression of key immunoregulatory-genes and depletion of cellular ikaros. Importantly, while effects on CD8+ T cells derived from UCB are similar, lenalidomide has contrasting effects on allospecific proliferation of APB and UCB-derived CD4+ T cells. While lenalidomide-treatment has no effect on alloproliferation of APB-derived CD4+ T cells, it reduces alloproliferation of UCB-derived CD4+ T cells. The reduction in UCB-derived CD4+ T cell alloproliferation is accompanied by selective expansion of CD4+CD25+FOXP3+ regulatory T cells (Treg), resulting in an overall reduction in UCB-derived T cell alloproliferation. These findings demonstrate that lenalidomide has a differential impact on alloresponses of T cells from different cell sources; alloresponses of APB-derived T cells are increased via selective expansion of polyfunctional CD8+ effectors, while alloresponses of UCB-derived T cells are limited by expansion of tolerogenic Treg. These findings have important implications for the future use of IMiDs in the setting of AHSCT.