262 Danny Thomas Place
Memphis, TN 38105
06/20/2011

The anti-tumor activity of key cells in a transplanted bone marrow graft, termed graft-versus-tumor activity (GVT), after hematopoietic cell transplantation (HCT) allows cure of pediatric cancers. However, wider application is limited by toxicities including often fatal graft-versus-host disease (GVHD). Immunosuppressive treatments to prevent or treat GVHD, in turn, can have the unwanted side effect of suppressing GVT. Therefore, the “holy grail” of allo-transplantation for children’s cancer remains to develop strategies to separate GVHD from the GVT capacity of an allograft.

A number of clinical strategies have been applied with this goal in mind, for example the use of donor-derived natural killer (NK) cells which is currently being applied at St Jude. A novel strategy which we are currently developing to augment GVT without GVHD after allo-transplantation is to utilize invariant natural killer T cells (iNKT cells), which facilitate donor cells engrafting while enhancing cytotoxicity of many cell populations, including NK cells. iNKT cells constitute < 0.1% of peripheral blood and < 1% of bone marrow T cells in humans, but they secrete large amounts of very potent molecules that can modulate the ability of other cells (such as NK cells) to kill tumor targets. Also, like NK cells, iNKT cells have their own cytotoxic pathways and play a major role in tumor immune surveillance.

Human iNKT cells also have important immunotherapeutic potential outside of transplantation, as a means to block relapse in patients who have responded favorably to chemotherapy alone. iNKT cells share numerous properties and receptors with NK cells. They rapidly produce key cell-death inducing molecules (granzymes and perforins) on stimulation, resulting in death of target cells which they recognize. Unlike NK cells, iNKT cells are not known to be inhibited by ligands such as Class I human leukocyte antigens (HLA), making them very useful adjuncts in settings of tumor escape from NK cytotoxicity via Class I upregulation.

We and others have shown that iNKT cells directly regulate GVHD after allotransplantation, and that transplant regimens which enrich for these cells do not adversely affect overall tumor clearance. One major additional strength of utilizing iNKT cells in immunotherapy is that they enhance engraftment and immune recovery of donor T cells after transplantation, thus allowing reduced time of low T cell numbers and associated risk for infectious complications, while directly preventing T cell-associated GVHD. Protocols to expand iNKT cells and to tailor the activity of key iNKT cell pathways would allow their broader application in immunotherapy.

We have developed a novel protocol which allows robust expansion of highly purified CD3+Vα24+iNKT cells from multiple potential cell therapy sources. Practically speaking, the application of expanded human iNKT cells to treat pediatric cancers can be achieved, if we can first carefully characterize direct and indirect ability of these iNKT cells to kill pediatric tumor targets. We have preliminary data suggesting that this will be the case. We intend to study the effect of these expanded iNKT cells directly on some key hematologic and non-hematologic pediatric cancers using in vitro and human-to-mouse (xenograft) models. We expect that expanded human iNKT cells will show direct killing capacity against key leukemias and solid tumors of relevance to children’s cancer treatment. This award will allow us to rapidly facilitate the preliminary data needed to support clinical trials investigating whether iNKT cells from either the patient (in a non-transplant setting) or a transplant donor can improve outcomes for children with these high-risk malignancies.