Translational Research: Cellular Therapeutics
Harness the Power of the "Good" Cellular Component
While the graft-versus-tumor effect provided by the donor graft can be very powerful in controlling the disease, disease relapse is still the primary reason that patients do not do well after an allogeneic transplantation. Two strategies are commonly deployed in managing post-transplant relapses: reducing the tumor burden by appro-priate means, and heightening the graft-versus-tumor effect. The former usually requires traditional chemotherapies, radiation or targeted therapies. However, there are several different ways to heighten the donor graft function. These include withdrawal of immunosuppression; immune stimulation with immunomodulators such as CpG, interferon or checkpoint inhibitors; and infusion of additional donor cells. At Stanford, we have a special interest in donor cellular therapeutics. The use of donor lymphocyte infusions (DLI) has been pivotal in treating post-transplant relapse. The efficacy of DLI depends on the dose of the infused T cells. However, higher doses of DLI are also associated with higher incidence of graft-versus-host disease (GVHD). To dissect the role of different T cell populations, a pre-clinical mouse model was conducted at Dr. Samuel Strober’s laboratory. In a seminal report (Blood 2011; 117:3230-3239), they found that CD8+ memory T cells were the only population capable of eradicating cancer cells without inducing GVHD. Based on this critical observation, Dr. Robert Lowsky started a clinical trial using enriched CD8+ memory T cells as an alternative to DLI in patients who relapsed after allogeneic transplant. In this phase I trial, 15 patients with a variety of diseases (acute myeloid leukemia, lymphoma, chronic lymphocytic leukemia, chronic myeloid leukemia, myeloma, and acute lymphoblastic leukemia) received CD8+ memory T cell infusions at three dose levels. The goal is to infuse a high dose of donor CD8+ memory T cells without triggering GVHD. Most of the patients (87%) received cytoreductive therapy prior to CD8+ memory T cell infusion. Five patients received the highest planned 10x106/kg dose. As expected, there were no severe adverse events after infusion, and no dose-limiting toxicities occurred. GVHD developed in only one patient, was limited to grade II involvement of the liver, and resolved following a course of steroids. Ten patients (67%) maintained or achieved response (7 complete response, 1 partial response, 2 stable disease) including one acute lymphoblastic leukemia patient who has responded to CD8+ memory T cells alone without any other therapy (see left). This is one example of our tireless commitment to understanding the function of critical cellular components from the donor graft, and our efforts to translate our research into clinical practice to advance the quality of patient care.