Cellular Therapeutics: Release the Power of Individual Cellular Component
While the role for the individual cell population of the donor graft is not fully understood after allogeneic transplant, recent works in the field have yielded some interesting observations which may lead to advances in clinical care. Stanford and other researchers have shown that ex vivo activation of T cells with interferon-γ (IFN-γ), CD3 agonist and Interleukin-2 results in the expansion of a T-cell population which shares functional and phenotypic markers with natural killer (NK) cells. These cells have been termed cytokine-induced killer cells (CIK). In a pre-clinical experiment, these CIK cells have shown anti-tumor activity against hematological malignancies from both mouse and/or human source, which is thought to be related to NKG2D engagement by its ligands on the cancer cells. In contrast to traditional T cells, CIK cells do not elicit GVHD even in MHC-mismatched model. To test its anti-tumor effect, Dr. Ginna Laport completed a phase I study using allogeneic CIK cells in patients who relapsed after allogeneic transplant. In this report (BBMT, 2011; 17:1679-1687), 18 patients were treated with different doses of CIK cells (1 – 10 x 107 CD3+/kg) without significant side effects. Two patients developed acute GVHD and one developed chronic GVHD after CIK cell infusion. All three cases were managed with immuno-suppression successfully. After CIK infusion, five of the 18 patients achieved or maintained a complete response for greater than one year. Based on this favorable result, Dr. Everett Meyer is now leading an ongoing clinical trial using expanded allogeneic CIK cells as adjuvants immediately after transplant in patients with myelodysplasic syndrome or myeloproliferative disorder to boost the anti-tumor effect and to facilitate the donor cell engraftment. The preliminary analysis from the first 12 patients showed a very encouraging result.
Relapse after allogeneic transplant remains a major clinical challenge. The use of donor lymphocyte infusion (DLI) has been pivotal in treating patients who relapse post-transplant. The efficacy of DLI depends on the dosage of the infused T cell number. However, higher doses of DLI are also associated with higher incidence of GVHD. To dissect the role of different T cell populations in the graft-versus-tumor action and GVHD, 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 patients were the only population capable of eradicating lymphoma 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 dose escalation trial, seven patients have received CD45RA-/CD8+ memory T-cells (Smart DLI) with the highest dose of 10 x 106/kg. Thus far, no patient developed GVHD related to Smart DLI.
These two examples highlight our tireless commitment to understanding the function of critical cellular components from the donor graft, and our tremendous efforts to translate our research into clinical practice to advance the quality of patient care. To further expand our ability to deliver a variety of novel cellular therapeutics, we are in the process of building a next generation cellular laboratory.