title: Cellular immunotherapy for refractory hematological malignancies.
abstract: BACKGROUND
  Acute myeloid leukemia (AML) and other aggressive refractory hematological malignancies unresponsive to upfront therapy remain difficult conditions to treat. Often, the focus of therapy is centered on achieving complete remission of disease in order to proceed with a consolidative stem cell transplant. At issue with this paradigm is the multitude of patients who are unable to achieve complete remission with standard chemotherapeutic options. A major benefit of transplantation is the graft versus tumor effect that follows successful engraftment. However, with this graft versus tumor effect comes the risk of graft versus host disease. Therefore, alternative treatment options that utilize immunotherapy while minimizing toxicity are warranted. Herein, we propose a novel treatment protocol in which haploidentical peripheral blood stem cells are infused into patients with refractory hematological malignancies. The end goal of cellular therapy is not engraftment but instead is the purposeful rejection of donor cells so as to elicit a potent immune reaction that appears to break host tumor tolerance.
  
  
  METHODS
  The trial is a FDA and institutional Rhode Island Hospital/The Miriam Hospital IRB approved Phase I/II study to determine the efficacy and safety of haploidentical peripheral blood cell infusions into patients with refractory hematological malignancies. The primary objective is the overall response rate while secondary objectives will assess the degree and duration of response as well as safety considerations. Patients with refractory acute leukemias and aggressive lymphomas over the age of 18 are eligible. Donors will be selected amongst family members. Full HLA typing of patients and donors will occur as will chimerism assessments. 1-2x108 CD3+ cells/kilogram will be infused on Day 0 without preconditioning. Patients will be monitored for their response to therapy, in particular for the development of a cytokine release syndrome (CRS) that has been previously described. Blood samples will be taken at the onset, during, and following the cessation of CRS so as to study effector cells, cytokine/chemokine release patterns, and extracellular vesicle populations. Initially, six patients will be enrolled on study to determine safety. Provided the treatment is deemed safe, a total of 25 patients will be enrolled to determine efficacy.
  
  
  CONCLUSIONS
  Cellular Immunotherapy for Refractory Hematological Malignancies provides a novel treatment for patients with relapsed/refractory acute leukemia or aggressive lymphoma. We believe this therapy offers the immunological benefit of bone marrow transplantation without the deleterious effects of myeloablative conditioning regimens and minus the risk of GVHD. Laboratory correlative studies will be performed in conjunction with the clinical trial to determine the underlying mechanism of action. This provides a true bench to bedside approach that should serve to further enrich knowledge of host tumor tolerance and mechanisms by which this may be overcome.
  
  
  BACKGROUND
  NCT01685606.
authors.affiliation: Division of Hematology/Oncology, Rhode Island Hospital/The Miriam Hospital, The Warren Alpert Medical School of Brown University, Providence, RI, USA. jreagan@lifespan.org
authors.forename: John L
authors.initials: JL
authors.lastname: Reagan
authors.forename: Loren D
authors.initials: LD
authors.lastname: Fast
authors.forename: Howard
authors.initials: H
authors.lastname: Safran
authors.forename: Martha
authors.initials: M
authors.lastname: Nevola
authors.forename: Eric S
authors.initials: ES
authors.lastname: Winer
authors.forename: Jorge J
authors.initials: JJ
authors.lastname: Castillo
authors.forename: James N
authors.initials: JN
authors.lastname: Butera
authors.forename: Matthew I
authors.initials: MI
authors.lastname: Quesenberry
authors.forename: Carolyn T
authors.initials: CT
authors.lastname: Young
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Quesenberry
mesh_terms: D006085:Graft Survival; D006086:Graft vs Host Disease; D019337:Hematologic Neoplasms / Q000628:therapy*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D015470:Leukemia, Myeloid, Acute / Q000628:therapy*; D012074:Remission Induction; D015203:Reproducibility of Results; D012107:Research Design; D033581:Stem Cell Transplantation / Q000379:methods