Do We Need Full Donor Chimerism? How Alloreactive Cell Therapies without Substantial Engraftment Might Treat Hematologic Cancers.
"Alloreactive cell therapy without substantial engraftment"; (ACT-WiSE) refers to adoptive transfer of natural ("non-engineered") human leukocyte antigen-mismatched lymphocytes to mediate anti-neoplastic alloreactivity in recipients without employing pharmacologic immunosuppression. By definition, ACT-WiSE entails subsequent rejection of most, if not all, donor cells. Macrochimerism is transient and microchimerism may be either short-lived or persistent. This strategy harnesses the anticancer potency of alloreactivity without incurring significant risk of graft-versus-host disease. "Microtransplantation" refers to a form of ACT-WiSE where the donor cell product contains hematopoietic progenitor cells. Microtransplantation therefore accelerates hematopoietic recovery and its immunomodulatory effects may differ from other forms of ACT-WiSE. Recent studies suggest that various forms of ACT-WiSE, including microtransplantation, may improve chemosensitivity in patients with myeloid malignancies, resulting in higher complete remission rates and increased survival. Microtransplantation has also demonstrated promising pilot results in relapsed or refractory Non-Hodgkin and Hodgkin lymphoma. ACT-WiSE and microtransplantation may establish a new class of allogeneic cell therapy of particular relevance to persons not considered candidates for traditional allogeneic hematopoietic cell transplantation (AHCT). Open questions include the optimal timing and cell dose of ACT-WiSE, which donor factors contribute to efficacy, and whether these remissions are durable after eradication of donor cells. We extrapolate from lessons learned in the course of traditional and haploidentical AHCT to propose ways of optimizing ACT-WiSE. We divide these into donor-related strategies (including rational donor selection and boosting NK-cell and T-cell alloreactivity) and patient- related strategies (that may favor development of autologous NK-cell and T-cell mediated anticancer cytotoxicity in the post-ACT-WiSE window).
Elizabeth F
EF
Krakow
Hui-Sheng
HS
Ai
Brian
B
Shaffer
Jean-Sebastien
JS
Delisle
Kai-Xun
KX
Hu
Duke University Medical Center, DUMC Box 3961, Durham, NC 27710, United States.
Anthony D
AD
Sung
D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D046528:Chimerism; D006086:Graft vs Host Disease; D019337:Hematologic Neoplasms / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D014019:Tissue Donors; D014184:Transplantation, Homologous; D016896:Treatment Outcome
Alloreactivity; T cells; graft-vs-host disease; immunotherapy; leukemia; natural killer cells; transplantation; tumorassociated
antigen.