Title:Do We Need Full Donor Chimerism? How Alloreactive Cell Therapies without Substantial Engraftment Might Treat Hematologic Cancers
Volume: 18
Issue: 3
Author(s): Elizabeth F. Krakow, Hui-Sheng Ai, Brian Shaffer, Jean-Sebastien Delisle, Kai-Xun Hu and Anthony D. Sung
Affiliation:
Keywords:
Alloreactivity, graft-vs-host disease, immunotherapy, leukemia, natural killer cells, T cells, transplantation, tumorassociated
antigen.
Abstract: "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).
