Nonengraftment Haploidentical Cellular Immunotherapy for Refractory Malignancies: Tumor Responses without Chimerism

Abstract

Allogeneic bone marrow transplantation relies on immunosuppression, which controls graft-versus-host disease (GVHD) and allows engraftment at the expense of diminished graft versus-tumor (GVT) activity. Advances in hematologic transplantation have prompted the development of effective, less-toxic regimens that attempt to balance GVH and GVT immunoreactions. We analyzed the safety and efficacy of haploidentical transplantation in a Phase I/II nonimmunosuppressive, nonmyeloablative setting. A total of 41 patients with relapsed refractory cancer received 100 cGy of total body irradiation (TBI), along with an infusion of 1 x 10(6) to 2 x 10(8) CD3+ cells/kg; 29 patients received the highest dose. A postinfusional cellular graft rejection syndrome resembling engraftment syndrome was noted at the 2 highest CD3+ infusion cohorts. There were 26 patients with hematologic malignancies with 14 responses, 9 of which were major. Two of 6 patients with lymphoma remained free of disease at 76 months and 82 months, respectively; there were 5 durable complete responses and 4 partial responses in 13 patients with acute myelogenous leukemia (AML). All responses occurred outside of donor chimerism. TBI at 100 cGy followed by HLA-haploidentical immunotherapy is a biologically active therapy for patients with refractory AML and lymphoma. Possible mechanisms contributing to its effectiveness include initial GVT kill, breaking of host tolerance to tumor through cross-reactive alloreactive responses, persistent nondetectable microchimerism, or some combination of these.

A 2-step approach to myeloablative haploidentical stem cell transplantation: a phase 1/2 trial performed with optimized T-cell dosing

“…In the Colvin et al study, this phenomenon was observed when the CD3 dose reached 1 ϫ 10 8 /kg and was most pronounced at 2 ϫ 10 8 /kg, the dose used in this trial. 37 Similar febrile reactions were not reported by O'Donnell et al, 29 probably because their median T-cell dose was 5-fold lower than that used in our trial.…”

Adoptive immunotherapy for myeloid malignancies

“…Previous work has shown the infusion of allogeneic matched and haploidentical peripheral blood stem cells with minimal conditioning can result in durable responses for patients with refractory leukemia/lymphoma in the absence of engraftment. [1][2][3][4] Furthermore, responders to therapy demonstrated a robust cytokine release syndrome that is similar to that seen in chimeric antigen receptor-modified T cells in its involvement of the release of interferon-γ (IFN-α) and interleukin-6 (IL-6). 2,5 Based on the loss of chimerism in responders, we hypothesize that the mechanism of action behind response is via the generation of a host versus tumor and not a graft versus tumor response.…”

“…Previous work has shown the infusion of allogeneic matched and haploidentical peripheral blood stem cells with minimal conditioning can result in durable responses for patients with refractory leukemia/lymphoma in the absence of engraftment. [1][2][3][4] Furthermore, responders to therapy demonstrated a robust cytokine release syndrome that is similar to that seen in chimeric antigen receptor-modified T cells in its involvement of the release of interferon-γ (IFN-α) and interleukin-6 (IL-6).2,5 Based on the loss of chimerism in responders, we hypothesize that the mechanism of action behind response is via the generation of a host versus tumor and not a graft versus tumor response.Our current cellular therapy protocol seeks to further develop cellular infusion as a form of immunotherapy for refractory hematological malignancies. 6 Patients are enrolled in an already FDA and institutional review board-approved trial that utilizes peripheral blood mononuclear cells (PBMNC) collected from human leukocyte antigen-haploidentical donors.…”

Cooperation of CD4+ T cells and CD8+ T cells and release of IFN-γ are critical for antileukemia responses of recipient mice treated by microtransplantation

“…As the incidence of acute myeloid leukemia (AML) increases with age, the majority of AML patients have numerous types of comorbidities and are less tolerant to high-intensity consolidation and allo-SCT, leading to a significantly worse prognosis. Microtransplantation, also known as human leucocyte antigen (HLA)-partially matched donor leucocyte infusion (DLI), is a fractional infusion of small amounts of allogeneic hematopoietic stem cells and has rapidly developed in recent years (2)(3)(4)(5)(6). In 2011, Guo et al (7) as well as Mackinnon and Chakraverty (8) first reported that the 2-year overall survival (OS) rate in elderly patients with AML increased from 11 to 39% with microtransplantation following chemotherapy.…”