Adoptive Immunotherapy with Cord Blood for the Treatment of Refractory Acute Myelogenous Leukemia: Feasibility, Safety, and Preliminary Outcomes

Abstract

Adoptive immunotherapy has shown efficacy in patients with relapsed/refractory acute myelogenous leukemia (AML). We conducted a prospective evaluation of cord blood (CB)-based adoptive cell therapy following salvage chemotherapy in patients with AML or myelodysplastic syndrome (MDS) and describe the safety and early outcomes of this approach. To enhance the antileukemic effect, we selected CB units (CBUs) with a shared inherited paternal antigen (IPA) and/or noninherited maternal antigen (NIMA) match with the recipients. Furthermore, the CBUs had total nucleated cell (TNC) dose <2.5 £ 10 7 /kg and were at least 4/6 HLA-matched with the patients; a higher allele-level match was preferred. Heavily pretreated adult patients with AML/MDS were enrolled. CBU searches were performed for 50 patients. CBUs with shared IPA targets were identified for all, and CBUs with NIMA matches were found for 80%. Twenty-one patients underwent treatment (AML, primary induction failure, n = 8; refractory relapse, n = 10, including 7 recipients of previous allogeneic HSCT; blast crisis chronic myelogenous leukemia, n = 1; MDS, n = 2). Most received combination chemotherapy; those not fit for intensive treatment received a hypomethylating agent. Response was defined as <10% residual blasts in hypocellular bone marrow at approximately 2 weeks after treatment. Ten of the 19 evaluable patients responded, including 5 of the 7 recipients of previous transplant. Response was seen in 4 of 4 patients with full CBU-derived chimerism, 2 of 2 of those with partial, low-level chimerism and 4 of 12 of the recipients with no detectable CBU chimerism. The most common adverse events were infections (bacterial, n = 5; viral, n = 2; fungal, n = 5). Grade IV acute graft-versus-host disease (GVHD) developed in 2 patients with full CBU chimerism; 2 other patients had grade 1 skin GVHD. A total of 11 patients died, 7 from disease recurrence and 4 from infections (1 early death; the other 3 in remission at the time of death). Overall, 12 patients proceeded to allogeneic HSCT; of those, 7 had responded to treatment, 3 had not (and had received additional therapy), and 2 had persistent minimal residual disease. In conclusion, the use of CB as adoptive immunotherapy in combination with salvage chemotherapy for patients with refractory AML/MDS is feasible, can induce disease control, can serve as a bridge to allogeneic HSCT, and has an acceptable incidence of adverse events. Alloreactivity was enhanced through the selection of CBUs targeting a shared IPA and/or NIMA match with the patients. CBUs with lower cell doses, already available in the CB bank and unlikely to be adequate grafts for adult transplants, can be used for cell therapy within a short time frame.

Adoptive immunotherapy with CB following chemotherapy for patients with refractory myeloid malignancy: chimerism and response

“…For details, refer to our previous publication. 4 This study was performed under US Food and Drug Administration application 16423 and is registered at www. clinicaltrials.gov as #NCT02508324.…”

“…From June 2015 to December 2019, 38 patients were treated with chemotherapy, followed by infusion of CBU cell therapy; 21 of whom were included in our previous publication. 4 For the purposes of this article, we excluded 3 patients who had measurable disease but no excess blasts, because they were not readily evaluable for response, as defined above. We also excluded 4 additional patients who were deemed unfit to receive intensive chemotherapy and were treated with decitabine-containing regimens.…”

“…In our initial report, we described feasibility, safety, and transient chimerism with a low incidence of acute graftversus-host disease (GVHD) and responses in some refractory patients. 4 In this article, we present updated outcomes on 31 patients who had measurable refractory disease and received intensive salvage chemotherapy followed by CB infusion. We report responses in 13 (42%) of them, in marked contrast with the published low response rates with chemotherapy only, and we identify patient and CB cell therapy characteristics that were associated with response.…”

The potential of cord blood to replenish young immune cells against cancer

“…Although UCB cells are immature, these immature T cells rapidly differentiate in the tumor microenvironment to the stage of memory effector cells. 68 There are five main adoptive cell therapies: (1) allogeneic HSCT; (2) single UCB infusion after chemotherapy for microtransplantation 69,70 ; (3) isolation of tumor infiltration lymphocytes, which are then expanded and reinfused in vitro; (4) the use of T cells genetically modified to express CAR or neoantigen-specific TCR; and (5) in vitro expansion of tumor-specific T cells with tumor-associated antigen. 71 CAR T cell immunotherapy has made remarkable achievements in clinical practice.…”

“…This study suggests that the combination of UCB infusion with lowdose decitabine and intermediate-dose cytarabine may represent a consolidative therapy for elderly patients with AML. In addition, Gergis et al used UCB for the treatment of refractory AML/MDS, 69 showing that UCB is a feasible adoptive immunotherapy. Particularly when combined with salvage chemotherapy, UCB can achieve disease control through an allogenic transfer with the acceptable occurrence of adverse events.…”