D. Scott. Wilbur

Purpose: Relapse is the dominant cause of failure after allogeneic hematopoietic cell transplantation (HCT) for aggressive hematologic malignancies. CD45-directed radioimmunotherapy (RIT) has been investigated to intensify conditioning and augment antitumor efficacy. After gaining clinical experience with β-emitting radionuclides, attention is now shifting toward α-emitters, such as astatine-211 ( ²¹¹ At), for their more potent and precise radiation delivery with minimized toxicity to surrounding tissues. Patients and Methods: To our knowledge, in this first-in-human, two-stage dose-finding study, we administered a single infusion of ²¹¹ At-labeled anti-CD45 monoclonal antibody before nonmyeloablative conditioning with fludarabine/2-3 Gy total body irradiation and allografting from HLA-matched or single-allele–mismatched donors in 45 adults (38-74 years of age) at a high relapse risk from myeloid malignancies or acute leukemia. Results: Seventeen patients were treated in stage I with 85-591 μCi/kg of ²¹¹ At. The patient receiving 591 μCi/kg developed veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), thereby establishing 500 μCi/kg as the protocol-defined maximum tolerated dose and prompting initiation of stage II at that dose in 28 patients. Infusion reactions were mild. ²¹¹ At-CD45 RIT did not delay hematopoietic recovery, impair donor chimerism, or increase graft-versus-host disease (GVHD) rates. In stage II, six patients (all receiving sirolimus as part of GVHD prophylaxis for unrelated donor HCT) experienced VOD/SOS. Among the 13 patients with circulating blasts at baseline, blasts cleared in 12 before initiation of fludarabine/total body irradiation, demonstrating immediate cytotoxic activity. Estimated 1-year relapse-free and overall survival were 42% (95% CI, 28%-56%) and 49% (34%-62%), respectively. Conclusion: ²¹¹ At-CD45 RIT can be incorporated into nonmyeloablative conditioning, with liver toxicity defining activity limits. Evidence of antitumor efficacy supports phase II evaluation.

Background: We are developing cytotoxic immunoconjugates (CICs) to eliminate HIV-infected cells. We investigated the efficacy and kinetics of killing by different forms of CICs targeted by the same monoclonal antibody (mAb), an immunotoxin (IT), antibody-drug conjugate (ADC), and radioimmunoconjugate (RIC). Methods: We compared in vitro effects of CICs made by conjugating anti-gp41 mAb 7B2 to deglycosylated ricin A chain (7B2-dgA), the anthracycline derivative PNU-159682 (7B2-PNU), or the α-emitting isotope actinium-225 (7B2-²²⁵Ac). Kinetic analyses of cell growth were performed measuring electrical impedance every 15 min over a 7-day period using cells stably expressing the HIV envelope and Env-negative parent cells. Results: 7B2-dgA and 7B2-²²⁵Ac were more potent and acted more rapidly to kill cells than 7B2-PNU. Both the 7B2-PNU and 7B2-²²⁵Ac induced bystander-cell killing, whereas the IT did not and consequently allowed the outgrowth of Env-negative cells. Low dose or brief exposure to 7B2-PNU resulted in an increased rate of cell growth. Conclusions: An IT, ADC, and RIC showed substantial differences in the degree of specific toxicity, kinetics, and mechanisms of killing. The results of this side-by-side comparison have implications for the development of CICs to treat HIV, as well as other conditions.

Terbium-161 (¹⁶¹Tb) is emerging as a promising radionuclide for cancer therapy due to its favorable nuclear properties that are similar to clinically established lutetium-177 (¹⁷⁷Lu) along with its therapeutic edge arising from the higher number of Auger and conversion electrons per decay. These low energy electrons result in higher cytotoxicity within a short range of the decaying nuclei to enhance therapeutic efficacy. Despite these promising characteristics, a significant challenge remains in the lack of a domestic ¹⁶¹Tb supply in the United States, which poses an obstacle to the advancement of ¹⁶¹Tb-based radiopharmaceutical research and development. This study developed a reliable cation-exchange high-performance liquid chromatography-based method for purification of reactor-produced ¹⁶¹Tb at quantities suitable to support research and preclinical studies. The purified ¹⁶¹Tb product showed high radionuclidic purity with excellent radiochemical purity, and the successful labeling studies with the DOTA chelator and DOTA-TATE peptide demonstrated the effective incorporation of the purified ¹⁶¹Tb into radiopharmaceuticals designed for targeted cancer therapy.

Purpose:Hematopoietic cell transplantation (HCT) has curative potential for myeloid malignancies, though many patients cannot tolerate myeloablative conditioning with high-dose chemotherapy alone or with total-body irradiation (TBI). Here we report long-term outcomes from a phase I/II study using iodine-131 (131I)-anti-CD45 antibody BC8 combined with nonmyeloablative conditioning prior to HLA-haploidentical HCT in adults with high-risk relapsed/ refractory acute myeloid or lymphoid leukemia (AML or ALL), or myelodysplastic syndrome (MDS; ClinicalTrials.gov, NCT00589316).Patients and Methods:Patients received a tracer diagnostic dose before a therapeutic infusion of 131I­anti-CD45 to deliver escalating doses (12–26 Gy) to the dose-limiting organ. Patients subsequently received fludarabine, cyclophosphamide (CY), and 2 Gy TBI conditioning before haploidentical marrow HCT. GVHD prophylaxis was posttransplant CY plus tacrolimus and mycophenolate mofetil.Results:Twenty-five patients (20 with AML, 4 ALL and 1 high-risk MDS) were treated; 8 had ≥ 5% blasts by morphology (range 9%–20%), and 7 had previously failed HCT. All 25 patients achieved a morphologic remission 28 days after HCT, with only 2 patients showing minimal residual disease (0.002–1.8%) by flow cytometry. Median time to engraftment was 15 days for neutrophils and 23 days for platelets. Point estimates for overall survival and progression-free survival were 40% and 32% at 1 year, and 24% at 2 years, respectively. Point estimates of relapse and nonrelapse mortality at 1 year were 56% and 12%, respectively.Conclusions:131I-anti-CD45 radioimmunotherapy prior to haploidentical HCT is feasible and can be curative in some patients, including those with disease, without additional toxicity.

Supplementary Table S1: Study Representativeness Table

Supplementary Table S2: Recipient - Donor Characteristics

Supplementary Figure S1: Outline of Treatment Plan

Supplementary Table S1: Study Representativeness Table

Purpose:Hematopoietic cell transplantation (HCT) has curative potential for myeloid malignancies, though many patients cannot tolerate myeloablative conditioning with high-dose chemotherapy alone or with total-body irradiation (TBI). Here we report long-term outcomes from a phase I/II study using iodine-131 (131I)-anti-CD45 antibody BC8 combined with nonmyeloablative conditioning prior to HLA-haploidentical HCT in adults with high-risk relapsed/ refractory acute myeloid or lymphoid leukemia (AML or ALL), or myelodysplastic syndrome (MDS; ClinicalTrials.gov, NCT00589316).Patients and Methods:Patients received a tracer diagnostic dose before a therapeutic infusion of 131I­anti-CD45 to deliver escalating doses (12–26 Gy) to the dose-limiting organ. Patients subsequently received fludarabine, cyclophosphamide (CY), and 2 Gy TBI conditioning before haploidentical marrow HCT. GVHD prophylaxis was posttransplant CY plus tacrolimus and mycophenolate mofetil.Results:Twenty-five patients (20 with AML, 4 ALL and 1 high-risk MDS) were treated; 8 had ≥ 5% blasts by morphology (range 9%–20%), and 7 had previously failed HCT. All 25 patients achieved a morphologic remission 28 days after HCT, with only 2 patients showing minimal residual disease (0.002–1.8%) by flow cytometry. Median time to engraftment was 15 days for neutrophils and 23 days for platelets. Point estimates for overall survival and progression-free survival were 40% and 32% at 1 year, and 24% at 2 years, respectively. Point estimates of relapse and nonrelapse mortality at 1 year were 56% and 12%, respectively.Conclusions:131I-anti-CD45 radioimmunotherapy prior to haploidentical HCT is feasible and can be curative in some patients, including those with disease, without additional toxicity.