Allogeneic stem cell transplantation (SCT) can be curative for high-risk (HR) hematologic malignancies, but until recently, access was limited to fully matched donors. The introduction of ...post-transplant cyclophosphamide (PTCy) has enabled patients to receive SCT using haploidentical (haplo) related donors; however, outcomes remain disappointing. Orca-Q, an investigational precision engineered cell therapy, represents an alternative strategy. The cellular composition of Orca-Q consists of enriched CD34+ stem cells, combined with specific T-cell subsets, manufactured from mobilized peripheral blood, and is intended to reconstitute the blood and immune systems.
Adults (18 to 65) with HR hematologic malignancies were enrolled on the haplo arm of a multicenter phase 1 study of Orca-Q (NCT03802695). Haplo was defined as ≥ 4/8 but < 7/8 matched related donor at HLA A, -B, -C, and -DRB1 typed using DNA-based high-resolution. Patients received MAC and single agent GVHD prophylaxis with tacrolimus.
21 patients (11 AML, 8 ALL, 2 CML in blast crisis), all 4/8 HLA matched, were enrolled between 1/2019 to 7/2022. Orca-Q was successfully manufactured centrally and delivered to all patients with vein-to-vein time of < 72 hours. Median age was 44 (range, 21 – 63) years, 57% were male. Median follow-up was 333 (range, 39 – 1020) days. DRI score was high/very-high in 5; intermediate in 13 (low-risk, 2; N/A, 1). All patients engrafted; median time of 13 (range, 8 – 25) and 16 (range, 12 – 25) days for neutrophil and platelet engraftment, respectively. Gr 3-4 aGvHD was rare with only 1 event of gr 3 aGvHD. Of 16 patients who had > 3 months follow-up, only 1 developed mild cGvHD. No patients had moderate-tosevere cGvHD. Estimated incidence of BMTCTN MOP3 infections was 27% at 1yr. 2 patients died from relapsed disease during the study period. The 1-year GvHD-and-relapse free survival (GRFS) was 71%.
Our findings suggest encouraging safety and efficacy outcomes using Orca-Q cell therapy for haplo-SCT, without PTCy, and only single agent tacrolimus. Patients treated with Orca-Q experienced a low adverse event profile, low incidence of overall and severe aGvHD/cGvHD, and improved GRFS. This phase 1 study continues to enroll patients across the US.
Chimeric antigen receptor (CAR) T cells targeting CD22 (CD22-CAR) provide a therapeutic option for patients with CD22
malignancies with progression after CD19-directed therapies. Using on-site, ...automated, closed-loop manufacturing, we conducted parallel Phase 1b clinical trials investigating a humanized CD22-CAR with 41BB costimulatory domain in children and adults with heavily treated, relapsed/refractory (r/r) B-ALL. Of 19 patients enrolled, 18 had successful CD22-CAR manufacturing, and 16 patients were infused. High grade (3-4) cytokine release syndrome (CRS) and immune effector-cell-associated neurotoxicity syndrome (ICANS) each occurred in only one patient; however, three patients experienced immune-effector-cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS). Twelve of 16 patients (75%) achieved CR with an overall 56% MRD-negative CR rate. Duration of response was overall limited (median 77 days), and CD22 expression was downregulated in 4/12 (33%) available samples at relapse. In summary, we demonstrate that closed-loop manufacturing of CD22-CAR T cells is feasible and is associated with a favorable safety profile and high CR rates in pediatric and adult r/r B-ALL, a cohort with limited CD22-CAR reporting.
Identifying plasma biomarkers early after allo-HCT may become crucial to prevent and treat severe aGvHD. We utilized samples from 203 allo-HCT patients selected from the Blood & Marrow Transplant ...Clinical Trials Network (BMT CTN) to identify new biomarker models to predict aGvHD and overall mortality. Two new biomarkers (Gal-3 and LAG-3), and previously identified biomarkers (ST2/IL33R, IL6, Reg3A, PD-1, TIM-3, TNFR1) were screened. Increased Gal-3 levels measured at Day +7 post-transplant predicted the development of aGvHD (grade 2-4) in the total population AUC: 0.602; P = 0.045 while higher Day +14 levels predicted overall mortality due to toxicity among patients receiving reduced intensity conditioning P = 0.028 but not myeloablative conditioning. Elevated LAG-3 levels (Day +21) were associated with less severe aGvHD 159.1 ng/mL vs 222.0 ng/mL; P = 0.046. We developed a model utilizing Gal-3, LAG-3, and PD-1 levels at Days +14 and +21 with an improved performance to predict aGvHD and overall non-relapse mortality. We confirmed four informative biomarkers (Reg3A, ST2, TIM-3, and TNFR1) predict severe aGvHD at day +14 and day +21 (grade 3-4). In conclusion, the combination of Gal-3 alone or in combination with LAG-3, and PD-1 is a new informative model to predict aGvHD development and overall non-relapse mortality after allo-HCT.
•This is the first study to evaluate the role of the Hematopoietic Cell Transplantation–Specific Comorbidity Index in patients uniformly receiving nonmyeloablative conditioning•This is the largest ...study of a single cohort of patients receiving nonmyeloablative conditioning with total lymphoid irradiation/antithymocyte globulin regimen•The Hematopoietic Cell Transplantation–Specific Comorbidity Index in nonmyeloablative setting is associated with all-cause mortality but not with nonrelapse mortality
The Hematopoietic Cell Transplantation (HCT)–Specific Comorbidity Index (HCT-CI) has been extensively studied in myeloablative and reduced-intensity conditioning regimens, with less data available regarding the validity of HCT-CI in nonmyeloablative (NMA) allogeneic transplantation. We conducted a retrospective analysis to evaluate the association between HCT-CI and nonrelapse mortality (NRM) and all-cause mortality (ACM) in patients receiving the total lymphoid irradiation and antithymocyte globulin (TLI/ATG) NMA transplantation preparative regimen. We abstracted demographic and clinical data from consecutive patients, who received allogeneic HCT with the TLI/ATG regimen between January 2008 and September 2014, from the Stanford blood and marrow transplantation database. We conducted univariable and multivariable Cox proportional hazards regression models to evaluate the association between HCT-CI and NRM and ACM. In all, 287 patients were included for analysis. The median age of the patients was 61 (range, 22 to 77) years. The median overall survival was 844 (range, 374 to 1484) days. Most patients had Karnofsky performance score of 90 or above (85%). Fifty-two (18%) patients relapsed within 3 months and 108 (38%) patients relapsed within 1 year, with a median time to relapse of 163 (range, 83 to 366) days. Among the comorbidities in the HCT-CI identified at the time of HCT, reduced pulmonary function was the most common (n = 89), followed by prior history of malignancy (n = 39), psychiatric condition (n = 38), and diabetes (n = 31). Patients with higher HCT-CI scores had higher mortality risks for ACM (hazard ratio HR, 1.95; 95% confidence interval CI, 1.22 to 3.14 for HCT-CI score 1 or 2 and HR, 1.85; 95% CI, 1.11 to 3.08 for HCT-CI score ≥ 3, compared with 0, respectively). Among individual HCT-CI variables, diabetes (HR, 2.31; 95% CI, 1.79 to 2.89; P = .003) and prior solid tumors (HR, 1.75; 95% CI, 1.02 to 3.00; P = .043) were associated with a higher risk of ACM. Higher HCT-CI scores were significantly associated with higher risk of death. HCT-CI is a valid tool for predicting ACM in NMA TLI/ATG allogeneic HCT.
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