Abstract
Background/Objectives: Relapse of hematologic malignancies after hematopoietic cell transplantation (HCT) confers high mortality because of progressive disease and graft-vs.-host disease (GVHD). Hence, we hypothesized that tumor-associated antigen-specific lymphocytes (TAA-L) would be specific, diminish immune escape, and could safely decrease cancer burden.
Design/Methods: We expanded lymphocytes reactive to TAA: WT1, PRAME, Survivin, which are over-expressed and immunogenic in hematologic malignancies. On a prospective study: NCT002203902, eligible patients received TAA-L infusions at 4 sequential dose levels: 0.5 to 4.0e7/m2 per dose.
Results: Thirty-two donor-derived TAA-L products were generated and lacked alloreactivity in vitro. TAA-L products comprised predominantly effector memory T-cells, with <15% of T-cells expressing exhaustion markers (PD1, TIM3, LAG3). Specificity of TAA-L showed greatest response to PRAME by ELIspot. Eleven HCT recipients (aged 9-70 years) with relapsed: Hodgkin's lymphoma (n=2), B-ALL (n=3), or AML (n=5), or high risk for relapse: AML post 2nd HCT (n=1)) received 1-3 doses of TAA-L. Patients had relapsed 2-12 months after HCT (9 allo, 1 auto) and all received therapy pre-TAA-L. Post infusion, there was only one adverse event possibly attributed to TAA-L (GVHD post viral infection on vidaza). One patient withdrew prior to study completion due to progressive disease with steroids for sepsis. Responses of evaluable patients (n=10) were: PD (n=2), PR (n=3), CR (n=5), with only 1 patient receiving adjunct therapy. Of the CR patients: AML (n=4); one patient who relapsed 10 months post HSCT is in a continuous CR for 314+ days after 3 doses of TAA-L only, one patient cleared peripheral blasts with TAA-L; one patient with Ph+-ALL achieved bcr-abl negativity post TAA-L only for the first time post-HSCT and has a continuous CR with 2 doses of TAA-L for 261 days. Immunosequencing of T-cell receptors showed expansion of TAA-L clones derived from the TAA-L product 4-5 weeks after infusion.
Conclusion: This unique immunotherapeutic has been well tolerated without causing life-threatening cytokine release syndrome. Despite aggressive and multiply relapsed disease, 8/10 evaluable patients have demonstrated evidence of disease control after TAA-L, with 50% complete response, suggesting that TAA-L may have efficacy in relapsed high-risk hematological malignancies after HCT.
Bollard: Torque: Membership on an entity's Board of Directors or advisory committees; Cellectis: Membership on an entity's Board of Directors or advisory committees; Neximmune: Consultancy, Membership on an entity's Board of Directors or advisory committees.
Author notes
Asterisk with author names denotes non-ASH members.
