Abstract
Abstract Combining targeted therapies with standard of care chemotherapy is a proven method for improving outcomes for cancer patients. SGN-CD19A is an antibody-drug conjugate (ADC) targeting the B-lineage specific marker CD19, and it is currently in phase 1 clinical trials for treatment of B-lineage acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL). HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) is a common frontline chemotherapy regimen used to treat adult ALL. To explore the potential for combining SGN-CD19A with these agents (CVAD) ALL patient-derived xenografts (PDX) were developed, as these models are known to more closely reflect clinical disease. PDX were established by intravenous implant of 1-5×106 unsorted ALL patient bone marrow isolate cells into irradiated NOD scid IL2Rgammanull (NSG) mice. Initially, patient isolates were comprised of a wide-ranging (20-77%) population of CD19+/CD10+/CD45low blast cells and a varied population (5-70%) of CD19+/CD10+/CD45high cells. After implant, cells homed to and expanded in the bone marrow, thereafter progressing into the spleen and peripheral blood. After passage in mice, phenotyping revealed an enrichment of the CD19+/CD10+/CD45low blast cells and a loss of the CD19+/CD10+/CD45high population. These passaged cells were utilized for subsequent activity experiments. To evaluate PDX sensitivity to SGN-CD19A, a single dose at 1, 3 or 10 mg/kg was administered when bone marrow in sentinel animals contained between 5-24% blast cells. Activity was measured by the extent of ALL blast cell reduction in the bone marrow compared to untreated mice. SGN-CD19A elicited a dose-dependent depletion (71-99%) of blast cells in bone marrow by day 14 post dose. Like SGN-CD19A, CVAD also produced a dose-dependent depletion of the ALL blasts. Next, PDX models were used to examine SGN-CD19A in combination with CVAD. SGN-CD19A + CVAD produced a statistically superior depletion of blast cells when compared to SGN-CD19A or CVAD alone. To better understand these combined therapies, NALM-6 and RS4;11 cell line disseminated xenografts were also evaluated. SGN-CD19A + CVAD significantly prolonged survival compared to either single treatment alone in these cell line derived xenografts as well. Remarkably, SGN-CD19A in combination with vincristine (NALM-6, RS4;11) or dexamethasone (RS4;11) resulted in a survival advantage that was similar to that of SGN-CD19A + CVAD. When SGN-CD19A was tested in combination with CVAD and CVAD components in the PDX models, it was observed that SGN-CD19A potentiated the single-agent activity of vincristine, cyclophosphamide and doxorubicin. Together, these data suggest that SGN-CD19A can combine with a frontline ALL chemotherapy regimen and potentially improve outcomes for patients with ALL. Citation Format: Ivan J. Stone, Tina Albertson, Che-Leung Law. Preclinical combination activity of SGN-CD19A and CVAD in patient-derived B-lineage acute lymphoblastic leukemia models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1339. doi:10.1158/1538-7445.AM2015-1339
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