Ospedale Pediatrico Bambino Gesù, Rome, Italy, 2. Bellicum Pharmaceuticals Inc., Houston, United States

Transcription

1 Impact of Post-Transplant Infusion of Donor T-Cells Genetically Modified with Inducible Caspase 9 Suicide Gene (BPX-501 Cells) on Children with Leukemia Given αβ T-Cell and B-Cell Depleted Haplo-HSCT Pietro Merli* 1, Alice Bertaina 1, Federica Galaverna 1, Mattia Algeri 1, Daria Pagliara 1, Giuseppina Li Pira 1, John Weinberg 2, Annemarie Moseley 2, Franco Locatelli 1 1 Ospedale Pediatrico Bambino Gesù, Rome, Italy, 2 Bellicum Pharmaceuticals Inc., Houston, United States

2 Haploidentical Transplant and BPX-501: Meeting Unmet Needs 1. Haplo donor readily available for patients who do not have matched donor 2. Wide use of haplo-hsct in children has been impaired to date by: High risk of GvHD morbidity/mortality with unmanipulated graft containing high T-cell numbers; Increased risk of non-engraftment, slow immune reconstitution and infections when T-cell depletion was employed. 3. Depletion of TCRαβ T cells from allograft and infusion of donor BPX-501 T cells transduced with icaspase9 suicide gene Specific T-cell depletion reduced GVHD; Enhanced immune reconstitution cellular and humoral. 4. In the event of uncontrolled GvHD due to BPX-501 (CD3+CD19+ T cells), rimiducid eliminates BPX-501 cells and resolves GvHD quickly and effectively

3 BPX-501 CaspaCide T cells ic9 Suicide Gene Caspase 9 CD19 Inducible Binding site for Rimiducid starts caspase apoptosis cascade Truncated CD19 marker allows selection for purity and tracking in blood From normal donor leukapheresis -- GMP facilities US / Europe Activated and expanded in culture, transduced with the ic9 suicide gene and selected for CD19+ cells Cryopreserved and stored in liquid nitrogen Maintain characteristics of normal T cells Broad T-cell repertoire Antiviral and antigen specific activity

4 BPX-501 after αβ+ T-cell depleted Haplo-HSCT

5 EU BP-004 Study Design Phase I portion: Classical 3+3 design 2.5 X 10 5, 5 X 10 5 & 1 X 10 6 BPX-501 T Cells/kg Phase II portion: MTD/RD 1 X 10 6 BPX-501 T Cells/kg 1. EU BP-004 centers: OBPG-Rome, GOSH-London, Great Northern-Newcastle 2. Haploidentical donor (usually a parent) 3. Non-mobilized apheresis for BPX-501 product 4. TCRαβ/CD19 B-cell Depleted Allograft 5. BPX-501 T cells Infused Day post Tx 6. No Post-Transplant GVHD Prophylaxis 7. Rimiducid (AP1903) Used for Uncontrollable GVHD

6 EU BP-004 Leukemia Patient Demographics N % Patients 47 Gender M/F 25 /22 53% / 47% Median Age (yrs) 7.8 ( ) Conditioning Regimen Busulfan-based 12 25% TBI-based 30 64% Other 5 11% Median Follow-up (months)* 11 (4-28) * surviving patients

7 EU BP-004 Leukemia Patient Demographics - Continued N % Disease ALL 28 (60%) Ph+ 4 (8%) t(4:11) 2 (4%) Infant MLL 3 (6%) AML 19 (40%) M0/M7 2 (4%) 7-/complex karyotype 2 (4%) FLT3+ 2 (4%) t(5:11) 1 (2%) MLL-PTD 1 (2%) CR at HSCT 47 (100%) CR1/CR2 21/26 (45/55%)

8 EU BP-004 Leukemia Patients: HSCT Donor Characteristics Donors N=47 Median Age (yrs) 37 (19-53) Donor Mother 24 (51%) Father 18 (39%) Sibling 5 (10%) Sex Mismatch 19 (40%) Female Male 12 (25%)

9 EU BP-004 Leukemia Donor Characteristics - Continued Donors N=47 NK Alloreactivity YES 25/47 (53%) NO 22/47 (47%) Genotype A/A 6/47 (13%) B/X 41/47 (87%)

10 EU BP-004 Leukemia Patient Outcomes: Engraftment Median Neutrophil Recovery = 16 days (9-24) Median platelet engraftment = 11 days (8-19) Median time to discharge = 21.5 days (14-103)

11 EU BP-004 Leukemia Patient Outcomes: GVHD

12 Uncontrolled agvhd due to BPX-501: Use of Rimiducid c e lls /m c l c e lls /m c l C D 3 + C D Rimiducid infusion C D 3 + C D C D 3 + C D C D 4 + C D 3 + C D C D BPX infusion D a y s a fte r H S C T b e fo re A P h a fte r A P h a fte r A P h a fte r A P Pre-rimiducid infusion Post-rimiducid infusion Rapid resolution of GVHD, recovery of non-alloreactive T cells without recurrence of GVHD

13 Recovery of Non-Alloreactive BPX-501 T cells after Rimiducid Rimiducid infusion Patient treated with rimiducid for agvhd Prompt resolution of symptoms Recovery of BPX-501 T cells to prior levels at 90 days after rimiducid infusion No recurrence of GVHD

14 EU BP-004 Leukemia Patient Outcomes: Relapse Cumulative Incidence of NRM Cumulative Incidence Incidence of NRM of Relapse A B A Cumulative incidence of relapse in historical leukemia patients treated with αβ TCR depletion only no BPX B Locatelli F. et al, Blood 2017 in press

15 EU BP-004 Leukemia Patient Outcomes: NRM Cumulative Incidence of NRM Cumulative Incidence of NRM Cumulative Incidence of Relapse A B A Cumulative incidence of NRM in historical leukemia patients treated with αβ TCR depletion only no BPX B Locatelli F. et al, Blood 2017 in press

16 EU BP-004 Leukemia Patient Outcomes: OS and LFS

17 EU BP-004 Leukemia Patient Outcomes: Summary Good engraftment with rapid hematological reconstitution Low incidence of acute, rescuable, GvHD Low incidence of extensive chronic GvHD Comparable low rate of NRM with respect to historical controls Re-expansion of BPX-501 cells after a sharp decrease following infusion of the dimerizing agent, without new GvHD flare Lower relapse rate in leukemia patients in comparison to historical controls

18 Department of Hemato-Oncology, IRCCS Bambino Gesù Children s Hospital, Rome BMT UNIT Franco Locatelli Alice Bertaina Letizia Brescia Barbarella Lucarelli Daria Pagliara Giuseppe Milano Mattia Algeri Federica Galaverna GRAFT MANIPULATION Giusy Li Pira Elia Girolami Elisabetta Cicchetti Simone Biagini Gian Pietro Conflitti David Malaspina Immunomonitoring Concetta Quintarelli Valentina Bertaina Matilde Sinibaldi Lorenzo Moretta DONOR SELECTION University of Genoa, IST and G. Gaslini Alessandro Moretta Michela Falco Daniela Pende Clinical Trial Study Coordinators Valentina Cirillo Maria Pia Cefalo