Demystifying Medicine 2019 Cellular Immunotherapy of Cancer - PowerPoint PPT Presentation

Demystifying Medicine 2019 Cellular Immunotherapy of Cancer

Improved Survival by Study Era 100 1996-2000 1989-1995 80 1983-1988 60 1978-1983 1975-1977 40 1972-1975 20 1970-1972 1968-1970 0 0 2 4 6 8 10 12 Data courtesy of GH Reaman, H Sather, Children ’ s Oncology Group

Sun/Whitlock, Leukemia, 2018

Blinatumomab

TCR vs CAR-T Cell Structure Fesnak et al. Nature Review Clin. Oncology, 2016

Image, Courtesy of NIH Medical Arts

CD19 CAR Clinical Updates (NCI-POB) Lee et al. Lancet 2015 67% CR rate (ITT) All responders with CRS

CD19 CAR Clinical Updates (Novartis) 81% Complete remission rate (not ITT)

Cytokine Release Syndrome Images, Courtesy of NIH Mediccal Arts Lee/Mackall Lancet 2015

Oh Where… Oh Where... Has my CD19 gone? Sotillo/Thomas-Tikhonenko, Cancer Discovery 2015

Lineage Switch (ALL à AML) • MLL -rearranged B-ALL (11q23) rearrangement • “Infant” ALL à VERY poor prognosis • Gardner et al. • 7 of 7 with MLLr -ALL attained MRD neg CR post –CD19 CAR • Relapses seen in 2 with myeloid phenotype • Similar experience seen in MLLr -ALL treated with blinatumomab • Jacoby et al. • CD19 CAR immune pressure induces lineage switch Gardner/Turtle, Blood 2015 O’Brien, Pediatric Blood Cancer 2016 Jacoby/Fry Nat Commun 2016

100 Absolute change in marrow blasts (%) 50 Dose Level 1 Dose Level 2 Dose Level 3 # # # # # # # # # * 0 No CRS Grade 1 CRS Grade 2 CRS -50 -100 8 5 6 3 2 7 0 1 4 2 7 8 9 3 4 5 6 9 0 1 1 Patient # 1 1 1 1 1 1 1 1 1 2 2 1 Individual ALL patients (n=21) Fry TJ, Nat. Medicine 2018

CD22 Antigen Expression at Relapse • Decrease in Site Density Patient 2 10000 Patient 8 Patient 11 CD22 Site Density, Sites/cell Patient 9 • Antigen loss 1000 Patient 15 • Both 100 • No 10 1 Pre-Treatment Relapse

Options for Simultaneous Targeting of CD19 and CD22 (Fry Lab) Bivalent-Bispecific Receptor + Co-administration Co-expression

Phase 1 Dose Escalation Study of Anti-CD19/CD22 Chimeric Antigen Receptor (CAR) T Cells in Children and Young Adults with Recurrent or Refractory CD19/CD22-expressing B Cell Malignancies • Hypothesis: Simultaneous Loop CAR: Linker 1 Linker 2 Linker 1 CD22VH CD22VL CD19VL CD19VH CD3 z targeting of CD19 and CD22 CD8 4-1BB 5 aa 18 aa 5 aa could diminish the risk of CD22VH CD19VL CD19VH CD3 z CD22VL CD8 4-1BB antigen loss escape • Novel bivalent, bispecific CAR None CD19 CD22 Loop CAR Day 3 to be tested in the clinic Day 6 • Actively enrolling Day 10 Day 17 XXXXX Day 23 Activity of Bispecific CAR: In vivo activity against CD19+/22+ B-ALL Qin et. al. Molecular Therapy Oncolytics

Acknowledgements • Terry J. Fry • Steve Highfill • Brigitte Widemann • David Stroncek • John Glod • Haiying Qin • Haneen Shalabi • Naoza Collins-Johnson • Bonnie Yates • Staci Martin • Cindy Delbrook • Lori Wiener • Maryalice Stetler-Stevenson • Sima Zadeh • Constance Yuan • Joan Galil A special thanks to all our patients, • Leah Hoffman • KamilleWest particularly those who are no longer with Cathy Cantilena • Pamela Wolters us, their families and referring teams. • Paul Jarosinski • Crystal L. Mackall Their memory lives on in our work. • Nursing • Daniel ”Trey” Lee • Rimas Orentas