SLIDE 1
Demystifying Medicine 2019 Cellular Immunotherapy of Cancer - - PowerPoint PPT Presentation
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
SLIDE 2
SLIDE 3
SLIDE 4
20 40 60 80 100 2 4 6 8 10 12 1996-2000 1989-1995 1983-1988 1978-1983 1975-1977 1972-1975 1970-1972 1968-1970
Data courtesy of GH Reaman, H Sather, Children’s Oncology Group
Improved Survival by Study Era
SLIDE 5
SLIDE 6
Sun/Whitlock, Leukemia, 2018
SLIDE 7
SLIDE 8
SLIDE 9
SLIDE 10
Blinatumomab
SLIDE 11
Fesnak et al. Nature Review Clin. Oncology, 2016
TCR vs CAR-T Cell Structure
SLIDE 12
Image, Courtesy of NIH Medical Arts
SLIDE 13
CD19 CAR Clinical Updates (NCI-POB)
Lee et al. Lancet 2015 67% CR rate (ITT) All responders with CRS
SLIDE 14
CD19 CAR Clinical Updates (Novartis)
81% Complete remission rate (not ITT)
SLIDE 15
Cytokine Release Syndrome
Images, Courtesy of NIH Mediccal Arts Lee/Mackall Lancet 2015
SLIDE 16
SLIDE 17
SLIDE 18
Oh Where… Oh Where... Has my CD19 gone?
Sotillo/Thomas-Tikhonenko, Cancer Discovery 2015
SLIDE 19
Lineage Switch (ALLà AML)
- MLL-rearranged B-ALL (11q23) rearrangement
- “Infant” ALLàVERY 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
SLIDE 20 1 8 5 6 3 1 2 1 7 1 1 4 2 7 8 9 1 3 1 4 1 5 1 6 1 9 2 2 1 1 1
- 100
- 50
50 100 Individual ALL patients (n=21) Absolute change in marrow blasts (%)
Dose Level 1 Dose Level 2 Dose Level 3
*
# # # # # # # #
No CRS Grade 1 CRS Grade 2 CRS
#
Patient #Fry TJ, Nat. Medicine 2018
SLIDE 21
CD22 Antigen Expression at Relapse
- Decrease in Site Density
- Antigen loss
- Both
- No
Pre-Treatment Relapse
1 10 100 1000 10000
CD22 Site Density, Sites/cell
Patient 2 Patient 8 Patient 9 Patient 11 Patient 15
SLIDE 22
SLIDE 23
SLIDE 24
Options for Simultaneous Targeting
- f CD19 and CD22 (Fry Lab)
+
Co-administration Co-expression Bivalent-Bispecific Receptor
SLIDE 25
Phase 1 Dose Escalation Study of Anti-CD19/CD22 Chimeric Antigen Receptor (CAR) T Cells in Children and Young Adults with Recurrent
- r Refractory CD19/CD22-expressing B Cell Malignancies
- Hypothesis: Simultaneous
targeting of CD19 and CD22 could diminish the risk of antigen loss escape
- Novel bivalent, bispecific CAR
to be tested in the clinic
- Actively enrolling
Activity of Bispecific CAR: In vivo activity against CD19+/22+ B-ALL
None CD19 CD22 Loop CAR Day 3 Day 6 Day 10 Day 17
XXXXX
Day 23
Loop CAR:
5 aa Linker 1 CD19VL CD22VH 18 aa Linker 2 CD22VL 5 aa Linker 1 CD19VH CD8 CD3z 4-1BB CD19VL CD22VH CD22VL CD19VH CD8 CD3z 4-1BBQin et. al. Molecular Therapy Oncolytics
SLIDE 26
SLIDE 27
Acknowledgements
- Terry J. Fry
- Brigitte Widemann
- John Glod
- Haneen Shalabi
- Bonnie Yates
- Cindy Delbrook
- Maryalice Stetler-Stevenson
- Constance Yuan
- Leah Hoffman
- Pamela Wolters
- Crystal L. Mackall
- Daniel ”Trey” Lee
- Rimas Orentas
- Steve Highfill
- David Stroncek
- Haiying Qin
- Naoza Collins-Johnson
- Staci Martin
- Lori Wiener
- Sima Zadeh
- Joan Galil
- KamilleWest
Cathy Cantilena
- Paul Jarosinski
- Nursing
A special thanks to all our patients, particularly those who are no longer with us, their families and referring teams. Their memory lives on in our work.