Faculty. Immuno-Oncology Scientific Updates: An Introduction to CAR T-Cell Therapy. June 2018

Transcription

1 ASCP Scientific Updates: An Introduction to CAR -Cell herapy June 2018 Immuno-Oncology Scientific Updates: An Introduction to CAR -Cell herapy June 2018 Faculty Andrew Fesnak, MD Assistant Professor of Clinical Pathology and Laboratory Medicine University of Pennsylvania Perelman School of Medicine 1

2 ASCP Scientific Updates: An Introduction to CAR -Cell herapy June 2018 Speaker Disclosures In the past 12 months, the following speakers have not had a significant financial interest or other relationship with the manufacturer(s) of the product(s) or provider(s) of the service(s): Andrew Fesnak, MD Learning Objectives asic understanding of CAR cell iology and design Current targets Manufacturing Future directions 2

3 ASCP Scientific Updates: An Introduction to CAR -Cell herapy June 2018 What are CAR cells? A Chimeric Antigen Receptor is an artificial molecule that combines cell-derived and cell-derived domains and functions. What are CAR cells? cell activation 3

4 ASCP Scientific Updates: An Introduction to CAR -Cell herapy June 2018 What are CAR cells? cell activation Opsonization Neutralization Fixation What are CAR cells? cell activation APC Opsonization Neutralization Fixation 4

5 ASCP Scientific Updates: An Introduction to CAR -Cell herapy June 2018 What are CAR cells? cell activation APC Opsonization Neutralization Fixation What are CAR cells? cell activation APC Opsonization Neutralization Fixation 5

6 ASCP Scientific Updates: An Introduction to CAR -Cell herapy June 2018 What are CAR cells? cell activation APC Opsonization Neutralization Fixation What are CAR cells? Putting it all together Fesnak, A.D., June, C.H. and Levine,.L., Engineered cells: the promise and challenges of cancer immunotherapy. Nature Reviews Cancer, 16(9), p.566. Highly specific MHC independent Durable activation 6

7 ASCP Scientific Updates: An Introduction to CAR -Cell herapy June 2018 eyond CD19: Hematologic CAR argets ersenev, A. What is the hottest CAR cell therapy target beyond CD Diverse Solid umor CAR argets ersenev, A. What is the hottest CAR cell therapy target beyond CD

8 ASCP Scientific Updates: An Introduction to CAR -Cell herapy June 2018 Common and Challenging Features of argets Varied Extracellular Conserved/specific Fesnak et al Nature Reviews Cancer How are CAR cells manufactured? Reinfusion Apheresis cell enrichment Fesnak et al Nature Reviews Cancer Quality control Expansion Activation, modification 8

9 ASCP Scientific Updates: An Introduction to CAR -Cell herapy June 2018 Evolving Cell Manufacturing echnology Variability and Continuous Improvement Run-to-run variability Continuous technologic improvement Can be costly 9

10 ASCP Scientific Updates: An Introduction to CAR -Cell herapy June 2018 What will next-gen CAR cells look like? Fesnak et al Nature Reviews Cancer CAR cells will be more effective More effective Fesnak et al Nature Reviews Cancer 10

11 ASCP Scientific Updates: An Introduction to CAR -Cell herapy June 2018 CAR cells will be more specific Safer enhanced specificity Fesnak et al Nature Reviews Cancer CAR cells will be better controlled in vivo Safer in vivo control Fesnak et al Nature Reviews Cancer 11

12 ASCP Scientific Updates: An Introduction to CAR -Cell herapy June 2018 Some CAR cells will be Allogeneic Allogeneic Endogenous CR -> GVHD? Endogenous HLA -> rejection? Fesnak et al Nature Reviews Cancer Universal CAR cells in Action Pilot ALEN-mediated disruption of endogenous CR, CD52 Lentiviral DN with CD19-directed CAR Molecular remission by day 28 Skin and marrow GVHD, controlled ridge to allo-transplant UCAR /6 patients with CR d /6 developed CRS; 3/6 neurotoxicity 3/6 prolonged cytopenia 1/6 acute cutaneous GVHD UCAR First PDCN patient developed CRS + capillary leak syndrome and died on day 9 post infusion First AML patient developed CRS + capillary leak syndrome which resolved with treatment by day 12 Clinical hold (Sept 4, 2017) Decrease dose of UCAR, conditioning; change to inclusion criteria to select for more stable patients UCAR22 IND submitted May 2018 UCARCS1 expect mfg in 2018 UCAR38 preclinical development 12

13 ASCP Scientific Updates: An Introduction to CAR -Cell herapy June 2018 Rethinking CAR Design More effective Safer Allogeneic asic understanding of CAR cell iology and design Highly specific MHC independent Durable activation Current targets Varied Extracellular Conserved/specific Manufacturing Run-to-run variability Continuous technologic improvement Can be costly Future developments More effective Safer Allogeneic 13

14 ASCP Scientific Updates: An Introduction to CAR -Cell herapy June 2018 Acknowledgements Clinical Cell and Vaccine Production Facility Megan Davis ruce Levine Don Siegel Andrea rennan Anne Lamontagne Lauren Lewitt Matt O Rourke Clare aylor All the members of the CVPF Division of ransfusion Medicine Don Siegel Nicole Aqui aku Kambayashi Una O Doherty Vijay hoj Immuno-Oncology Scientific Updates: An Introduction to CAR -Cell herapy June