1. Suzanne Schauwecker, MD, PhD Blood bank rotation presentation 9/20/18
CAR-T Cell Therapy
Suzanne Schauwecker, MD, PhD
Blood bank rotation presentation
9/20/18

2. Outline Mechanism of CAR T cell therapy Manufacturing process
Challenges of expanding CAR T cell therapy to a larger patient population world-wide
Harmonization of standards nationally and internationally

3. Chimeric antigen receptor (CAR)- T cell therapy
T cells are removed from the patient’s blood
Engineered to express a chimeric antigen receptor
Reprograms T cells to target tumor cells

4. CAR T cell therapy – Where are we?
Tisagenlecleucel (CTL019) is FDA-approved for patients up to 25 years of age with B-cell precursor ALL (refractory or in second or greater relapse) and for patients with DLBCL (relapsed and refractory)
KTE-C19/axicabtagene ciloleucel (axi-cel) is FDA-approved for patients with NHL or DLBCL (relapsed and refractory)
Currently being investigated in several hematologic and solid tumor types
144 current clinical trials in the US, 240 in China, Australia, Austria, Belgium, Canada, France, Germany, Israel, Italy, Japan, Netherlands, Norway, Russia, Singapore, Spain, Sweden, Switzerland, Thailand, United Kingdom
High response rates for B cell malignancies

5. Mechanism of CAR T Cell Therapy
CARs: genetically engineered fusion proteins
Antigen recognition domain derived from a monoclonal antibody
Intracellular T cell signaling and costimulatory domains
Clinical development of anti‐CD19 chimeric antigen receptor T‐cell therapy for B‐cell non‐Hodgkin lymphoma, Volume: 108, Issue: 6, Pages: , First published: 16 March 2017, DOI: ( /cas.13239)

6. Mechanism of CAR T Cell Therapy
CARs: genetically engineered fusion proteins
Antigen recognition domain derived from a monoclonal antibody
Intracellular T cell signaling and costimulatory domains
Clinical development of anti‐CD19 chimeric antigen receptor T‐cell therapy for B‐cell non‐Hodgkin lymphoma, Volume: 108, Issue: 6, Pages: , First published: 16 March 2017, DOI: ( /cas.13239)

7. Mechanism of CAR T Cell Therapy
Engineered to express a chimeric antigen receptor
Reprograms T cells to target tumor cells
Clinical development of anti‐CD19 chimeric antigen receptor T‐cell therapy for B‐cell non‐Hodgkin lymphoma, Volume: 108, Issue: 6, Pages: , First published: 16 March 2017, DOI: ( /cas.13239)

8. CD19: Target for B cells

9. Manufacturing of Tisagenlecleucel

10. T Cell Activation
The product mimics in vivo T cell activation from antigen-presenting cells (above) by utilizing the two activation signals CD3 and CD28, bound to a three-dimensional bead similar in size to the antigen-presenting cells (below). Thermo Fisher Scientific
Artificial antigen-presenting cells: anti-CD3/anti-CD28 beads
IL-2

11. Manufacturing of Tisagenlecleucel
Transduction: incubation with a viral vector encoding the CAR

12. Manufacturing of Tisagenlecleucel
Culture expansion takes 9-11 days and may reach up to 5 L

13. Clinical Process for Tisagenlecleucel

14. Manufacturing of Tisagenlecleucel

15. Challenges of Expanding to Larger Patient Populations
Scaling CAR T cell therapy
Wider range of indications
Larger patient populations
Complex manufacturing process
Some aspects are semi-automated
Others are manual
Generating consistently high-quality viral vector
Predictable genetic modification of cells
Sterility
The final CAR T cell product must be individually generated for each patient
Chain of custody regulations
Global regulatory concerns

16. Challenges of Expanding CAR T Cell Therapy Globally
Donor screening and testing, traceability and labeling, patient confidentiality, and apheresis requirements vary widely among countries
Donor starting material and final product may be shipped internationally
Requirements for quality control of starting materials vary
Requirements for the human or animal serum used for cell culture differ
Greater global regulatory collaboration and harmonization is necessary

17. Harmonization of Standards
The clinical trial approval process is not yet fully harmonized between European Union member states
This may change in 2019 when a new regulation goes into effect

18. Harmonization of Standards
CAR T cells are considered genetically modified organisms (GMOs)
GMOs are regulated differently among EU member states
Legislation and application forms were drafted with plant GMOs in mind

19. Harmonization of Standards
GMO applications are often managed by a different government agency than the competent health authority
Some countries require a public consultation
Risk of releasing confidential data to the public

20. Harmonization of Standards
Different EU member states regard WBCs as blood-derived products vs. tissues and cells for further manufacturing
Various labeling and cell donor testing requirements vary across countries

21. Harmonization of Standards
NCCN task force report on CAR T cell therapy
Multidisciplinary panel of experts in oncology, cancer center administration, and health policy
Met for the first time in March 2018
Report published this month

22. CD19 CAR T Cell Therapy, Management of Toxicities
Cytokine release syndrome

23. Follow-Up

24. Operational Considerations

25. Outline Mechanism of CAR T cell therapy Manufacturing process
Challenges of expanding CAR T cell therapy to a larger patient population world-wide
Harmonization of standards nationally and internationally

26. References
Levine BL, Miskin J, Wonnacott K, Keir C. Global manufacturing of CAR T cell therapy. Molecular Therapy: Methods & Clinical Development. 2017;4:
Makita S, Yoshimura K, Tobinai K. Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. Cancer Science. 2017;108(6):
Buechner J, Kersten MJ, Fuchs M, Salmon F, Jager U. Chimeric antigen receptor-T cell therapy: Practical considerations for implementation in Europe. HemaSphere. 2018;2:1.
Ogba N, Arwood NM, Bartlett NL, Bloom M, Brown P, Brown C, Lihua Budde E, Carlson R, Farnia S, Fry TJ, Garber M, Gardner RA, Gurschick L, Kropf P, Reitan JJ, Sauter C, Shah B, Shpall EJ, Rosen ST. Chimeric antigen receptor T cell therapy. NCCN Task Force Report. J Natl Compr Canc Netw 2018;16(9):1092–1106.
Locke FL, Davila ML. Regulatory challenges and considerations for the clinical application of CAR-T cell anti-cancer therapy. Expert Opinion on Biological Therapy. 2017;17(6):
Maus MV, Nikiforow S. The why, what, and how of the new FACT standards for immune effector cells. Journal for ImmunoTherapy of Cancer. 2017;5:36.