AN OVERVIEW OF CELLULAR THERAPY

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1 AN OVERVIEW OF CELLULAR THERAPY Nicole Aqui, M.D. Chief, Transfusion and Apheresis Services Division of Transfusion Medicine Department of Pathology and Laboratory Medicine University of Pennsylvania

2 Conflict of Interest Financial interest due to a patent in T cell culture systems (Novartis)

3 Outline A Brief History Immunology 101 T cell Immunotherapy Dendritic Cell Vaccines Mesenchymal Stem/Stromal Cells Summary

4 A Brief (and biased) History of Cellular Therapy

5 But how did we get here?

6 A short lesson in Immunology

7 Innate vs. Adaptive Immunity

8 T cells and Cancer Immunosurveillance Schreiber, Old, Smyth. Science. 2011

9 Evidence to Support Immunosurveillance Despite suppressive microenvironment, intratumoral T cells correlate with increased overall survival in multiple human cancers (ovarian, colorectal, melanoma Zhang, et al. N Engl J Med 2003 Sato, et al. PNAS 2005

10 Approaches to Redirect Immune Response Towards Cancer - TILS Adoptive TIL Therapy Source Tumor site Specificity Antigen-specific Restifo N, Dudley M, Rosenberg S. Nature Reviews Immunology 2012

11 Approaches to Redirect Immune Response Towards Cancer - CARs Adoptive CAR-T Cell Therapy Source Peripheral blood Tumor site Specificity Antigen-specific Engineered

12 CAR T cells and Cancer Clinical Applications Hematologic Malignancies ALL, CLL, NHL, Multiple Myeloma Targets CD19, CD22, BCMA, CD38, CD33, CD123 Solid Tumors Mesothelioma, pancreatic and ovarian CA, glioblastoma Targets mesothelin, EGFRvIII, mucin-16

13 T cells Beyond Cancer HIV and CCR5

14 T cell Immunotherapy for HIV Gu, Trends in Biotechnology, 2015

15 Innate vs. Adaptive Immunity

16 Dendritic Cell Function

17 Dendritic Cell Vaccine Manufacturing Anguille et al., Pharmacological Reviews 2015

18 DC Vaccines Clinical Applications Ovarian Cancer

19 DC Vaccines Sipuleucel-T Di Lorenzo et al. Nature Reviews Clinical Oncology 2011

20 DC Vaccines Sipuleucel-T 25.8 months 21.7 months KantoffPW et al. N EnglJ Med 2010

21 Dendritic Cell Vaccines Clinical Applications Phase III Studies for Cancer Prostate Colorectal Glioblastoma Melanoma

22 Innate vs. Adaptive Immunity Mesenchymal Stem/Stromal Cell???

23 What is an MSC? ISCT Definition (2006) MSCs must be adherent to plastic under standard tissue culture conditions; MSCs must express certain cell surface markers such as CD73, CD90, and CD105, and lack expression of other markers including CD45, CD34, CD14, or CD11b, CD79alpha or CD19 and HLA-DR surface molecules; MSCs must have the capacity to differentiate into osteoblasts, adipocytes, and chondroblasts under in vitro conditions

24 Mesenchymal Stromal Cells - Function Function Tyndall, Nature Reviews Rheumatology 2014

25 Number of registered clinical trials of mesenchymal stem/stromal cells based therapy on ClinicalTrials.gov Xin Wei et al. Acta Pharmacol Sin 2013

26 Percentages of the common diseases now treated with mesenchymal stem cells Xin Wei et al. Acta Pharmacol Sin 2013

27 MSC Clinical Applications - Sources Bersenev Alexey. Cell therapy clinical trials 2014 report.

28 Summary As our knowledge of how immune cells interact has advanced, so has progress in the field of cellular therapy. The most promising results have been in T cell immunotherapy for the treatment of cancer and HIV. Although DC vaccines can induce objective clinical and immunological responses in several tumor types, the immunogenic potential is still considered sub-optimal. The therapeutic potential of MSCs in diverse disease states is still being explored. Exciting times ahead!!!

29 Acknowledgments UPENN Transfusion Medicine Faculty Don Siegel, MD PhD Una O Doherty, MD PhD Taku Kambayashi, MD PhD Vijay Bhoj, MD PhD Andrew Fesnak, MD PhD Carl June, MD Bruce Levine, PhD UPENN Apheresis Staff Leah Irwin, Nurse Manager Lita Jamensky Caitlin Cahill Melissa Murter Jane Mason Jennifer Green Marcia Hole Kevin Schell Karen Fogle Jennifer Schwartz Julie Colanero Kelli Henes Colleen Henry