Alexey Bersenev, MD, PhDAdvanced Cell Therapy Laboratory,Yale-New Haven Hospital, Yale University www.celltrials.info

8th the BioProcessing Summit, Boston, Aug. 15, 2016

CELL THERAPY – Definitions, Classifications and Trends

2011 2012 2013 2014 20150

50

100

150

200

250

300

56 58

85

117

133

111

179

243259

293

industry academia

Total number of cell therapy trials: academic vs. industry

• Cell therapy – administration of cells to the body with therapeutic purpose

• Regenerative medicine - replaces or regenerates human cells, tissues or organs, to restore or establish normal function

• Cellular immunotherapy – using immune or other types of cells for modulation of host immune system or direct elimination of pathogen/ tumor

Definitions:

What if cell is just a vehicle for therapeutic agent?

Is irradiated cancer cell line a cellular therapy?

Is manipulation of cell in vivo (cells are not administered) a cell therapy?

Is cell-based therapy better term?

Problem with definitions - Cell (cellular) Therapy

cells

tissue engineering

Scaffold (matrix)

genes

small molecules

Regenerative Medicine as generic term

RegenerativeMedicinebio-

molecules device

RM is not equal to cellular immunotherapy. Equation is confusing!

Tissue engineering was rebranded as RM

RM and Cell Therapy may have different challenges and obstacles (example: EPO as regenerative)

Organizations successfully exploit RM brand to attract public trust, money, and lobby politicians (CIRM, ARM)

Problem with definitions - Regenerative Medicine

• Immunocellular

• Regenerative

Classification based onmechanism of action

2011 2012 2013 2014 20150%

20%

40%

60%

80%

100%

46 62

137 156 174

121 175

191 220 252

Immuno- Regenerative-

Trend: Immunocellular therapy vs. cell-based regenerative medicine

• Autologous

• Allogeneic

• Auto + Allo

• Xenogeneic

Classification based on donor cell origin

Industry is not in favor of allo- model

Total number of registered clinical trials

2011 2012 2013 2014 20150

20

40

60

80

100

120

140

31 26

48

707924 29

34

45

54

alloauto

Trend: Allo- vs. auto- commercial trials

Origin:

• Somatic cell therapy• Germline cell modifications

Differentiation:

• Stem cells• Progenitor cells• Mature (differentiated) cells

Cell types classifications

2011 2012 2013 2014 20150

20

40

60

80

100

120

140

52

80

90

116

140

22

42

60

81

96

3825

13

2226

3 38

11

41

32

17

MSC total

T-cells

BM MNC

HSPC

adipose SVF

ESC

DC

NK cells

Trend: Interest to major cell types

2011 2012 2013 2014 20150

20

40

60

80

100

23 2419

28

4031

58

71

89

100

industry academic

Cell therapy trials: cell type – mesenchymal stem cells

2011 2012 2013 2014 20150%

20%

40%

60%

80%

100%

5 9

13 2226

6 13

10 1837

Fresh SVF Adipose SC expanded

Trend: Interest to adipose tissue-derived cells

Based on:

• Degree of cell manipulation• Homology• Risks to recipient

Disregard:

• Cell biology, cell type and origin• Therapeutic intention

Regulatory classifications

Cell Therapy (somatic cell, including stem

cells)

Gene Therapy Devices related to cells

351 HCT/P (drug, biologic or device) 361 HCT/P (tissues)

cartilage, bone, tendon, skin, ocular tissue, reproductive cells

and tissues…

HCT/P

Regulatory classification: USA

Cells & Tissues but not HCT/Ps:(blood and blood components, minimally manipulated bone marrow for

homologous use, xenogenic cells/ tissue…)

Regulatory classification: EU

Cell-based/ gene therapy

Biologic - ATMP (EMA – CAT)

Somatic Cell

(including stem cells)

Gene Therapy

Transplants/

Transfusions

Tissue Engineering

Regulatory classification: Japan

Class I (iPS/ ES cells,

gene-modified cells, allo-)

Class II(auto- somatic cells

– cultured/ nonhomologous

use)

Class III(auto- somatic cells – homologous use,Processed somatic

cells)

Regenerative Medical Product Blood Transfusions

HPC transplantationAssisted Reproduction(no gene modification, not derived

from stem cells)

Processed cells (manufacturing) Not processed orSpecific processed cells

Cell Therapy Gene Therapy Tissue Engineering

Biologics (medicinal product) Human Tissue

cartilage, bone, ligament, tendon, skin, heart valves, blood vessel,

fascia, amnion

MFDS (former KFDA)

Regulatory classification: South Korea

Cell Therapy as medical practice (minimally manipulated auto- or allo- cells)

Some products hard to fit in definitions (ATMP or 361/351). To avoid confusions, contact regulators as early as possible

Not always clear difference between ”product” and “medical procedure” / “tissue for transplantation”

Autologous not gene-modified cells freshly used at point-of-care is not easy to fit in definitions of “regulated product” Immunocellular therapy called “regenerative medical product” (Japan)

No definitions for ”stem cell product”

Confusions about regulatory definitions