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Automated manufacture of T-cell immunotherapies

using gamma retroviral transduction

Lee Markwick, PhD AMC, Manchester March 2018


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Automated generation of CAR T cells

T cell enrichment and activation

Transduction

Expansion

d0

d1

d2-10

d10-14Final product (max of 14 days)

Starting material

8th March 2018 Automated manufacture of T-cell immunotherapies - Lee Markwick Ph. D.


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CliniMACS

BufferMACS GMP

TransAct

GMP Lentiviral

VectorMACS GMP

TexMACS

CliniMACS Prodigy TS 520

CliniMACS

Reagents:

CD4 / CD8,

CD62L

MACS GMP

IL-2, IL-7, IL-15,

IL-21flow reagents and

REA antibodies

7 color immuno-

phenotyping kit

MACSPlex

Cytokine Kit

Rapid Cytokine

Inspector Kit

MACS GMP

TexMACS

IPC/QC

CliniMACS Prodigy TCT Process

CliniMACS Prodigy TCT Process for RV and LV

Cell selection Cell activation Cell transduction Cell expansion Final

formulation



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TCT process - robust and reproducible with pts material

Robust expansion of healthy

material (n=12) and pts material

(n=6)

Good viability of healthy material

(n=12) and pts material (n=6)


formulation

E.g. dose: 107 CAR+ T cells / kg

(130kg patient)

Patient material T cellsCAR+ T

cells

Melanoma 2.35E9 1.38E9

Lymphoma 3.68E9 1.54E9

Lymphoma 3.31E9 -

Lymphoma frozen 4.90E9 1.09E9

Lymphoma frozen 3.20E9 0.72E9


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TCT process - robust and reproducible in serum free conditions


formulation


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New Activities to enable TCT for retroviral vector

Enrichment

TCT Retro

Activation

in 70 ml

Volume chamber

time

200

100 Vo

lum

e r

ed

uctio

n

Ad

ditio

n R

V +

en

ha

ncer

Sp

in 4

00

g, 3

2°C

day 26-24h incubation

Cultu

re

wa

sh

Sta

rt

sh

akin

g



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Retroviral transduction


formulation

Vectofusin-1®

• Transduction enhancer

• Fully synthetic, non toxic, soluble peptide

• No pre-treatment/coating needed - added directly to viral supernatant!

• Straight forward and simple protocol

• Available in research and GMP grade

Automated manufacture of T-cell immunotherapies - Lee Markwick Ph. D.8th March 2018


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Retroviral Transduction


formulation



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Cellular composition of final product


formulation



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Functionality: Killing of CD20+ JeKo-1 cells

Cytokine secretion profiles Cytotoxicity


Healthy donorHealthy donor

Patient material Patient material


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Robust manufacturing of polyfunctional gene-engineered T cells:

In vivo mouse model



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Cell Manufacturing Centres


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Integral Single Unit Manufacturing

▪ Parallel Manufacturing.

▪ Instantly scalable

✓ More devices, more products

▪ Simplicity at Scale.

✓ One process, one device

▪ Complexity Minimisation:

✓ Process steps

✓ Connections

✓ Device upkeep & maintenance


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Facility Considerations(Layouts for 2000 patients p.a.)

Cell Gene Therapy Insights 2017;3(4).David James


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CliniMACS Prodigy in clinical trial and licensed commercial product…



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Miltenyi Biotec manufacturing suite



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Automation & Operation

March 13, 2018 Jason Jones, Miltenyi Biotec Ltd


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Parallel manufacturing of cell and gene therapy products…

March 13, 2018


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Not just CAR T-cells…

Donor /

patient

Blood

LeukapheresisPatient

Cell

selection

Cell

transduction

Cell

formulation

Cell

activation

Cell

expansion

MoDC

CAR T cells

TCR T cells

NK cells

Gene-modified

stem cells

MSCs

Treg cells

Antigen-specific

T cells



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Automated manufacture of T-cell immunotherapies · left border border right border top for Photos...

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