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Experiences with cell therapy in oncologywith inclusion of regulatory and ethical aspects
Barbara De Moerloose
Symposium Cell Therapies
Brussels – June 29th 2019
CAR T-cell therapy in pediatric oncology
immuno-T.inmotion.care/
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CAR T-cell immunotherapy
C (chimeric)A (antigen)R (receptor)
T-lymphocytes +
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M. Casucci & A. Bondanza, J Cancer, 2011 3
Multiple generations of CARs
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Anti CD19 CAR T in relapsed/refractory ALL
2014
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Anti CD19 CAR T phase 1-2
• U Penn (CHOP)
• CTL019 (→ tisagenlecleucel, Kymriah®)
• 60 patients (3-21 years)
• R/R ALL
• 93% complete remission
• 67% EFS at 6 months
• 78% OS at 6 months
4 years of follow-up
Maude et al, 2014
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Eliana CTL019 phase 2 in relapsed/refractory ALL
2018
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ELIANA: Pivotal Phase 2 Study
• Tisagenlecleucel was produced at a central manufacturing site with global distribution
• 25 sites across 11 countries in North America, Europe, and Asia-Pacific
8
Manufacturing sites
* *
*
ELIANA is the first global, multicenter trial of CAR T-cell therapy
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Anti CD19 CAR T: side effects
- << Infusion reactions
- < Tumour lysis syndrome
- Pyrexia, febrile neutropenia
- Cytokine release syndrome (CRS)
- Macrophage activation syndrome (MAS) or HLH
- Neurologic toxicity= CAR Related Encephalopathy Syndrome (CRES)
= Immune effector cell associated neurotoxicity syndrome (ICANS)
- Cytopenia
- B-cell aplasia (= on-target, off-tumor effect)
Hypogammaglobulinemia as long term toxicity
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Eliana study (CTL019) in relapsed/refractory ALL
Maude et al, 2018
= 75% gr3-4
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Eliana study (CTL019) in relapsed/refractory ALL
73%
90% 1y EFS = 50%3m CR/CRi = 81%
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Overall survival Eliana vs single-center study
60%
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Media hype
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Some remarks…
Efficacy analysis (per protocol) Patients (N= 75)
Primary endpoint
ORR (CR+Cri) within 3 months, n (%) 61 (81)
95% CI 71-89
Sensitivity analysis (intent-to-treat) Patients (N= 92)
ORR (CR+Cri) within 3 months, n (%) 61 (66)
95% CI 56-76
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�Defining placement of CAR therapy (bridge or alternative to SCT?)
�Controlling disease prior to infusion
�Logistics
�Delivery capacity, # slots
�Harvest of autologous lymphocytes
�Lymphopenic patients
�Infants
�Prevention of relapse (most are CD19-negative)
… and challenges (1)
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16Sadelain, Cell, 2017
… and challenges (2)
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� Implementation plan; continuous training; ICU availability …
→ centraliza8on in specialized sites
� Toxicity profile ∼ age, disease, CART construct…
� Guidelines for CRS and ICANS grading (ASBMT?) & treatment algorithms ∼ age, disease, CART construct…
… and challenges (3)
Teachey et al. Nat Reviews/Clinical Oncology 2018:
Toxicity management after CART therapy:
one size does not fit ‘ALL’
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CART = GMO (genetically modified organism)
⇒ Biovigilance
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�Financial & regulatory hurdles Advanced therapy medicinal product (ATMP); Kymriah 475,000 dollar
… and challenges (4)
Sadelain, Cell, 2017
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Regulatory aspects
• ATMP (advanced therapy medicinal product)
• ATMPs regulation (EC) No1394/2007
• EU specific legislation and authorisation procedure
2018: marketing authorisation for Yescarta® and Kymriah®
• Risk management plan – risk minimisation procedure (RMP)
�Accreditation of apheresis and infusion sites
�Reporting on side effects and outcome (until 15y after infusion)
�Patient informed consent
�Post-authorisation registry
= legally binding
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Belgian situation
• Kymriah® reimbursed by RIZIV/INAMI since June 1st 2019
320.000 € (280.000 + 2x 20.000)
• Apheresis, cell processing, coordination, logistics, data management …
are not reimbursed.
→ Re-evaluation after 2 years
• Technical apheresis agreement (hospital x pharma)
• Risk management plan – risk minimisation procedure (RMP)�Accreditation of apheresis and infusion sites → by pharma
�Patient informed consent
�Reporting on side effects and outcome (until 15y after infusion)
�Post-authorization registry (EBMT registry)
• JACIE accreditation for “immune effector cell” activities
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Conclusion
• New treatment modality
• ↑ cure rates for R/R ALL
• Severe side effects in some patients
• Limited follow-up time
• Complex treatment; multiple stakeholders
• ‘18: EU approval for Kymriah and Yescarta
• June 1st ‘19: Kymriah reimbursed in Belgium
• RMP and post-authorisation registry
• JACIE accreditationimmuno-T.inmotion.care/
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Functie
Afdeling of dienst
Universitair Ziekenhuis Gent
C. Heymanslaan 10 | B 9000 GentT +32 (0)9 332 21 11E [email protected]
www.uzgent.be
Volg ons op
PROF. DR. BARBARA DE MOERLOOSEKliniekhoofd, Afdeling Pediatrische Hemato-Oncologie en Stamceltransplantatie, UZGentHoofddocent, UGent