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/

CAR T-cell immunotherapy

C (chimeric)A (antigen)R (receptor)

T-lymphocytes +

M. Casucci & A. Bondanza, J Cancer, 2011 3

Multiple generations of CARs

Anti CD19 CAR T in relapsed/refractory ALL

2014

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

Eliana CTL019 phase 2 in relapsed/refractory ALL

2018

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

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

Eliana study (CTL019) in relapsed/refractory ALL

Maude et al, 2018

= 75% gr3-4

Eliana study (CTL019) in relapsed/refractory ALL

73%

90% 1y EFS = 50%3m CR/CRi = 81%

Overall survival Eliana vs single-center study

60%

Media hype

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

�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)

16Sadelain, Cell, 2017

… and challenges (2)

� 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’

CART = GMO (genetically modified organism)

⇒ Biovigilance

�Financial & regulatory hurdles Advanced therapy medicinal product (ATMP); Kymriah 475,000 dollar

… and challenges (4)

Sadelain, Cell, 2017

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

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

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/

Functie

Afdeling of dienst

Universitair Ziekenhuis Gent

C. Heymanslaan 10 | B 9000 GentT +32 (0)9 332 21 11E info@uzgent.be

www.uzgent.be

Volg ons op

PROF. DR. BARBARA DE MOERLOOSEKliniekhoofd, Afdeling Pediatrische Hemato-Oncologie en Stamceltransplantatie, UZGentHoofddocent, UGent

barbara.demoerloose@uzgent.be