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  • Experiences with cell therapy in oncology with 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

    -

  • 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 accreditation

    immuno-T.inmotion.care/

  • Functie

    Afdeling of dienst

    Universitair Ziekenhuis Gent

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

    www.uzgent.be

    Volg ons op

    PROF. DR. BARBARA DE MOERLOOSE Kliniekhoofd, Afdeling Pediatrische Hemato-Oncologie en Stamceltransplantatie, UZGent Hoofddocent, UGent

    barbara.demoerloose@uzgent.be

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