receptores de antígenos quiméricos de células t (car t-cells)£o regional... · chimeric antigen...
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Vanderson Rocha, MD, PhD
Professor de Hematologia, Hemoterapia e Terapia Celular–
Diretor da Fundação Pro-sangue
Universidade de São Paulo
Receptores de antígenos quiméricos de
células T (CAR T-cells)
Terapia ‘CAR’
CAR-T Cell
• Overview of the concept of CAR-T Cell therapy
• Current evidence and practical issues in the application of CAR-T cell therapy for the management of:
- ALL
- Lymphoma
- AML
- MM
- Solid tumors
Acute Lymphoblastic Leukemia–
Potential Cell-Therapy Targets
CD19: An ideal target
CAR-T cell
Current Chimeric Antigen
Receptors T-Cell in Clinical Trials
Chimeric antigen receptor (CAR) technology
Reprogramming a patient’s T cells to “hunt” and destroy cancer
MOA data is based on in vitro/in vivo data. Clinical benefit is unknown
CTL019 is an investigational compound. Efficacy and safety have not been established. There is no guarantee that CTL019 will become commercially available.
The reprogrammed T cells are expanded in the manufacturing facility.
4
The reprogrammed T cells are reintroduced into the patient’s
blood.
ReprogrammedT cells
6
The patient receives lymphodepletingchemotherapy to reduce the level of white blood cells and help the body accept the
reprogrammed T cells.
Lymphodepletingchemotherapy 5
White blood cells, including T cells, are separated from the patient’s blood in a process
called leukapheresis. They are then sent to a manufacturing facility for reprogramming.
T-cell
1
Ex vivo, in a manufacturing facility, genes encoded to
recognize specific cancer cells are transferred into the patient’s
T cells using an inactive virus (viral vector).
2
Inactiveviral
vector
Within the patient’s body, the T cells expand. The CTL019 cells “hunt” cancer cells expressing CD19,
attach to them, and initiate direct cell death.
Cancercell
CLT019
CTL019 attaches to cancer cells
Cancer cell death is initiated
7
Once the gene transfer is complete, T cells are now reprogrammed to “hunt”
cancer cells by expressing a CAR on its surface. For CTL019, the T cell is
programmed to hunt the CD19 protein on the surface of B cells.
3CLT019
CAR T-cells
http://www.bloodjournal.org/content/118/18/4761.full?sso-checked=true
1) Coleta de células T
do doador
3. integraçãocom DNA da cél.
2) Infecção das células
T pelo vetor viral
1. ligação
2. fusão
4. leitura do DNA inserido e formação de
novas proteínas(receptores)
5. Inserção dos receptoresna membrana da célula
4) Monitorização do
paciente
a) Resposta da doenca:
• Tomografia
• Biópsia de medula óssea/
• Citometria de fluxo
b) Persistência das CAR T-
cells:
• imunohistoquimica de
biópsia de medula óssea
• Reação de PCR (biologia
molecular) e citometria
de fluxo
3) Transferência da
célula T adaptada
para o paciente
+/-
Lymphodepleting
conditioning
CD3
Cel T
Patient Stabilization
Lymphodepleting Chemoterapy
CAR T cells na LLA crianças
*Tisagenlecleucel
NEJM 2018
EBMT 2018
ELIANA: CTL019 (tisagenlecleucel)
• Single arm, global study 25 sites in 11 countries across North America, Europe, Australia and Asia
Maude et al NEJM 2018:378:439-448
Duration of response and relapse-Free Survival
ELIANA: Overall Survival
Toxicity
• Cytokine Release Syndrome (CRS)
- Correlates with T cell proliferation and efficacy
- Severity related to disease burden
- Observed in 88%; 27% requiered CTI support
- Reversed with novel approach – cytokine blockade
• Neurotoxicity
- Seen in several CD19 immunotherapy trials: NCI, CHOP/UPenn/ MSKCC
• Chronic B cell aplasia requiring Ig replacement
• Macrophage activating syndrome
Neelapu SS et al Nat Rev Clin Oncol 2018:15:47-62
Cytokine Release Syndrome
Severe CRS management
• Supportive Care
- Vasopressor, O2, ventilation, Blood products (FFP, cryo)
• Lympholytics
- Steroids tried with some effect but potencial to reduceefficacy
• Cytokine-directed therapy
- IL-6 noted to be very elevated
- Anti-IL-6 therapy highly effective with no apparenteffect on efficacy
Tocilizumab
• IL-6 receptor antagonist
- Block IL-6 mediated effects
- Indicated in: juvenile idiopathic arthritis, Rheumatoid arthritis; now indicated por CRS treatment(aug 30,2017)
- Rare side effects of transaminitis and neutropenia
Grupp et al NEJM 2013:368:1509-1518
Current labeled indications for CTL019
• ALL up to age 25 years
• Refractory or second relapse
Other key points:
• No donor required
• Not is necessary the patients be in complete remission to receive treatment
• There is a plan for a registry
www.pharma.us.Novartis.com/files/kymriah.pdf- feb 13,2018
Mechanisms of Relapse
Gardner et al ASH 2017 Abstract 219
Shah BD et al ASCO 2017 Abstract 3024
CAR T cells nos Linfomas
Phase 2 ZUMA 1: KTE-019 (AxicabtageneCiloleucel) in Refractory Aggressive NHL
Neelapu SS et al NEJM 2017:377:2531-2544
Phase 2 Zuma-1
Phase 2 ZUMA 1
• Adverse effects:
– Grade 5 AEs in 3 patients: but drug related 2 events (1 HLH and 1 cardiac arrestin the setting of CRS)
– Grade >3 AEs: CRS (13%) , Neurologic events (28%)
• Special considerations:
– Use a lymphodepleting regimen of Cy and fludarabine before infusion; premedicate with acetaminophen and a H1-antihistamine
– Treat severe CRS with tocilizumab and corticosteroids
– Do not administer to patients with active infection or inflammatory disorders
– Target dose 2x106 (maximum 2x108) CAR-positive viable T cells per Kg bodyweight
Neelapu SS et al NEJM 2017:377:2531-2544
Patient Case: Ongoing 9+ mo Durable CR in Refractory DLBCL
Baseline Day 90
• 62-yo M with DLBCL
• Prior therapies- R-CHOP
- R-GDP
- R-ICE
- R-lenalidomide
• No response to last 3 lines of therapy
48Neelapu & Locke et al ASH 2016, #LBA-6
CAR T cells na LMA
CD123-Specific CAR T Cells
• Phase 1
• 6 pts with relapsed AML following HCT received CD123-Specific CAR T cells
• 2 pts on dose level 1 (50M CAR+ T): 1 CR
• 4 pts on dose level 2 (200M CAR+ T: 1 CR + 1 sustained CR and 2 pts achieving reduction of marrow blasts
• No DLT or treatment-related cytopenias
Budd et al., Blood 2017;130:811
CD33-specific CAR T cells
• Results still at case report level.
• Transient effect on blasts.
• Ongoing trials in AML:
NCT # (recruting) Phase Site
NCT01864902 1/2 China
NCT02958397 1/2 China
NCT03126864 1 US (MDACC)
NCT03222674 1/2 China
CAR T cells no Mieloma
GHOSH ET AL. Leukemia & Lymphoma 2017
CAR T cells nos tumores sólidos
Anti-solid tumor T-cells
Problems/Issues with CAR or TCR treatment of solid
tumors
Cross reaction – potentially lethal off-target/off-tissue cell
killing
Currently poorly effective against solid tumors
Immunosuppressive microenvironment
Low efficacy, low persistence
Yong C , Immunology and Cell Biology 2017
Yong C , Immunology and Cell Biology 2017
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