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