CAR T cells Alice Di Rocco Università Sapienza Roma

 
CAR T cells Alice Di Rocco Università Sapienza Roma
CAR T cells

 Alice Di Rocco
Università Sapienza Roma
CAR T cells Alice Di Rocco Università Sapienza Roma
Learning Objectives

1. CAR-T cell therapy: una nuova frontiera di cura

2. Indicazioni cliniche e stato dell’arte nelle LAL B

3. Meccanismi di resistenza e nuove strategie

4. Tossicità associata con le CAR T
CAR T cells Alice Di Rocco Università Sapienza Roma
The New Column in Cancer Treatment

Over the past decade, immunotherapy has emerged as the “fifth pillar” of cancer treatment
CAR T cells Alice Di Rocco Università Sapienza Roma
A THREE STEP TREATMENT

 Kochenderfer JN, Nat Rev 2013
CAR T cells Alice Di Rocco Università Sapienza Roma
Overview of AntiCD19 CAR Constructs
 Second- and third-generation CARs incorporate
 costimulatory domains either individually or in combination

 Anti-CD19 Anti-CD19 Anti-CD19

 CD28 4-1BB 4-1BB/CD28

 CD3-ζ CD3-ζ
 CD3-ζ

CD28: 4-1BB: CD28/4-1BB:
 • Involved in early and rapid expansion • Enhances early expansion and long-term • The impact of 4-1BB/CD28
 with limited long-term persistence in persistence in vitro1,2 combined costimulatory domains
 vitro2 • Induces central memory T-cell on expansion, persistence, and
• Correlated with effector memory T- differentiation for enduring protection and central memory is being
 cell differentiation known to provide immunosurveillance in vitro1 investigated1
 immediate protection in vitro1 • Metabolic profile supports gradual sustained
 • Metabolic profile supports rapid expansion (oxidative metabolism)
 expansion (glycolytic metabolism)

 1. Kawalekar OU et al. Immunity. 2016;44(2):380-390. 2. Milone MC et al. Mol Ther. 2009;17(8):1453-1464.
CAR T cells Alice Di Rocco Università Sapienza Roma
AntiCD19 CAR T Products
Tisagenlecleucel Axicabtagene-ciloleucel Lisocabtagene-maraleucel

 Frigault et al. J Clin Invest. 2020
CAR T cells Alice Di Rocco Università Sapienza Roma
CAR-T cell: approvazione AIFA

 TERAPIA TARGET INDICAZIONI

 • LAL R/R; età < 25 anni
Tisagenlecleucel CD19
 KYMRIAH
 • DLBCL R/R sottoposto > 2 linee di chemioterapia
 sistemica:
 - DLBCL NOS
 - Linfoma follicolare trasformato
 - Linfoma ad alto grado B

 • DLBCL R/R sottoposto > 2 linee di chemioterapia
 Axicabtagene CD19 sistemica:
 Ciloleucel - DLBCL NOS
 YESCARTA - Linfoma follicolare trasformato
 - Linfoma ad alto grado B
 - PMBCL
CAR T cells Alice Di Rocco Università Sapienza Roma
Understanding the CAR-T Journey

 CAR T infusion

First screen Eligibility Leukapheresis Lymphodepletion hospitalisation Follow up

 Median = 40 days
 Range = 30 -132 days

 --> Time pressure from patient identification to apheresis and infusion can be a significant constraint

 --> The CAR T multisciplinary team to discuss indication and analyze eligibility requirements

 EHA-EBMT Sitges 2020
CAR T cells Alice Di Rocco Università Sapienza Roma
Yakoub-Agha et al. haematologica | 2020; 105(2)
CAR T cells Alice Di Rocco Università Sapienza Roma
Learning Objectives

1. CAR-T cell therapy: una nuova frontiera di cura

2. Indicazioni cliniche e stato dell’arte nelle LAL B

3. Meccanismi di resistenza e nuove strategie

4. Tossicità associata con le CAR T
Relapsed/refractory B-cell ALL in pediatric and young
 adult patients

  B-cell acute lymphoblastic leukemia (ALL) is the most common malignancy diagnosed in children

 Despite current treatment options, ~15% pediatric and young adult patients with ALL experience relapsed/
 refractory (r/r)disease
 – Median overall survival is 3 to 9 months

 Unmet medical need for novel treatment options for pediatric and young adult patients with r/r ALL to provide
 – Deep and durable remission
 – Curative treatment opportunities
 – Improved quality of life

 Pui CH, et al. J Clin Oncol. 2011;29(5):551-565.
CTL019 CAR-T cells and childhood ALL:
 the first cases

-100 to 100,000 times in vivo proliferation
- durable antitumor activity and prolonged persistence in patients with B-cell tumors, including
1 sustained CR in a patient with ALL.
 Grupp S et al, NEJM 2013
Eliana study

• Multi-center global study
• Anti CD19 4-1BB CD3 
• Median age 11 yrs (3-23 yrs)
• 61% had had prior Allo-HSCT
• Median BM Blast 74%
 30 R/R ALL patients (25 pediatrics)

 27patients (90%) obtained CR @1 mo

 Maude et al; NEJM 2014;
• 12- and 18-month relapse free survival rate among responders was 66% (95% CI 52-77)
• Overall remissione rate (CR+CRi) within 3 months was 82% (95% CI 72-90)
 - Among patients with CR/CRi within 3 months, 98% (64/65) achieved MRD - BM

 Maude et al; NEJM 2018; 378: 439-48
ADULT ALL TRIAL DATA
 MSKCC study- outcome data

• Phase 1, single center study (Feb 2010- median FU 29 moths

 June 2016

• 83 R/R ALL patients enrolled

• Median age 44 (23-74 yrs)

 • Of 53 infused patients : 83% CR

 • Median EFS 6.1 mos

 • Media OS 12.9 mos

JH Park et al. NEJM 2018; 378:449-459
Should patients have a subsequent Allo-HSCT?

MSKCC
 data

 JH Park et al. NEJM 2018; 378:449-459

Seattle
 data

 Hay et al. Blood 2019; 11:133
Zhang et al. Blood Adv 2020
Learning Objectives

1. CAR-T cell therapy: una nuova frontiera di cura

2. Indicazioni cliniche e stato dell’arte

3. Meccanismi di resistenza e nuove strategie

4. Tossicità associata con le CAR T
Limitations to durable remissions after CAR T cell therapy

 Shah et al. Nat Rev Clin Oncol 2019
Antigene positive relapse
CD19 + relapse is associated with loss of CAR T-cell persistence  Early relapse
 1

 Causes Solutions
 1.T cell fitness  Healty donor or early –disease collection

 2. T cell phenotype  T cell isolation protocol
 3. CAR co-stimulatory domain Evaluate best co-stimulatory domain on
 vivo (disease-specific)
 4. Checkpoint inhibition Combination strategies, CAR T gene editing

 5. Genetic mutation in crucial pathways Critical evaluation of enrolled patients

Kotani H . et al; ASH 2018; abs 2047
Cohen AD et al; JCI 2019
Brudno et al; JCO 2018
Rupp et al . Sci Rep 2017
Antigen modulation in CD19-CAR T cell trials
CD19 - relapse is observed despite persistent CAR T cells and ongoing B-cell aplasia.

 9-25% after CD19-CART
 58% after CD22-CART
 Shah et al. Nat Rev Clin Oncol 2019
Learning Objectives

1. CAR-T cell therapy: una nuova frontiera di cura

2. Indicazioni cliniche e stato dell’arte

3. Meccanismi di resistenza e nuove strategie

4. Tossicità associata con le CAR T
Cytokine release syndrome (CRS)
 • Most common toxicity in immune effector cell therapy

 • Usually occurs within first 2 weeks after cell infusion
 - Incidence, onset, and severity vary between trials

 • Inflammatory process related to T-cell activation

 • Leads to elevations in cytokines and inflammatory markers
 IFNγ IL-6 soluble IL-2Rα IL1
 IL-2 Soluble IL-6R GM-CSF TNFa

 • Risk factors for severe CRS:

 -Bulk CD8+ T-cell selection -Higher Cell dose
 -High disease burden -Costimulatory domain (CD28 vs 41BB)
 -Lymphodepleting regimen -Elevated baseline CRP
 -Early onset CRS (
Cytokine release syndrome (CRS)
 CLINICAL SYMPTOMS
 Severe
  fever From mild flu-like
 inflammatory
  hypotension symptoms
 syndrome
  widespread organ dysfunction

 CLINICAL EFFECTS

 10
Riegler and al., Therapeutics and clinical risk managment, 2019
Cytokine release syndrome (CRS)
 MANAGEMENT

 1. IDENTIFY CRS:
  Symptoms of CRS: not unique to CRS
  Exclude other causes of fever: Infection+++
  Differentiate from HLH
  For the most part: CRS not after D14
 2. Laboratory parameters: NOT INCLUDED in the definition Published CRS grading systems:

 Cytokines/ CRP/ Ferritin CTCAE version 4.03

 CTCAE version 5

 Lee criteria 1

 3. GRADING CRS: To adapt treatment Penn criteria 2

 MSKCC criteria 3

 CARTOX criteria 4

1 Lee and al. Blood, 2014. 2 Porter and al., J Hematol Oncol, 2018. 3 Park, N engl J Med, 2018 4 Neelapu, Nat Rev Clin Oncol, 2018
Cytokine release syndrome (CRS)
ASCT CRS consensus grading

 Lee and al., Biol Blood Marrow Transplant, 2019
Yakoub-Agha et al. haematologica | 2020; 105(2)
Immune effector cell-associated neurotoxicity syndrome
 (ICANS)
 Neurologic symptoms may include altered mental status, aphasia,
 altered level of consciousness, and seizures or seizure-like activity.

 The start of neurologic symptoms has been noted between 3 to 23
 days (median 10 days)

 The symptoms are variable and generally occur as CRS is resolving
 or after CRS resolution.

 Seizure prophylaxis with Keppra (500 mg BID) in high risk patients
 for those treated with CNS irradiation or other intensive CNS
 directed therapy.

 Borrega JG et al journal. HemaSphere (2019) 3:2(e191)
Neurotoxicity (ICANS)
 ICANS= Immune effectors Cells Associated Neurologic Syndrome

 RISK FACTORS

 Pre existing neurological comorbidities
 Other severe CRS risk factors

 INCIDENCE RATE

 • From 32 to 64%, 5-7 days after CAR T cells
 infusion
 • Grade ≥ 3: 11-42%
 • Often during CRS, or after CRS resolved
• Severity correlates strongly with CRS severity

Santomasso, ASCO, 2019
Neurotoxicity (ICANS)
 ICANS= Immune effectors Cells Associated Neurologic Syndrome

 GRADING: ASCT ICANS consensus grading

Lee, BBMT, 2019
Yakoub-Agha et al. haematologica | 2020; 105(2)
Other toxicities associated with CAR-T
 1. CYTOPENIAS

 Neutropenia: ~ 80%
 INCIDENCE
 Thrombocytopenia ~ 50%

The most important factors related to the development of cytopenias include the conditioning regimen,
cytokines released in CRS, the macrophage activation syndrome, and the exposure multiple prior
chemotherapy treatments

 2. B CELL APLASIA: hypogammaglobulinemia

9 weeks after infusion
Persist > 4 years after CAR T cells infusion 43% in children (Eliana)
14 and 15% in adults with DLBCL for tisagenleclecel and axi-cel respectively

The presence of hypogammaglobulinemia is mainly associated with the achievement of a complete response

 Hill et al., Blood reviews, 2019; Cordeiro et al., BBMT, 2019
Other toxicities associated with CAR-T:
 Infections risk
 INCIDENCE
 CD19 CAR T cells phase I/II study in adults : NHL=62 , ALL=47, CLL=24

 Infection bacterial> fungal
 late infections: Persistent disease= 48%, neutropenia=22%

Hill et al., Blood, 2018
Take Home messages

1. La terapia CAR-T si conferma come uno dei più promettenti e innovativi trattamenti in grado di
 «curare» pazienti che altrimenti non avrebbero una possibilità terapeutica.

2. La tossicità CAR-T specifica a breve termine e a lungo termine rimane ancora un limite del
 trattamento che necessita di ulteriori studi per meglio identificare i meccanismi fisiopatogenetici.

3. Nuove strategie per aumentare la specificità, la sicurezza e l’efficacia si stanno sperimentando in
 numerosi trials clinici al fine di migliorare i risultati clinici nell’ambito sia delle neoplasie
 ematologiche sia dei tumori solidi.
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