CAR T cells Alice Di Rocco Università Sapienza Roma
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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
The New Column in Cancer Treatment Over the past decade, immunotherapy has emerged as the “fifth pillar” of cancer treatment
A THREE STEP TREATMENT Kochenderfer JN, Nat Rev 2013
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.
AntiCD19 CAR T Products Tisagenlecleucel Axicabtagene-ciloleucel Lisocabtagene-maraleucel Frigault et al. J Clin Invest. 2020
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
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
Yakoub-Agha et al. haematologica | 2020; 105(2)
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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