CAR-T cells for DUMMIES

Dr Reuben Benjamin

King’s College Hospital

This medical education meeting was organised and funded by Janssen-Cilag Ltd

EM-17942| September 2019

This meeting was organised and funded by Janssen

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Disclosures

• Research funding from Servier and Pfizer

• Ad boards for Cellectis, Gilead, Novartis, Pfizer and Servier

• Honoraria from Amgen, Celgene, Takeda and Janssen

CAR-T talk – learning objectives

• What are CAR-T cells?

• How effective is CAR-T therapy in haematological malignancies?

• What are the side effects of CAR-T cells?

• How to access CAR-T therapy in the UK?

• CAR-T – the future!

CAR-T cell: chimeric antigen receptor T cell

Structure of a CAR-T cell

Antigen-binding domain

Transmembrane domain

Co-stimulatory domain

Activation domain

Genetically modified T cells expressing an artificial receptor that binds cell surface antigen in an HLA-independent manner

Yu S, et al. J Hematol Oncol. 2017;10:78. HLA: histocompatibility leukocyte antigen

Autologous CAR-T production

Levine BL. Cancer Gene Therapy volume. 2015; 22:79–84.

T-cell collection from healthy donor

T-cell adoptive transfer to multiple lymphodepleted patients

Allogeneic CAR-T

CAR-Tlentivirus

T-cell transduction

Endogenous TCR and C52 knock-out by TALENs

Allogeneic ‘off the shelf’ CAR-T cells

TALENs: transcription activator-like effector nucleases; TCR: T cell receptor

Liu J, et al. J Hematol Oncol. 2017;10:35; Ren J, et al. Oncotarget. 2017;8:17002–11.

Early phase 1 CD19 CAR-T trials in B-ALL

• Lee et al1, NIH CR = 67%n = 21 children

• Maude et al2, U.Penn CR = 90%n = 30 (25 children, 5 adults)

• Park et al3, MSKCC CR = 91% n = 33 adults

1. Lee, et al. Lancet. 2014; 2. Maude, et al. New Engl J Med. 2014; 3. Park, et al. ASCO 2014.

B-ALL: B-cell acute lymphocytic leukaemia;CR: complete remission;

MSKCC: Memorial Sloan Kettering Cancer Center; NIH: National Institutes of Health; U.Penn: University of Pennsylvania

ELIANA trial – Tisagenlecleucel for B-ALL <25 years

ORR on ITT = 61/92 (66%)

ORR (CR/CRi) = 61/75 (81%)

RFS 6 months = 80%

RFS 12 months = 59%

Maude, et al. N Engl J Med. 2018; 378:439-48.CRi: complete remission with incomplete haematologic recovery;

ORR: overall response rate; RFS: relapse-free survival

CD19 CAR-T trials in DLBCL

• ZUMA-1 trial1

– Axicabtagene ciloleucel (Yescarta)

– 24-month PFS 39%, 24-month OS 51%

• JULIET trial2

– Tisagenlecleucel (Kymriah)

– 18-month CR 40%, 18-month 43%

• TRANSCEND trial3

– Lisocabtagene maraleucel (JCAR17)

– Six-month CR 39%

1. Neelappu, et al. ASH 2018; 2. Schuster, et al. New Engl J Med. 2018; 3. Abramhson, et al. EHA 2017.

DLBCL: diffuse large B-cell lymphoma;OS: overall survival; PFS: progression-free survival

• Tisagenlecleucel (Kymriah, Novartis)

– FDA, EMA approved for R/R B-ALL <25yrs $475,000

– FDA, EMA approved for R/R DLBCL/TFL $373,000

• Axicabtagene ciloleucel (Yescarta, Gilead)

– FDA, EMA approved for R/R DLBCL, PMBCL $373,000

CAR-T cell product approvals

EMA: European Medicines Agency;FDA: Food and Drug Administration;

PMBCL: primary mediastinal large B-cell lymphoma;R/R: relapsed/refractory;

TFL: transformed follicular lymphomaPharmaphorum. Novartis matches Gilead on price in new CAR-T use.Available at: https://pharmaphorum.com/news/novartis-matches-gilead-kymriah/.

CRB-401 Phase 1 trial – for myeloma

≥50% BCMA expression

<50% BCMA expression (n=10)

≥50% BCMA expression (n=12)

Dose range: 150–450 × 106 CAR+ cells

Dose Escalation (N=21) Dose Expansion (N=22)

150 ×106

450 ×106

800 ×106

50 ×106

Raje N, et al. ASCO 2018. Abstract 8007. BCMA: B-cell maturation antigen

Demographics

ParameterEscalation

(N=21)

Expansion

(N=22)

Median (min, max) age, yrs 58 (37, 74) 65 (44, 75)

Median (min, max) time since diagnosis, yrs 4 (1, 16) 6 (1, 36)

ECOG PS n (%)

0

1

10 (48)

11 (52)

6 (27)

16 (72)

High-risk cytogenetics, n (%)

del(17p), t(4;14), t(14;16) 8 (38) 9 (41)

Median prior regimens 7 8

Prior autologous SCT, n (%) 21 (100) 19 (86)

Raje N, et al. ASCO 2018. Abstract 8007. ECOG PS: Eastern Cooperative Oncology Group performance status; SCT: stem cell transplant

Progression-free survival

PFS at inactive (50 × 106) and

active (150–800 × 106) dose levelsPFS in MRD-negative patients

• mPFS of 11.8 months at active doses (≥150 × 106 CAR+ T cells) in 18 subjects in dose escalation phase

• mPFS of 17.7 months in 16 responding subjects who are MRD-negative

mPFS = 11.8 mo

mPFS = 2.7 mo

mPFS = 17.7 mo

Raje N, et al. ASCO 2018. Abstract 8007.

Side effects of CAR-T cells

• Cytokine release syndrome

• Neurotoxicity (CRES / ICANS)

• B-cell aplasia

• Macrophage activation syndrome

Reuben Benjamin, personal communication.CRES: CAR-T cell-related encephalopathy syndrome;

ICANS: immune effector cell-associated neurotoxicity syndrome

Cytokine release syndrome

- Constitutional symptoms - fever, malaise- Cardiovascular - tachycardia, hypotension- Respiratory - tachypnoea, hypoxia- Renal - acute kidney injury- Coagulation - DIC- Hepatic - transaminitis- Neurologic - headache, confusion, aphasia, seizures

➢ Graded 1–5 using Lee et al1 scale➢ Treated with supportive care, tocilizumab (anti-IL-6R), steroids, anakinra

(anti-IL-1R), anti-IL-6

Lee, et al. Blood. 2014; 124(2):188–195. DIC: disseminated intravascular coagulation

ASBMT Consensus grading for CRS

Lee, et al. BBMT; DOI: 10.1016/j.bbmt.2018.12.758.ASBMT: American Society for Blood and Marrow Transplantation;

CRS: cytokine release syndrome

ASBMT Consensus grading for ICANS

Lee, et al. BBMT; DOI: 10.1016/j.bbmt.2018.12.758.

Toxicity profile of selected CAR-T products

Product CRS (Grade ≥3) CRES (Grade ≥3) Clinical Trial

Axicabtageneciloleucel (Yescarta)

13% 28% ZUMA-11

Tisagenlecleucel(Kymriah)

23% 12% JULIET2

Lisocabtagenemaraleucel

1% 13% TRANSCEND3

bb2121 2% <1% CRB-4014

1. Yescarta SPC [updated June 2019]. Available at: www.medicines.org.uk/emc/product/9439; 2. Schuster, et al. NEJM. 2018; 3. Abramson. ASCO 2018; 4. Raje N, et al. ASCO 2018. Abstract 8007.

CAR-T pathway in EnglandLocal Hospital MDT

CAR-T Centre MDT

NHSE National Panel

ApheresisCAR-T Centre

Bridging treatmentLocal Hospital

CAR-T treatmentCAR-T Centre

Routine follow-upLocal Hospital

Long-term safety follow-upCAR-T Centre

AdultNewcastleMRIChristieBristolBirminghamUCLHKing’s

PaediatricGOSHManchesterNewcastle

Additional centres with trialsSecond wave of centres

Reuben Benjamin, personal communication.

GOSH: Great Ormond Street Hospital;MDT: multidisciplinary team;

MRI: Manchester Royal Infirmary;NHSE: NHS England;

UCLH: University College London Hospital

Challenges with CAR-T treatment

• Toxicity of treatment– Multi-speciality involvement, unexpected adverse events

• Kinetics of disease– Need for bridging therapy

• Lack of access to CAR-T– CAR-T centre capacity, manufacturing slots, funding, training

• Unrealistic patient expectations– Publicity/Car-T hype

• Post-treatment relapse

Reuben Benjamin, personal communication.

Mechanisms of CAR-T failure

• Lack of persistence

• CAR-T exhaustion

• Antigen escape

• Immunosuppressive tumour microenvironment

• Immunity against CAR components

Reuben Benjamin, personal communication.

• 18-year-old female

• Pre-B-ALL – normal cytogenetics

• Diagnosed 10/2014

• Normal cytogenetics

• Treatment– UKALL 2011 regimen C / maintenance– Relapse in 05/2016– FLAG-Ida ➔no response– Inotuzumab x2 (07/08/2016) ➔progressive disease– Clofarabine/cyclophosphamide/etoposide (09/2016) ➔persistent disease

(100% blasts)

Case study 1

FLAG-Ida: fludarabine, idarubicin, granulocyte-colony stimulating factor, high-dose cytarabine

Vincristine/dexamethasoneCirculating blasts

LymphodepletionFludarabine/cyclophosphamide/alemtuzumab

Day 06 x 106 CARs

Day+ 5 6 7 8 9 10

NoradrenalineTocilizumab Tocilizumab CPAP Dialysis

Dexamethasone Amiodarone

Cardiac arrest

Temperature

CPAP: continuous positive airway pressure; MAP: mean arterial pressure

PulseMAPResp rate

Case Study 2

• 38-year-old with DLBCL

• R-CHOP x6 ➔ early relapse

• R-DHAP ➔ progressive disease

• Referred for CAR-T therapy

• Steroids to hold disease, then one week off pre-apheresis

• R-IVE post-apheresis ➔ progressive disease

• Admitted for lymphodepletion but with fevers, sweats

R-CHOP: rituximab-cyclophosphamide, doxorubicin, vincristine, prednisone;R-DHAP: rituximab-dexamethasone, cytarabine, cisplatin;

R-IVE: rituximab-ifosfamide, epirubicin, etoposide

Clinical course

D-8 D-6 D-4 D-2 D0 D+5 D+10 D+18

Fludarabine/cyclophosphamide

CRS CRESTocilizumab 3 doses, dexamethasone, anakinra

Dexamethasone, anakinra

Cell infusion ICU Discharge

CAR-T cells – the future

• Bispecific CARs

• Regulatable CARs

• Use of fully human CARs

• CARs that evade the tumour microenvironment

• Combination treatment with checkpoint inhibitors

• ‘Off the shelf’ CARs

• CARs in other cells (NK, gammadelta, NKT)

• CARs for solid tumours

Reuben Benjamin, personal communication.

Summary

• Huge promise for CAR-T therapy in DLBCL, B-ALL and myeloma

• Significant challenges in delivering treatment safely

• New indications and next generation CARs to come

• How can we afford CAR-T therapy?!

Reuben Benjamin, personal communication.