Disclosures
- Novartis, Gilead, Celgene speaker fees
ALLCAR19: UPDATED DATA USING AUTO1, A NOVEL FAST-OFF RATE
CD19 CAR IN ADULT RELAPSED/REFRACTORY B-ACUTE
LYMPHOBLASTIC LEUKAEMIA
Claire Roddie, Maeve A O'Reilly, Maria A V Marzolini, Leigh Wood, Juliana Dias Alves Pinto, Mahnaz Abbasian, Ketki Vispute, Mark W Lowdell, Graham Wheeler, Joanna Olejnik, Bilyana Popova, Kim Champion, Alexia Gali, Yashma Pathak, Victoria Spanswick, Helen Lowe, John A Hartley, Farzin Farzaneh, David Linch, Martin Pule and Karl Peggs
2
Adult B-Acute Lymphoblastic Leukemia:
Current standard of care
- Adult B-ALL prognosis is poor; long-term remission rates limited to 30-40%
- 50% of all adult patients will relapse, with 5-year OS 7% (Fielding et al., 2007)
- Currently the only curative option for r/r ALL is allo-SCT in CR2, but <50% achieve CR2
- Blinatumomab and inotuzumab ozogamicin act as a bridge to allo-SCT (Topp et al. 2015; Kantarjian et al., 2019)
- CD19 CAR T can deliver excellent response rates but with considerable toxicity, particularly in elderly patients
- Currently available CARs: high affinity CD19 binders
- AUTO1: Lower affinity CD19 binder with fast off-rate*
- Physiological T-cell activation
- Reduced toxicity
- Improved engraftment
- Potential long-term persistence, to deliver sustained responses
*Ghorashian S, Pule MA, Amrolia P et al. Nature Medicine 2019.
ALLCAR19 Study Design:
B-ALL arm
AUTO1 Manufacturing
AUTO1 Infusion Leucapheresis/Enrolment
Day 0 | Day 9 |
* | ** |
Bridging Therapy as |
Necessary
Day-6
Registration | Pre-Conditioning | |||||
Flu 30mg/m2 | ||||||
Cy 60 mg/kg | ||||||
Day 0
BM blasts ≤20%
Infuse 100 x 106 CD19 CAR T-cells
Day 0
BM blasts >20%
Infuse 10 x 106 CD19 CAR T-cells
1st Disease
Assessment
Day 28 | M24 EoS |
Safety & Efficacy
Follow Up
Day 9
Infuse 310 x 106 CD19 CAR T-cells
Day 9
Infuse 400 x 106 CD19 CAR T-cells
No G3-5 CRS/ICANS
ALLCAR19 (NCT02935257)
ALLCAR19 Study:
Endpoints and Eligibility
Primary Endpoints
- Grade 3-5 toxicity causally related to the ATIMP
- Feasibility of adequate leucapheresis & generation of AUTO1 CAR T-cells
Secondary Endpoints
- Depth of response at 1 and 3 months post ATIMP
- Persistence of CD19CAR T-cells in peripheral blood
- Incidence and duration of hypogammaglobulinaemia & B-cell aplasia
- Relapse rate, disease-free, overall survival, 1 & 2 years
Inclusion
- Age 16 to 65 years
- High risk or relapsed histologically confirmed CD19+ B- ALL following standard therapy requiring salvage in whom alternative therapies are deemed inappropriate by their treating physician
Exclusion
- CD19 negative disease
- Overt CNS involvement/isolated extramedullary disease
- Active hepatitis B, C or HIV infection
- Stem Cell Transplant patients only: no active GVHD
- Significant neurotoxicity following blinatumomab
No exclusion for prior blinatumomab or inotuzumab ozogamicin
ALLCAR19 Manufacturing:
Product Characteristics & Feasibility
Registered
n = 26
Enrolled/Leucapheresed
n = 25
Manufactured
n = 24
4 died of PD or infection in bridging
Treated
n = 20
- 100% of successful harvests result in a QP released product
- Semi-automatedclosed manufacturing process was used in 18/24 products
- Advantages of closed process includes:
- rapid, standardised manufacture
- trend towards lower exhaustion markers
- enrichment for Tcm and Tnaive CAR+ cells (47%)
- Mean transduction efficiency 66.5%
- range 50 ‒ 83%
Temra | Tnaïve |
17% | 17% |
Tem | Tcm |
30% | |
36% |
Patient Characteristics:
Treated (n=20)
Baseline Characteristics | N=20 (%) | ||
Median age, years (range) | 43 (18-62) | ||
Gender | 13M/7F | ||
Chromosomal/Molecular status | |||
• | Ph+ (bcr-abl) | 6 | (30%) |
• | MLL | 1 | (5%) |
• | Other | 8 | (40%) |
• | Normal | 4 (20%) | |
• | Failed | 1 | (5%) |
Prior lines of treatment | |||
• | Median (range) | 3 | (2-6) |
• | Prior Inotuzumab | 10 (50%) | |
• | Prior Blinatumomab | 5 (25%) | |
• | Prior allo-HSCT | 13 (65%) | |
- sibling/haplo/VUD | 4p/1p/8p | ||
Leukemia Burden Prior to | N=20 (%) | ||
Lymphodepletion | |||
Morphological disease | |||
• | ≤ 5% blasts | 7 (35%) | |
• | 5 - 49% blasts | 4 (20%) | |
• | ≥ 50% blasts | 9 (45%) | |
CNS status at registration | |||
• | CNS 1 | 0 | (0%) |
• CNS II - III | 0 | (0%) | |
Other extranodal sites | 3 | (16%) | |
20 patients have been infused (data cut off 12-Nov-2020)
AUTO1 Pharmacokinetics:
Expansion and Persistence by qPCR
M12
* Mueller, KT et. al. Blood 130(21) 2017
ALL-16 developed a HAMA reaction to reject CAR
Safety Profile
CRS (Lee Criteria) | Neurotoxicity (ICANS#) | ≥ Grade 3 Cytopenia | Day -6 | At Day 28 | ||
• CRS (any) in 10/20 | • ICANS (any) in 4/20 | • ≥ Grade 3 Neutropenia | 7/20 | 8/17 | ||
• | Grade 2 in 7/20 | • | Grade 2 in 1/20 | |||
• | ≥ Grade 3 CRS in 0/20 | • | Grade 3 in 3/20 |
- CRS
- All patients who developed Grade 2 CRS had high burden B-ALL
- Tocilizumab was used in 7/20 patients (35%)
- Neurotoxicity (ICANS)
- ≥ Grade 2 ICANS was reported in 4/20 patients: all had ≥ 50% blasts; all cases were preceded by CRS
- 3/4 cases resolved to G1 in <24h with steroids, 1/4 cases resolved to G1 in 72h with steroids
- ≥ Grade 3 neutropenia:
- Pre-datedtreatment in 7/20 patients
- At Day 28, 8/17 evaluable patients had ≥ Grade 3 neutropenia with most resolving by Month 2/3
- 7/20 patients died on study:
- 2/20 died from progressive B-ALL
- 1/20 died post-progression from allo-transplant-related complications (VOD/sepsis)
- 4/20 from infection: 2/4 before D28 (sepsis; invasive fungal); 1/4 at M6 in CR (MDR-pseudomonas in blood); 1/4 at M3 of
COVID-19
# Immune Effector Cell Associated Neurotoxicity Syndrome
CRS & NT will be graded using the ASTCT/ASBMT Consensus Grading (Lee et al. 2019)
Efficacy & Duration
ALL-29 | ||||||||||||
ALL-24 | Median follow-up 16.9 months (range 0.6 - 30.5 m) | |||||||||||
ALL-22 | ||||||||||||
ALL-20 | ||||||||||||
Process | ALL-19 | |||||||||||
ALL-16 | ||||||||||||
ALL-18 | ||||||||||||
Closed | ALL-17 | |||||||||||
ALL-15 | ||||||||||||
ALL-14 | ||||||||||||
ALL-13 | ||||||||||||
ALL-12 | ||||||||||||
ALL--11 | ||||||||||||
ALL-09 | ||||||||||||
Process | ALL-07 | |||||||||||
ALL-06 | ||||||||||||
ALL-05 | ||||||||||||
Open | ALL-03 | |||||||||||
ALL-01 | ||||||||||||
ALL-02 | ||||||||||||
0 | 3 | 6 | 9 | 12 | 15 | 18 | 21 | 24 | 27 | 30 | 33 | |
0 | 3 | 6 | 9 | 12 | 15 | 18 | 21 | 24 | 27 | 30 | 33 | |
Patient ID | Duration (months) | |||||||||||
Complete Remission | MRD negative CR (PCR/Flow) | CD19 -ve Relapse | Allogenic BMT | |||||||||
Not Evaluable | Ongoing Disease | CD19 +ve Relapse | Death | |||||||||
MRD < 10-4 by PCR or < 5 x 10-4 based on limits of detection of assay
Data cutoff 12-Nov-2020, Evaluable = All patients with at least M1 follow-up or death prior to Month 1.
AUTO1: Efficacy Overview
All patients | Closed process | ||
Est [95% CI] | Est [95% CI] | ||
N * | 19 | 13 | |
ORR | 84% | 92% | |
MRD Neg CR | 84% | 92% | |
DOR | |||
Median | Not reached | Not reached | |
6 months | 81% [52%, 94%] | 83% [48%, 96%] | |
12 months | 68% [39%, 85%] | 65% [31%, 85%] | |
EFS | |||
Median | Not reached | Not reached | |
6 months | 69% [43%, 85%] | 85% [52%, 96%] | |
12 months | 52% [28%, 71%] | 60% [29%, 81%] | |
OS | |||
Median | Not reached | Not reached | |
6 months | 68% [43%, 84%] | 85% [51%, 96%] | |
12 months | 63% [37%, 80%] | 76% [43%, 92%] | |
N = All patients with at least M1 follow-up or RIP prior to Month 1. Event = death or morphological relapse.
DOR, EFS and OS data are preliminary considering the small n
ALLCAR19 Study:
Extending Eligibility to Indolent NHL, HG-NHL and CLL
Cohort 1: Indolent B-NHL
(Dose = 200 million CD19 CAR T-cells)
- relapsed/refractory (r/r) Follicular Lymphoma
- r/r Mantle Cell Lymphoma
- r/r Marginal Zone Lymphoma
- ≥2 prior lines of therapy including Rituximab and anthracycline
Cohort 2: High grade B-NHL
(Dose = 200 million CD19 CAR T-cells + Pembrolizumab)
- r/r DLBCL, PMBCL, transformed FL
- not Richter's transformation
- ≥2 prior lines of therapy including Rituximab and anthracycline
Cohort 3: CLL/SLL
(Dose = 230 million CD19 CAR T-cells/ split dose)
- r/r CLL/SLL
- ≥2 prior lines of therapy including Ibrutinib/BTKi
ALLCAR19 Study:
Cohort 1:Indolent NHL- products and demographics
Registered
n = 8
Enrolled/Leucapheresed
n =8
2 currently in manufacture
Manufactured
n = 6
2 pending infusion
Treated
n = 4
Temra Tnaïve
21% 10%
Tcm
Tem26%
43%
- N=6 products QP released
- Semi-automated,closed manufacturing
- Tcm/Tnaive CAR+ (36%)
- Transduction efficiency (mean 76%)
Baseline Characteristics | N=8 (%) |
Median age, years (range) | 57 (39 - 68) | ||
Gender | 6M/2F | ||
Histological diagnoses | |||
• | MCL | 2 | (25%) |
• | FL | 6 (75%) | |
Disease Stage | |||
• | Stage I/II | 0 | (0) |
• | Stage III/IV | 8 | (100%) |
Prior lines of treatment | |||
• | Median (range) | 3 | (2-4) |
• | Prior ASCT | 4 (50%) | |
• | Prior allo-HSCT | 1 | (12.5%) |
- sibling/haplo/VUD | 0p/0p/1p |
4 patients have been infused (data cut off 12-Nov-2020)
ALLCAR19 Study:
Cohort 1:Indolent NHL- toxicity, responses, engraftment
Toxicity | Responses based on Lugano Criteria and IHC (CD20) | |||||||||
PRE-LD | MONTH 1 | |||||||||
n = 4 | ||||||||||
n = 4 | ||||||||||
CRS | ||||||||||
any grade | 3/4 | CMR | 4/4 | |||||||
≥ Grade 2 | 0/4 | |||||||||
PR | 0/4 | |||||||||
Neurotoxicity (ICANS) | SD | 0/4 | ||||||||
any grade | 0/4 | |||||||||
PD | 0/4 | |||||||||
≥ Grade 3 Neutropenia | |
Day -6 | 0/4 |
Day 28 | 0/4 |
Engraftment | |
Serial LN Biopsies, CD20 by IHC, Dr Teresa Marafioti, UCL |
AUTO1:
Conclusions
- Tolerable Safety Profile was observed:
- Despite high disease burden and despite heavily pre-treated patient population on study
- No Grade 3 CRS was observed
- Only 3/20 patients developed Grade 3 ICANS (rapid resolution with steroids)
- Robust expansion and prolonged CAR persistence was observed
- Efficacy in adult r/r ALL:
- MRD negative CR was achieved in 16/19 (84%) patients at 1 month
- EFS at 6 and 12 months is 69% and 52% respectively, in all treated patients
- Responses are durable and ongoing CRs observed beyond 24 months, supporting the development of AUTO1 as a stand-alone therapy
- Promising early activity and safety has been observed in indolent NHL
Global Phase Ib/II AUTO1 study in r/r ALL has started
Acknowledgements
UCL Cancer Institute
Martin Pule
Karl Peggs
Teresa Marafioti
Paul Maciocia
Pati Wawzyniecka
Gordon Cheung
Leyla Mekkaoui
David Linch
Marina Mitsikakou
Ketki Vispute
Rajeev Gupta
CCGTT
Juliana Pinto
Amaia Cadinanos
Mahnaz Abbassian
Leticia Bosshard
Louisa Green
Mhairi Vaughn
Vitoria Meyer
Mark Lowdell
Rita Rego
Owen Bain
Fiona O'Brien
UCLH
Maeve O'Reilly
Maria Marzolini
Leigh Wood
Clemency Every-Clayton
Lorna Neill
Strachan MacKenzie
Chloe Marden
Diana Palomares Munoz
UCL CABI
Mark Lythgo
Tammy Kalber
Vector (RCTS)
Farzin Farzaneh
Sabine Downing
Lucas Chan
UCL ECMC GCLP Lab
John Hartley
Helen Lowe
Victoria Spanswick
Alexia Gali
Yashma Pathak
UCL Institute of Child Health
Waseem Qasim
Adrian Thrasher
Sameer Fahetullah
Lauren Nickolay
Barry Flutter
UCL CTC
Bilyana Popova
Graham Wheeler
Jo Olejnik
Laura Clifton Hadley
Kim Champion
GOSH
Sara Ghorashian
Persis Amrolia
Autolus
Shaun Cordoba
Shimobi Onouha
Vijay Reddy
Virginie Cerec
Nushmia Khokhar
Michael Zhang
A huge thank you to the patients and their families
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Autolus Therapeutics plc published this content on 05 December 2020 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 07 December 2020 09:10:06 UTC