Immatics N : ACTolog® IMA101 Phase-1-Data at the 35th Annual SITC conference
11/10/2020 | 07:29am EST
Follow us on
Results of the First-in-human Clinical Trial with Personalized Multi-target Adoptive Cell Therapy (ACTolog® IMA101)
Apostolia M. Tsimberidou1, Kerstin Guenther2, Amir Alpert3, Borje Andersson1, Zoe Coughlin3, Stephen Eck3, Jens Fritsche2, Norbert Hilf2, Patrick Hwu1, Mamta Kalra3, Sabrina Kuttruff-Coqui2, Dominik Maurer2, Regina Mendrzyk2, Ali Mohamed3, Becky Norris1,
Abstr. No. 293
Anna Nowak2, Rita Ort1, Carsten Reinhardt2, Fabian Richter2, Arun Satelli3, Oliver Schoor2, Kerry Sieger3, Harpreet Singh2,3, David Vining1, Claudia Wagner2, Toni Weinschenk2, Cassian Yee1, Steffen Walter3
1 The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA 2 Immatics Biotechnologies GmbH, Paul-Ehrlich-Str.15-17, 72076 Tuebingen, Germany 3 Immatics US, Inc. 2201 Holcombe Blvd., Suite 205, Houston, Texas 77030, USA.
BACKGROUND
RESULTS
Table 3. Treatment-Emergent Adverse Events
Figure 3. Characterization of TCRs in ACTolog®
Background
Adoptive cell therapy (ACT) in solid tumors is challenging due to lack of targets with high tumor specificity, tumor heterogeneity and tumor escape by loss of single antigen (Ag) expression.
ACTolog® (IMA101) is a personalized multi-target adoptive cell therapy (ACT) approach in which autologous T cell products are directed against multiple novel defined peptide-HLA (pHLA) cancer targets identified by the target discovery platform XPRESIDENT®.
ACTolog® target warehouse: COL6A3 exon 6, PRAME, MAGEA1, MAGEA4, MAGEA8, CTAG1A/NY- ESO-1, MXRA5, MMP1. Targeting the novel tumor stroma target COL6A3 exon 6 is intended to disrupt the tumor microenvironment.
Tumors positive for ≥1 target from the ACTolog® target warehouse (HLA-A*02:01 restricted targets) are identified using the in vitro diagnostic device IMADetectTM (qPCR assay).
Up to 4 tumor-specific T cell products are manufactured from leukapheresis product.
Clinical proof of concept in melanoma established (Cassian Yee, MD Anderson) with a single-target T cell product demonstrating T cell persistence long-term at levels >1% and objective responses
Chapuis et al, Sci Transl Med (2013) and Chapuis et al, JCO (2016).
Study Objectives
Primary: To evaluate the safety and tolerability of ACTolog® alone (Cohort 1) or in combination with atezolizumab (Cohort 2)
Secondary: To evaluate in vivo persistence of transferred T cells and tumor response
Exploratory:Ex vivo functionality of transferred T cells, T cell infiltration in the tumor, progression- free survival (PFS) and overall survival (OS)
METHODS
Patients
HLA-A*02:01 positive patients with relapsed/refractory solid tumors whose tumor expressed ≥1 cancer target underwent leukapheresis, and endogenous T cells specific for up to 4 targets were primed and expanded in vitro.
Preconditioning regimen: fludarabine 40 mg/m² and cyclophosphamide 500 mg/m² on days -6 to -3
ACTolog® up to 4x1010 total cells (day 0)
IL-2(1x106 IU SC BID, 28 doses)
Patients in Cohort 2also received atezolizumab starting on day 21 or later upon hematologic recovery (1200 mg IV every 3 weeks up to 12 months).
Severity of adverse events (AE) was assessed according to CTCAE v5.0 and AE were coded according to MedDRA. Patients are counted only once per adverse event and severity classification.
Response was assessed by RECIST 1.1 and irRECIST. Progression-free-survival (PFS) was measured from date of entry on the treatment part of the study to date of disease progression or treatment discontinuation. Overall survival (OS) was measured from date of entry on the treatment part of the study until date of death or last follow-up.
All data are as of October 6th, 2020 (unclean data).
Figure 1. ACTolog® Treatment Schema
HLA-A*02:01 (+)
Table 1. Patients Screened and Treated
Screening/Treatment Status
No. of Patients (%)
Screened
214 (100)
HLA-A*02:01-positive
99
(46.3)
Screening tumor biopsy
61 (28.5)*
≥1 Target positive
54
(25.2)
Leukapheresis
43
(20.1)
Cohort 1 (intention-to-treat)
4
(1.9)
Cohort 2 (intention-to-treat)
10 (4.7)
Total treated with T cell product
14 (6.5)
* 60/61 tumor biopsies were evaluable for assessment of target expression.
Table 2. Patient Characteristics and Outcomes
Pt
Age/
No. of
Yrs
Targets
Viable/ Specific Cells
Best
PFS
OS
Tumor Diagnosis
prior
from
Infused per Product
Cohort3
Response
ID
Gender
Positive
[mo]
[mo]
Rx1
Dx2
[x1010]
(wk)4
012
56/F
Breast
10
18
COL6A3,
MXRA5: 0.42/ 0.10
1
SD
2.4
28.4
adenocarcinoma
MXRA5
[4]
(PD)
(D)
PRAME,
PRAME: 1.16/ 0.84
COL6A3,
SD
3.3
22.8
028
28/F
Synovial sarcoma
5
10
MXRA5: 1.02/ 0.42
1
MXRA5,
[4]
(PD)
(D)
NY-ESO-1: 1.37/ 0.59
NY-ESO-1
Myxoid
PRAME,
PRAME: 1.16/ 0.76
SD
4.7
21.6
027
36/M
12
7
COL6A3,
COL6A3: 1.16/ 1.09
1
liposarcoma
[12]
(PD)
(D)
NY-ESO-1
NY-ESO-1: 1.16/ 1.07
048
37/M
SCC of
5
13
COL6A3,
COL6A3: 1.69/ 1.47
1
SD
12.9
22.2
nasopharynx
MMP1
[10]5,6
(PD)
(D)
096
58/F
SCC of anus
8
5
PRAME,
PRAME: 0.97/ 0.49
2
SD
3.4
10.6
COL6A3
COL6A3: 0.76/ 0.26
[6]
(PD)
(D)
Infiltrating duct
COL6A3,
COL6A3: 1.61/ 1.27
SD
3.2
7.9
071
31/F
9
4
PRAME,
2
breast cancer
PRAME: 0.33/ 0.03
[6]
(PD)
(D)
MMP1
PRAME,
PRAME: 1.74/ 1.58
SD
5.8
8.6
095
49/F
Synovial sarcoma
5
4
COL6A3,
COL6A3: 0.91/ 0.63
2
[17]
(PD)
(D)
MXRA5
MXRA5: 1.32/ 0.82
COL6A3,
COL6A3: 1.16/ 0.97
SD
7.3
18.6
139
24/F
Ovarian cancer
4
2
MMP1,
MMP1: 1.41/ 0.85
2
[24]5
(PD)
(A)
MXRA5
MXRA5: 1.16/ 1.00
145
56/F
Invasive duct
3
4
COL6A3,
COL6A3: 1.04/ 0.89
2
PD
1.8
6.7
breast cancer
NY-ESO-1
NY-ESO-1: 1.74/ 1.61
[6]
(PD)
(D)
163
63/F
Mesothelioma of
8
6
PRAME
PRAME: 0.68/ 0.55
2
SD
13.7
13.9
the peritoneum
[52]
(PD)
(A)
173
32/F
Infiltrating duct
8
4
COL6A3
COL6A3: 1.39/ 1.09
2
SD
3.4
4.7
breast cancer
[6]
(PD)
(D)
164
57/F
Colon
5
2
COL6A3
COL6A3: 0.72/ 0.40
2
PD
2.0
4.0
adenocarcinoma
[6]
(PD)
(D)
172
44/F
SCC of anus
3
4
COL6A3
NA7
NA
NA
NA
NA
199
20/F
Small cell sarcoma
7
6
COL6A3
COL6A3: 0.58/ 0.44
2
SD
3.7
3.7
of mandible
[11]5
(SD)
(A)
205
56/F
Colon
4
3
COL6A3,
COL6A3: 0.77/ 0.46
2
PD
1.8
2.9
adenocarcinoma
MMP1
[6]
(PD)
(D)
1 prior systemic treatments. 2 years from diagnosis. 3 intention-to-treat.4 weeks from T cell infusion. 5 Patients did not progress per RECIST1.1 while on study. 6 Left study with SD (RECIST1.1) at week 10 and remained SD for 12.9 months during follow-up without further treatment. 7 The patient received lymphodepletion, but was not infused with T cell product. (D) Deceased; (A) Alive
Feasibility (Table 1, 2)
54 of 60 (90%) evaluable patients who underwent a tumor biopsy were positive for ≥1 target from the ACTolog® target warehouse.
Very high ACTolog® cell doses (mostly >1010) were administered.
50% of patients received multi-target ACTolog® products (up to 3).
Clinical Outcome (Table 2)
The median PFS was 3.4 months (95% CI, 2.0-7.4 months).
The median OS was 10.6 months (95% CI, 4.7-22.8 months).
Six (42.9%) of 14 evaluable patients had disease stabilization at 12 weeks. Prolonged disease stabilization was noted in three patients for 12.9 months, 7.3 months, and 13.7 months.
All Grades
≥Grade 3
Adverse event [by MedDRA term]
No.
%
No.
%
Anemia
14
93.3
12
80.0
Neutrophil count decreased
14
93.3
14
93.3
Platelet count decreased
12
80.0
7
46.7
White blood cell count decreased
12
80.0
10
66.7
Nausea
11
73.3
0
Cytokine release syndrome
10
66.7
0
Vomiting
9
60.0
0
Lymphocyte count decreased
8
53.3
8
53.3
Constipation
7
46.7
0
Hyponatremia
6
40.0
0
Fatigue
6
40.0
0
Hypokalemia
5
33.3
1
6.7
Febrile neutropenia
5
33.3
1
6.7
Hypotension
4
26.7
1
6.7
Abdominal pain
3
20.0
1
6.7
Device related infection
2
13.3
2
13.3
Electrocardiogram QT prolonged
1
6.7
1
6.7
Cellulitis
1
6.7
1
6.7
Dysphagia
1
6.7
1
6.7
Mucosal inflammation
1
6.7
1
6.7
Sinus bradycardia
1
6.7
1
6.7
Bacteremia
1
6.7
1
6.7
Staphylococcal bacteremia
1
6.7
1
6.7
Orthostatic hypotension
1
6.7
1
6.7
N=15. All treatment-emergent adverse events (TEAE) with grade 1-2 occurring in ≥6/15 patients and all events with ≥Grade 3 regardless of relatedness to study treatment and irrespectively of severity are presented.
Safety profile (Table 3)
The most common TEAEs were expected cytopenias, mostly associated with the lymphodepleting regimen.
Grade 1-2 cytokine release syndrome was noted in 10 (71.4%) of 14 treated patients.
Figure 2. T cell Persistence and Tumor Infiltration
a)
T cell Persistence in Blood
b)
T cell Infiltration in Tumor
5
Cells
Pre-Infusion
3.9
4.2
4
Post-Infustion
ofTotal
3
2
1.3
1.8
1.6
%
1
004-4.9e
003-2.9e
002-2.4e
0.2
0.1
002-1.8e
N/A
003-8.4e
0.9
0.6
0
12
28
27
8
96
71
95
39
45
63
73
164
4
0
0
0
0
0
0
0
1
1
1
1
Infused T cells were tracked in patients' blood via flow-cytometry-based immunomonitoring (a) and in tumor biopsy via TCRβ sequencing (b). Target-specific T cells were in most cases not detectable in pre-infusion biopsies.
a)
T cell clone composition
b)
Tracking of T cell clones
c)
TCR functional avidity
of T cell products
4
in the blood
rearrangments)
3
100
2
*
(productive
1
cellsT rearrangments)
PRAME
cellsTof%
50
15
0
% of (productive
cellsTof% rearrangments)(productive
COL6A3
10
*
0
5
*
PRAME Sorted COL6A3 Sorted
0
1
ek
e
ek
ne
e
ek
k
e
k
e
Baseli
ay
ee
W
2
e
W
W
12
W
D
1
W
3
7
Patient #096 entered the study with PD and received two polyclonal T cell products (COL6A3, PRAME). TCRs were identified from the T cell products and functional avidity was determined after TCR re- expression in Jurkat cells. Both products contained clones with high functional avidity (c). The clone with highest avidity gained dominance in the blood post-infusion (*) (a, b). Patient showed 26% tumor shrinkage at 6 weeks, associated with high T cell frequencies at 2 weeks (b). T cell frequencies dropped at 8 weeks (b) and phenotype shifted towards terminal differentiation (data not shown) associated with progression of the patient at 12 weeks.
CONCLUSIONS
ACTolog® demonstrates feasibility of a multi-targetmulti-T cell product approach
To our knowledge, this is the first demonstration of feasibility of "actively personalized" (Brittenet al., Nat Biotech, 2013) ACT directed to multiple defined pHLA targets, where each product combination is guided by confirmed target expression in patient-derived biopsies.
The target positivity rate of 90% demonstrated that such a warehouse approach leads to minimal patient attrition due to lack of target expression which is common in other ACT trials.
ACTolog® was generally well-tolerated in heavily pretreated patients
ACTolog® shows remarkable T cell persistence and tumor infiltration
ACTolog® treatment resulted in high target-specific T cell levels and persistence with total frequencies up to ~80% of all peripheral CD8+ T cells in the blood (Figure 2a).
Target-specificT cells were detectable in post-treatment tumor biopsies (Figure 2b).
Individual TCRs in the endogenous T cell products showed a broad range of avidities, however the majority being of low avidity (EC50>10-8 M, data not shown), reflecting the range to be expected in the natural immune repertoire.
ACTolog® revealed long-term disease stabilization in some patients
All three patients with prolonged disease stabilization showed high frequency of target- specific T cells (>40% of CD8+ T cells) in the blood post-infusion.
Two of these three patients received a COL6A3 exon 6-specific T cell product suggesting that targeting the tumor stroma may be a promising approach.
ACTolog® results warrant further evaluation of a multi-target ACT approach using potent high- avidity TCRs (i.e. autologous TCR-engineered T cells)
This work was supported by a Product Development Research Grant from CPRIT (DP150029) Corresponding author: atsimber@mdanderson.org;
Immatics NV published this content on 10 November 2020 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 10 November 2020 12:28:02 UTC
Canada
Deutschland
España
France
Italia
Schweiz (DE)
United Kingdom
Report
