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ACHILLES THERAPEUTICS PLC

(ACHL)
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SITC 2021 Poster 193: The Achilles VELOSTM Process 2 boosts the dose of highly functional cNeT

11/12/2021 | 07:12am EST

The Achilles VELOSTM Process 2 boosts the dose of highly functional clonal neoantigen-reactive T cells for

193

precision personalized cell therapies

Joseph Robinson1, Amber Rogers1, Daisy Melandri1, Amy Baker1, Anabel Ramirez Aragon1, Sidra Nawaz1, Michael Epstein1, Shreenal Patel1, Jennine Mootien1, Andrew Craig1, Satwinder Kaur-Lally1, Hinal Patel1, Andreas Schmitt2, Farah Islam3, Mariam Jamal-Hanjani3, David Lawrence4, Martin Forster3, Samra Turajlic2, Sergio A. Quezada1, Katy Newton1, Eleni Kotsiou1

  1. Achilles Therapeutics UK Limited, London, United Kingdom; 2) Royal Marsden NHS Foundation Trust, London, United Kingdom; 3) University College London Cancer Institute, London, United Kingdom; 4) UCLH and Barts NHS Trusts, London, United Kingdom; 5) Corresponding author - for further information please email: s.quezada@achillestx.com

Introduction

Adoptive transfer of ex-vivo expanded Tumour-Infiltrating Lymphocytes (TIL) has shown promise in the clinic. However, the non-specific expansion of TILs and the lack of understanding of the active component of TIL has resulted in poor correlation between clinical response and dose as well as poor understanding of response and resistance mechanisms. The VELOSTM manufacturing process generates a precision and personalised treatment modality by targeting clonal neoantigens with the incorporation of an antigen-specific expansion step to enrich the product for these specificities. Achilles has developed a second VELOSTM process to boost the neoantigen-reactive cell dose while maintaining key qualitative features associated with function. Here we report the in-depth characterisation of clonal neoantigen-reactive T cells (cNeT) products expanded using the two VELOSTM processes.

Methods

Figure 1: Clonal neoantigen specific TIL can be identified following the culture of tumour fragments in VELOSTM Process 2

A

B

C

10

10

(%)reactivityNeoantigen

20

cellsreactiveTotal

10

9

Pateint 1

CD3lTota

cells

15

Pateint 3

Patient 2

+

10

9

10

8

Patient 4

10

Patient 5

10

8

10

7

5

10

7

0

10

6

Proc. 1

Proc. 2

Proc. 1

Proc. 2

Proc. 1

Proc. 2

Following culture of tumour fragments with IL2, processes 1 and 2 yielded similar numbers of TIL (A; values scaled to tumour mass). Achilles' proprietary potency assay was used to identify the proportion of clonal neoantigen reactive cells within the TIL (B). The total number of clonal neoantigen reactive TIL was similar in processes 1 and 2 (C). Lines at median; n=5.

Figure 2: VELOSTM Process 2 generates a 29 fold greater number of T cells

Results

Figure 4: VELOSTM Process 2 generates a product with multiple clonal neoantigen reactivities

Single peptide reactivities

Patient

Process 1

Process 2

Difference

1

1

4

+3

2

1

3

+2

3

2

5

+3

4

2

17

+15

5

No data

18

N/A

The number of individual clonal neoantigen reactivities was determined by ELISpot. VELOSTM Process 2 generated a product with reactivities to multiple clonal neoantigens without loss of reactivities compared to Process 1. For patient 5, insufficient cells were generated by Process 1 to carry out ELISpot.

Figure 5: VELOSTM Process 2 generates a product made up of mainly CD4+ and CD8+ effector memory cells

A

B

CD4+

CD8+

Figure 7: T cells from VELOSTM Process 2 retain sensitivity to IL2

AB

+

40

10

CD3in

normalizedMFI

+

5pSTAT%

20

5

0

rolcontto

0

PBMC Proc. 1Proc. 2

PBMC Proc.1 Proc.2

T cells were stimulated with low dose IL2 (100IU/ml) and phosphorylation

of STAT5 was measured by flow cytometry. Phosphorylation occurred in similar proportions of CD3+ cells in both processes (A). Geometric mean fluorescence intensity (MFI) of pSTAT5 staining was also similar (B). Bars at median; n=4.

Figure 8: T cells from VELOSTM Process 2 retain capacity to secrete cytokines

A

B

C

400

30

15000

+

+

CD3in FIM

300

+

CD3in MFI

CD3in MFI

10000

20

200

500

50

• Matched tumours and peripheral blood from patients

undergoing routine surgery were obtained from patients with

primary NSCLC (n=3) or metastatic melanoma (n=2)

(NCT03517917).

• TIL were expanded from tumour fragments in the presence of

IL-2.

• Peptide pools, corresponding to the clonal mutations identified

using the PELEUSTM bioinformatics platform, were generated.

A

expansion

1000

100

Fold

10

1

0.1

Proc. 1

Proc. 2

B

dose

10

11

cell

10

10

-

CD56

10

9

+

D3C

10

8

C

Patient 1

Patient 2

Patient 3

Pateint 4

Patient 5

Proc. 1

Proc. 2

(%)cells

CD45of +

Proportion

100

50

0

NK (CD3

-

+

CD56 )

+

+

CD3 CD56

-

+

CD3 CD56

Proc. 1

Proc.2

CD4

+

TEMRA

+

Central memory

CD8

Effector memory

Process 1

Process 2

+

+

10

+

25

250

IL2

αTNF

γINF

0

0

0

Proc.1

Proc.2

Proc. 1

Proc. 2

Proc.1

Proc.2

T cells were stimulated with a poly clonal stimulus (Staphylococcal Enterotoxin B) and cytokine production was measured using Achilles proprietary potency assay. CD3+ cells from Process 1 and Process 2 generated similar amounts of INFγ (A), IL2 (B) and TNFα (C). Graphs show geometric mean fluorescence intensity (MFI) normalized to control; bars at median; n=5.

• cNeT were expanded by co-culture of TIL with peptide-pulsed

autologous dendritic cells.

• For VELOSTM Process 2 additional media supplementation was

added throughout the process. Cell expansion was boosted at

the end of the co-culture with an optimized stimulation

cocktail.

• Neoantigen

reactivity

was assessed using our

proprietary

potency

assay with peptide pool

rechallenge followed by

intracellular

cytokine

staining. Single peptide

reactivities

were

identified using ELISpot

and flow

cytometric

analysis for

in-depth

phenotyping of cNeT was performed.

During the selective expansion phase of the VELOSTM process, Process 2 gave a greater fold expansion of T cells (A; lines at median) and an increase in total T cells generated (B; values scaled to tumour mass; lines at median). The majority of cells generated by both processes were CD3+CD56- (C; bars show means). * p<0.05 one tailed Wilcoxon test, n=5.

Figure 3: VELOSTM Process 2 generates a 18 fold greater number of cNeT

A

B

C

reactivityNeoantigen

100

reactivityoantigenNe

80

1011

CD4in

CD8in

dosecellReactive

Patient 1

60

(%)

(%)

1010

Patient 2

40

Patient 3

+

+

20

Patient 4

Patient 5

10

109

10

5

108

1

0

10

7

Proc. 2

Proc. 1 Proc. 2

Proc. 1 Proc. 2

Proc. 1

Using Achilles' proprietary potency assay, the active drug component (cNeT) was quantified for both CD4+ (A) and CD8+ (B) cells. No difference in the proportion of cNeT was observed between Process 1 and Process 2. The overall number of cNeT generated by Process 2 was significantly higher than was generated by Process 1. Lines at medians; * p<0.05 one tailed Wilcoxon test; n=5.

Phenotyping was carried out by flow cytometry at the end of the co-culture period. The VELOSTM processes generated products made up of both CD4+ and CD8+ cells (A; n=5). Products were primarily effector memory cells (CD45RA-CD197-) with some TEMRA cells (CD45RA+CD197-) and few central memory cells (CD45RA-CD197+) . The products of Process 2 had a lower proportion TEMRA cells compared to Process 1 (B; n=4). Pie charts show mean frequencies.

Figure 6: cNeT from VELOSTM Process 2 express similar levels of immune checkpoint molecules

100

(%)

Process 1

TcNe

Process 2

of

50

Proportion

0

CD279+

CD278+

TIGIT+

CD366+

Restimulation with clonal neoantigen pareptide pools and staining for cytokine secreting cells enables phenotyping of the active drug component of the product of the VELOSTM process. cNeT from Process 2 showed no increase in immune checkpoint molecules compared to cNeT from Process 1. Bars at median; n=4.

Conclusions

  • Achilles proprietary potency assay quantifies cNeT dose facilitating optimization of the VELOSTM process.
  • VELOSTM Process 2 generates an increased cNeT dose compared to Process 1
  • cNeT generated using VELOSTM Process 2 maintain key phenotypic features associated with function
  • This proof of concept data supports the transfer of VELOSTM Process 2 to clinical manufacture for two first in human studies

for treatment of solid cancer.

References

  1. McGranahan N., et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science. 6280: 1463-1469 (2016)
  2. Robertson J., et al. Adoptive cell therapy with tumour-infiltrating lymphocytes: the emerging importance of clonal neoantigen targets for next-generation products in non- small cell lung cancer. Immuno-oncology Technology. 3:1-7 (2019)
    Acknowledgements
    The authors would like to thank the participating patients and their families for donation of material used in this study.
    Disclosures

This study was funded by Achilles Therapeutics UK Limited.

© Achilles Therapeutics UK Ltd. 2021

Disclaimer

Achilles Therapeutics plc published this content on 12 November 2021 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 12 November 2021 12:10:15 UTC.


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