On November 9, 2021 Precision BioSciences, Inc. (Nasdaq: DTIL), a clinical stage biotechnology company using its ARCUS genome editing platform to develop allogeneic CAR T and in vivo gene editing therapies, reported that the abstract titled, "Allogeneic CAR T cells with Deoxycytidine Kinase Knockdown Demonstrate Resistance to Fludarabine" has been accepted for poster presentation at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 36th Annual Meeting taking place November 10 – 14, 2021 in Washington, D.C (Press release, Precision Biosciences, NOV 9, 2021, View Source [SID1234594872]).

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Abstract/Poster Details:

Abstract Number & Title: Abstract #140. Allogeneic CAR T cells with Deoxycytidine Kinase Knockdown Demonstrate Resistance to Fludarabine
Category: Cellular Therapies
Authors: Michelle B. Pires, M.S., and Aaron J. Martin, Ph.D., both of Precision BioSciences

Abstracts for the SITC (Free SITC Whitepaper) 36th Annual Meeting are now available on the SITC (Free SITC Whitepaper) Annual Meeting website and in the Journal for ImmunoTherapy of Cancer (JITC). This abstract will be presented as an electronic poster that will be displayed on the SITC (Free SITC Whitepaper) 2021 virtual meeting platform from 7 AM EST on Friday, November 12, 2021 until the virtual meeting platform is closed on January 9, 2022.

In this preclinical study, ARCUS gene editing was used to disrupt the endogenous T cell receptor by inserting a transgene carrying a CD19-specific CAR and an RNAi sequence designed to specifically knockdown deoxycytidine kinase (dCK), a protein that converts fludarabine from its prodrug form to an active compound. This single-step approach generated allogeneic, fludarabine-resistant (FluR) CAR T cells. In these cells, the dCK RNAi sequence produced a 70% reduction in dCK mRNA abundance, and resistance to fludarabine was confirmed in vitro. Additionally, treatment of tumor-bearing mice with fludarabine and FluR CAR T cells resulted in enhanced tumor clearance and survival compared to mice receiving control CAR T cells alone or control CAR T cells and fludarabine.

On November 9, 2021 BerGenBio ASA (OSE:BGBIO), a clinical-stage biopharmaceutical company developing novel, selective AXL inhibitors for severe unmet medical needs, reported that it will deliver an e-poster presentation at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 36th Annual Meeting, taking place online from 10th-14th November 2021 (Press release, BerGenBio, NOV 9, 2021, View Source [SID1234594871]).

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The e-poster presentation provides pre-clinical and clinical data suggesting that bemcentinib restored response to anti-PD-1 treatments in non-small cell lung cancer (NSCLC) patients harboring STK11 mutations. STK11 is an important tumor suppressor gene reported in some studies to confer immunotherapy resistance in NSCLC. STK11 mutations are present in about 10-20% of NSCLC patients.

In pre-clinical NSCLC mouse models harboring STK11 mutations, sensitivity to PD-1 blockade was evaluated in the absence and presence of bemcentinib. Systemic inhibition of AXL with bemcentinib resulted in the expansion of tumor-associated T cells and restored therapeutic response to anti-PD-1 check point inhibition.

In parallel, data from BerGenBio’s Phase II bemcentinib and pembrolizumab combination study (BGBC008) in advanced NSCLC showed that 3 of 3 evaluable patients with identified STK11 mutations demonstrated objective clinical response / clinical benefit to the combination of bemcentinib and pembrolizumab.

Martin Olin, Chief Executive Officer at BerGenBio, commented: "While the data are limited, they suggest a mechanism by which treatment with bemcentinib could restore sensitivity to anti-PD-1 treatment in NSCLC patients harboring STK11 mutations. Up to 20% of the NSCLC patient population has been reported to harbor STK11 mutations representing a large subgroup of NSCLC."

Mutations in the tumor suppressor STK11/LKB1 have in some studies been reported as associated with negative predictive and prognostic impact in NSCLC patients receiving anti-PD-1/PD-L1 treatments. STK11 mutant tumors are characterized by a suppressive tumor micro-environment devoid of cytotoxic T cells. The study hypothesized that targeting the receptor tyrosine kinase AXL, a known driver of an innate immune suppressive microenvironment, would restore sensitivity to PD-1 blockade in pre-clinical models as well as in patients harboring STK11 mutated NSCLC.

Full abstracts are available on the SITC (Free SITC Whitepaper) website here: View Source

Full details of the presentation are below.

Title: AXL targeting with bemcentinib restores PD-1 blockade sensitivity of STK11/LKB1 mutant NSCLC through innate immune cell mediated expansion of TCF1+ CD8 T cells

Author: Rolf A. Brekken et al.

Session/Abstract ID: 602

The presentation will be made available on BerGenBio’s website, under ‘Presentations’.

On November 9, 2021 Applied DNA Sciences, Inc. (NASDAQ: APDN) (Applied DNA or the "Company"), a leader in Polymerase Chain Reaction (PCR)-based DNA manufacturing and nucleic acid-based technologies, reported the publication of a study in Molecular Therapy: Methods and Clinical Development on a methodology for the manufacture of novel types of CAR constructs that employ the Company’s LinearDNA as part of a manufacturing process for the efficient generation of CD19-specific CAR T-cells (CAR19 T-cells) based on co-electroporation of a LinearDNA transposon and mRNA encoding of piggyBac transposase (Press release, Applied DNA Sciences, NOV 9, 2021, View Source [SID1234594870]). PCR-produced LinearDNA is manufactured by LineaRx, the Company’s majority-owned subsidiary, to serve as a pure, fast, and flexible alternative to plasmid DNA (pDNA) for biotherapeutic applications.

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The study, titled "Enzymatically produced piggyBac transposon vectors for efficient non-viral manufacturing of CD19-specific CAR T cells", details the utility of LinearDNA in the cost-effective production of preclinical CAR T cells. Its authors, members of the Institute of Hematology and Blood Transfusion (ÚHKT) in Prague, Czechia, and the Faculty of Natural Sciences at Charles University, also in Prague, propose that the combination of LinearDNA and a transposon/transposase system offers therapy developers an effective research tool for making experimental CAR T cells rapidly and efficiently without the need for complicated virus production or the use of pDNA.

Pavel Otáhal, contributing author and Head of the Gene Immunotherapy Research Department at ÚHKT, stated, "Our study compares the manufacture of CAR19 T-cells via PCR-made transposon DNA (LinearDNA) with mRNA encoding of the transposase against a conventional plasmid approach. We found CAR T efficacy of the LinearDNA system versus the plasmid system to be identical. Further, we found no mutations in the coding sequence of LinearDNA and with >99% purity that obliviated the need for purification typical of a plasmid approach. As an institution dedicated to diagnosing and treating serious blood diseases and with the ability to pursue investigational medicines from development to manufacture and clinical trial for patients who have exhausted all approved treatment options, having a cost-effective and rapid production chain is integral to ÚHKT’s mission. We find LinearDNA to be an excellent platform for CAR T-cell therapy development."

Dr. James A. Hayward, president and CEO of Applied DNA, said, "The clinical successes of CAR T-cell therapy against blood cancers have been impressive, though limited by the complex production of viral vectors that are currently needed for T-cell genetic transformation and the use of pDNA. These manufacturing complexities have likewise hindered research on CAR T-cell therapies. As described in the publication, the use of LinearDNA, coupled with non-viral transfection systems, we believe, overcomes many of the existing manufacturing complexities associated with pDNA and viral vectors, thereby offering therapy developers a rapid and cost-effective tool for manufacturing preclinical CAR T cells. The authors’ findings as it relates to LinearDNA coincide with the industry’s growing interest in alternatives to pDNA for CAR T-cell therapies with approximately 50% of recent CRO orders coming from CAR T cell developers."

The detailed study write-up can be found at: Molecular Therapy: Methods and Clinical Development, the leading journal for research in the areas of gene transfer, vector development and design, stem cell manipulation, development of gene-, peptide-, protein-, oligonucleotide-, and cell-based therapeutics to correct genetic and acquired diseases, vaccine development, preclinical target validation, safety/efficacy studies, and clinical trials.

On November 9, 2021 BerGenBio ASA (OSE: BGBIO), a clinical-stage biopharmaceutical company developing novel, selective AXL inhibitors for severe unmet medical needs, reported that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation for bemcentinib in combination with an anti-PD-(L)1 agent as treatment for patients with STK11 altered advanced/metastatic NSCLC patients without actionable mutations (Press release, BerGenBio, NOV 9, 2021, View Source [SID1234594869]).

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Fast Track designation is intended to facilitate the development and review of drugs used to treat serious conditions and to fill an unmet medical need. It will enable BerGenBio to have more frequent interactions with the FDA throughout the drug development process so that an approved product can potentially reach the market faster.

In a separate release today 9 November 2021, BerGenBio announced that in pre-clinical NSCLC mouse models harboring STK11 mutations, sensitivity to PD-1 blockade was evaluated in the absence and presence of bemcentinib. Systemic inhibition of AXL with bemcentinib resulted in the expansion of tumor-associated T cells and restored therapeutic response to anti-PD-1 check point inhibition.

Further, data from BerGenBio’s Phase II bemcentinib and pembrolizumab combination study (BGBC008) in advanced NSCLC showed that 3 of 3 evaluable patients with identified STK11/LKB1 mutations demonstrated objective clinical response / clinical benefit to the combination of AXL inhibitor bemcentinib and pembrolizumab.

Martin Olin, Chief Executive Officer of BerGenBio, commented: "We are very pleased to receive Fast Track designation from the FDA for the second time this year and look forward to continuing to explore bemcentinib’s potential as a treatment option for NSCLC patients. It has been reported that patients habouring STK11 mutations represents up to 20% of the total NSCLC patient population, representing a large, identifiable subgroup of patients who may benefit from treatment with an AXL inhibitor such as bemcentinib."

On November 9, 2021 Immunocore Holdings Plc (Nasdaq: IMCR), a late-stage biotechnology company pioneering the development of a novel class of T cell receptor (TCR) bispecific immunotherapies designed to treat a broad range of diseases, including cancer, infectious and autoimmune disease, reported that it will present six posters at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 36th Annual Meeting, to be held in Washington, D.C. and virtually between November 10-14th (Press release, Immunocore, NOV 9, 2021, View Source [SID1234594868]).

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The Company will present a Phase 1b study of tebentafusp in combination with durvalumab (anti-PDL1) and/or tremelimumab (anti-CTLA4) in metastatic cutaneous melanoma (mCM) and new clinical data analyzing gene expression and overall survival from the metastatic uveal melanoma (mUM) tebentafusp monotherapy program. Four additional posters depicting new analyses from tebentafusp in metastatic uveal melanoma, as well as the Company’s proprietary soluble TCR bispecific ImmTAC platform will be made available for on-demand viewing throughout the SITC (Free SITC Whitepaper) 36th Annual Meeting on the SITC (Free SITC Whitepaper) website.

In a phase 1b trial in mCM of tebentafusp in combination with checkpoint inhibitors, in which the majority of patients had previously received prior anti-PD(L)1 therapy, the maximum target doses of tebentafusp (68 mcg) plus durvalumab (20 mg/kg) with and with/out tremelimumab (1 mg/kg) were tolerated in both doublet and triplet arms of the study. Preliminary evidence of tebentafusp clinical activity in mCM patients who received prior anti-PD(L)1 therapy, currently an unmet medical need, included 1-year overall survival (OS) rate of 76%. In mCM patients who were refractory (defined as best response of progressive disease) to prior anti-PD(L)1, the 1-year OS rate was 61%.

"At SITC (Free SITC Whitepaper), we build upon our previously released survival data in metastatic uveal melanoma with the clinical results of tebentafusp in combination with checkpoint inhibitors in metastatic cutaneous melanoma patients who previously received anti-PD(L)1 therapy. In this population with poor prognosis, and which is an unmet need, treatment with tebentafusp in combination with checkpoints resulted in a 76% one-year overall survival rate" said David Berman, Head of Research and Development at Immunocore.

In a new analysis of baseline gp100 protein expression by immunohistochemistry of tumor biopsies from the Phase 2 and Phase 3 tebentafusp monotherapy mUM trials, OS benefit was observed for both high and low gp100 protein tumor expression. Additionally, circulating tumor DNA (ctDNA) reductions were also observed for both high and low gp100 protein tumor expression, while high gp100 expression at baseline was associated with greater T cell infiltration into the tumor and greater IFNg, granzyme B and perforin expression.

"We are encouraged that the survival benefit from tebentafusp in metastatic uveal melanoma was independent of baseline gp100 tumor expression in this new analysis based on immunohistochemistry. This benefit, apparent even in patients with low gp100 protein expression, may reflect the high sensitivity of our TCR bispecific platform, which may be able to recognize cancer cells with very low target expression" said David Berman.

POSTER PRESENTATIONS

Title: Overall survival on tebentafusp in metastatic uveal melanoma (mUM) across the range of tumor gp100 expression levels

Poster #: 868
Author: Emma Leach
Location: Poster Hall (Hall E)
Date & Time: November 13th – 12:30-2:00 pm and 7:00-8:30 pm ET
Title: Results from Phase Ib study of tebentafusp (tebe) in combination with durvalumab (durva) and/or tremelimumab (treme) in metastatic cutaneous melanoma

Poster #: 546
Author: Omid Hamid
Location: Poster Hall (Hall E)
Date & Time: November 13th – 12:30-2:00 pm and 7:00-8:30 pm ET
Title: Updated survival of patients with previously treated metastatic uveal melanoma who received tebentafusp

Poster #: 538
Author: Joseph J. Sacco
Title: Selective affinity-enhanced T cell receptor bispecific targeting of KRASG12D neoantigen driven cancers

Poster #: 882
Author: Andrew Poole
Location: Poster Hall (Hall E)
Date & Time: November 13th – 12:30-2:00 pm and 7:00-8:30 pm ET
Title: IL-2 Combination with ImmTAC Overcomes CD163+ Macrophage Inhibition of Redirected T Cell Killing of Tumour Cells

Poster #: 571
Author: Esra Güç
Location: Poster Hall (Hall E)
Date & Time: November 12th – 12:40-2:10 pm and 7:00-8:30 pm ET
Title: Radiomic Markers Associated with Clinical Benefit in Advanced Uveal Melanoma Patients with Radiographic Progression on Tebentafusp

Poster #: 819
Author: Volkan Beylergil
Virtual ePosters presented at the conference will be made available throughout the SITC (Free SITC Whitepaper) 36th Annual Meeting on the SITC (Free SITC Whitepaper) website.