On June 5, 2023 NKGen Biotech Inc. (NKGen), a clinical-stage biotechnology company focused on the development and commercialization of innovative autologous, allogeneic and CAR-NK Natural Killer (NK) cell therapeutics, reported a poster presentation of preclinical and Phase I/IIa clinical data by its parent company, NKMax Co., Ltd. (NKMax) (Press release, NKMax America, JUN 5, 2023, View Source [SID1234632518]). The poster titled "The safety and efficacy of SNK01 (autologous natural killer cells) in combination with cytotoxic chemotherapy after failure of prior tyrosine kinase inhibitor in non-small cell lung cancer: Preclinical mouse model and phase I/IIa clinical study" was presented on June 4th at the 2023 ASCO (Free ASCO Whitepaper) Annual Meeting.

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"The SNK01 program continues to show positive progress, with the most recent preclinical and Phase I/IIa clinical data presented at ASCO (Free ASCO Whitepaper)," said Paul Y. Song, M.D., Chief Executive Officer of NKGen. "Lung adenocarcinoma accounts for nearly 40% of all non-small cell lung cancers (NSCLC) and represents the fastest growing subtype of lung cancer worldwide, especially among non-smoking women. Approximately 15-25% of lung cancer patients diagnosed in the U.S., and up to 50% of patients in Asia, will have an EGFR-positive mutation. While Tyrosine Kinase Inhibitors (TKIs) have shown tremendous efficacy in the front-line setting, salvage regimens have proven to be far less effective in TKI resistant disease. No SNK01-related adverse event of Grade 3 or higher was observed when autologous natural killer cells (SNK01) were delivered in combination with cytotoxic chemotherapy, including cetuximab. The data also demonstrated antitumor activity in both a cell-derived TKI resistant xenograft (CDX) mouse model and in patients with EGFR-mutated non-small cell lung cancer who failed prior TKI treatment. The results of this study are promising and warrant further evaluation. We are excited about the potential therapeutic benefits of SNK01, particularly in this growing population of refractory patients with difficult-to-treat cancers."

In the preclinical study, a humanized CDX mouse model with functional human immune system using an osimertinib-resistant lung cancer cell line was established. Mice were divided into four groups based on treatment (no treatment [n=2]; cetuximab monotherapy [n=3]; SNK01 monotherapy [n=4]; SNK01 in combination with cetuximab [n=4]) and treated weekly for five weeks (SNK01, 1×107 cells/dose; cetuximab, 20 ug/dose). Tumors were tracked weekly through an in vivo imaging system and extracted after completion of treatment. Flow cytometric analysis showed that NK cells (CD45+/CD56+/CD3-) were significantly increased in the groups administrated SNK01, while cytotoxic T cells (CD45+/CD3+/CD8+) in the cetuximab group decreased. The volume of tumor extracted after completion of treatment was the smallest in SNK01 plus cetuximab group.

In the Phase I/IIa dose-escalation clinical trial (ClinicalTrials.gov Identifier: NCT04872634), 12 patients with EGFR-mutated NSCLC who failed prior TKI treatment were enrolled and received weekly infusions of SNK01 for seven or eight weeks (4×109 cells/dose [n=6]); or 6×109 cells/dose [n=6]), SNK01 combination with gemcitabine/carboplatin (n=6) or gemcitabine/carboplatin/cetuximab (n=6). This trial was designed as dose-escalation of SNK01 following a "3+3" design. The primary and secondary endpoints were safety and efficacy, respectively. Median age of patients was 61 years, 33.3% were male, and all patients had lung adenocarcinoma. Dose-limiting toxicity was not observed, therefore the maximum tolerated dose of SNK01 was determined to be 6×109 cells/dose. No SNK01-related adverse events of Grade 3 or higher were observed. The objective response rate was 25% (3/12), disease control rate (DCR) was 100%, with 3/12 patients experiencing a partial response (25%) and 9/12 with stable disease (75%). Median progression free survival (PFS) was 143 days. Some patients are still being followed and an updated PFS will be provided at a later date.

On June 5, 2023 Erasca presented its investor presentation (Presentation, Erasca, JUN 5, 2023, View Source [SID1234632510])

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On June 5, 2023 Cellectis (the "Company") (Euronext Growth: ALCLS – NASDAQ: CLLS), a clinical-stage biotechnology company using its pioneering gene-editing platform to develop life-saving cell and gene therapies, reported preclinical data at an oral presentation and two poster presentations at the International Society for Cell & Gene Therapy (ISCT) 29th annual event that took place at the Paris Convention Center in Paris, France on May 31 – June 3, 2023 (Press release, Cellectis, JUN 5, 2023, View Source [SID1234632507]).

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"Our breadth of scientific presence at the 29th ISCT annual event reflects the type of cutting-edge research our teams undertake, which we believe is essential to address patients’ unmet medical need. We are proud of the pre-clinical results presented and remain deeply focused on the development of our product candidates to deliver breakthrough treatments that could benefit thousands of patients worldwide," said André Choulika, Ph.D., Chief Executive Officer at Cellectis.

Oral Presentation

UCART20x22: allogeneic dual CAR T-cells for the treatment of B-cell malignancies

Autologous CAR T-cell therapies have shown outstanding responses in the treatment of selected blood cancers, predominantly B-cell malignancies. Nevertheless, long term studies revealed that some patients treated with CD19 or CD22 CAR T-cells can relapse due to low target antigen expression in tumor cells or to antigen loss. The therapeutic options after CAR T-cell relapses are limited, emphasizing the need to develop novel therapies to improve current survival rates. There is also need for allogeneic "off-the-shelf" therapies that could be readily available at the time of treatment decision and overcome limitations of current autologous approaches.

UCART20x22 is Cellectis’ first dual-targeting, allogeneic cell therapy product candidate targeting CD20 and CD22, to address the current challenges in the treatment of B-cell malignancies.

UCART20x22 features TALEN-mediated disruptions of the TRAC gene (to minimize the risk of graft-versus-host disease) and of the CD52 gene (to permit use of a CD52-directed monoclonal antibody in patients’ lymphodepletion regimen) to enhance CAR T engraftment, expansion, and persistence.

Cellectis demonstrates that UCART20x22 displays robust activity in vitro and in vivo, against targets expressing heterogeneous levels of CD22 and CD20. We have used in vitro cytotoxicity assays against different tumor cell lines, showing strong activity whether these cells express a single antigen (CD20 or CD22) or both antigens simultaneously, as well as IFNg release in response to antigen specific stimulation.

The oral presentation highlighted the following preclinical data:

Robust in vitro and in vivo cytolytic activity against tumors expressing different antigen combinations.
Efficient in vitro targeting of primary B-cell Non-Hodgkin Lymphoma (B-NHL) samples harboring different CD20 and CD22 expression levels, suggesting that UCART20x22 has the potential to reach a large patient population.
Dose dependent tumor control in vivo, using batches manufactured internally, harboring a tumor cell line as well as in a Patient Derived Xenograft (PDX) model of B-NHL.
Overall, Cellectis provided pre-clinical proof-of-concept data for a first allogeneic dual CAR T-cell to overcome current mechanisms of resistance to CAR T-cell therapies in B-NHL, while providing a potential therapeutic alternative to CD19 targeting and allowing to reduce the time from treatment decision to infusion.

UCART20x22 is currently evaluated in the NATHALI-01 Phase 1/2a clinical study in patients with relapsed/refractory B-NHL (NCT05607420).

The oral presentation is available on Cellectis’ website: View Source

Poster Presentations:

Non-viral DNA delivery associated to TALEN gene editing leads to highly efficient correction of sickle cell mutation in long-term repopulating hematopoietic stem cells

Sickle cell disease stems from a single point mutation in the HBB gene which results in sickle hemoglobin. For patients who are not eligible for an allogeneic stem cell transplantation, nuclease-based gene therapy approaches provide a relevant therapeutic alternative to restore functional hemoglobin production.

Cellectis leveraged TALEN technology to develop a gene editing process leading to highly efficient HBB gene correction via homology directed repair, while mitigating potential risks associated to HBB gene knock-out. Furthermore, we compared viral (TALEN-V) and non-viral (TALEN-NV) DNA template delivery strategies in mobilized healthy donor (HD) or non-mobilized homozygous sickle patient (HbSS) hematopoietic stem and progenitor cells (HSPCs).

Both strategies led to high and comparable efficiencies of HBB gene correction in vitro in HD and HbSS, without affecting viability, purity or clonogenic potential of corrected HSPCs.

The poster presentation highlighted the following data:

TALEN-mediated engineering efficiently corrects the mutated HBB gene in clinically relevant HSPCs and promote phenotype correction in fully mature RBCs.
Cellectis optimized TALEN gene editing process mitigates potential safety challenges by reducing the frequency of HBB gene inactivation (<10% β-thal cells).
Non-viral DNA template-mediated HBB repair mitigates p53 DNA damage response activation, preserves edited LT-HSCs fitness and enables their efficient engraftment in vivo using an immunodeficient murin model.
These results show that non-viral DNA delivery associated to TALEN gene editing reduces the toxicity usually observed with viral DNA delivery and allows high levels of HBB gene correction in long-term repopulating hematopoietic stem cells.

The poster presentation is available on Cellectis’ website: View Source

Comprehensive Analysis of the Editing Window of TALE Base Editors

One of the most recent advances in the genome editing field has been the addition of the so-called "C-to-T TALE base editors" (TALE-BE), an innovative platform for cell therapy that relies on the deamination of cytidines within double strand DNA, through the formation of an uracil (U) intermediate. These molecular tools are fusions of a transcription activator-like effector (TALE) domain for the binding of a specific DNA sequence, split-DddA deaminase halves that will catalyze the conversion of a cytosine (C) to a thymine (T) upon reconstitution, and an uracil glycosylase inhibitor (UGI).

Cellectis aimed to systematically investigate the influence of the sequence context surrounding the targeted Cytosine on TALE-BE C to T conversion efficiency.

Recently we developed a strategy that allowed us to comprehensively characterize editing efficiencies in function of the TC position within the TALE-BE editing windows. This method is specifically taking advantage of the highly precise and efficient TALEN mediated ssODN knock-in in primary T cells, allowing to focus on how target composition and spacer variations can affect TALE-BE activity/efficiency.

The poster presentation highlighted the following data:

Determined optimal spacer length (13/15 bp) for highly efficient TALE-BE for both C40/C40 and C11/C11 scaffolds.
Determined optimal common sequence context for high editing rates.
Determined that editing efficiency of the C11/C11 scaffold is highly dependent on Cytosine position requirements, resulting in more stringent activity in a context of 15 bp spacer size and decreasing the effects of bystander editing.
Overall, we believe that the knowledge obtained will allow to better design efficient TALE-BE while improving the specificity profiles of this innovative editing platform.

The poster presentation is available on Cellectis’ website: View Source

On June 5, 2023 Foundation Medicine, Inc., a pioneer in molecular profiling for cancer, reported that it has entered a strategic collaboration with Merck KGaA, Darmstadt, Germany to develop FoundationOneLiquid CDx and FoundationOneCDx as companion diagnostics in the U.S. market for selected marketed and pipeline treatments (Press release, Foundation Medicine, JUN 5, 2023, View Source [SID1234632502]). This new agreement builds on the data solutions partnership Merck KGaA, Darmstadt, Germany and Foundation Medicine entered in 2020 to help accelerate the development of novel targeted therapies, individually and in combination.

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"We look forward to ongoing collaboration as they leverage our portfolio of end-to-end solutions to generate meaningful evidence, help optimize therapy development, and deliver companion diagnostic solutions using our tissue and liquid comprehensive genomic profiling tests."

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If the companion diagnostic indications are approved, based on tissue availability and the presentation of individual patients, oncologists will be able to use FoundationOne CDx or FoundationOne Liquid CDx to identify those with genomic alterations that may make them eligible for a specific targeted therapy.

"We’re proud to announce this new phase of our partnership with Merck KGaA, Darmstadt, Germany, and continue building on our shared commitment to advance personalized treatment options for patients," said Jason Adams, vice president of biopharma enterprise partnerships at Foundation Medicine. "We look forward to ongoing collaboration as they leverage our portfolio of end-to-end solutions to generate meaningful evidence, help optimize therapy development, and deliver companion diagnostic solutions using our tissue and liquid comprehensive genomic profiling tests."

Foundation Medicine’s portfolio of FDA-approved comprehensive genomic profiling tests offer physicians both blood- and tissue-based testing options for detecting genomic alterations that help guide personalized treatment decisions. The company’s robust suite of data and assay solutions support biopharmaceutical organizations as they work to design and deliver new targeted therapies, starting with biomarker discovery and clinical trial enrollment through to companion diagnostic development and commercialization.

On June 5, 2023 CatalYm reported first Phase 2a data from its ongoing GDFather-2 trial (GDF-15 Antibody-mediaTed Human Effector Cell Relocation Phase 2) (NCT04725474) at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting 2023 in Chicago, Illinois (Press release, Catalym, JUN 5, 2023, View Source [SID1234632501]). The early data presented during today’s oral "Developmental Therapeutics-Immunotherapy" session revealed lasting and confirmed responses in several solid tumor types investigated following treatment with visugromab and the anti-PD-1 inhibitor nivolumab. In addition, the combination continues to demonstrate a good safety and tolerability profile across all cohorts. CatalYm’s lead candidate, visugromab, is a humanized, monoclonal antibody designed to neutralize the tumor-produced Growth Differentiation Factor-15 (GDF-15), a central regulator of tumor resistance development.

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"These early data from our Phase 2a cohorts corroborate the encouraging anti-tumor-response we have seen in the Phase 1 study and further elucidate the considerable therapeutic potential of visugromab in very advanced and anti-PD1/PD-L1 relapsed/refractory solid tumor patient populations. They also confirm and further refine our scientifically guided indication selection to identify the solid tumor patients that would most benefit from a GDF-15 modulating approach," said Prof. Dr. Eugen Leo, Chief Medical Officer at CatalYm.

The presentation at ASCO (Free ASCO Whitepaper) by International Coordinating Investigator Prof. Dr. Ignacio Melero Bermejo, MD, Co-Director of Immunology and Immunotherapy (CIMA) at the Universidad de Navarra, Pamplona/Spain, builds on the further matured Phase 1 trial data announced in September 2022 which showed a significant clinical benefit in last line tumor patients that were anti-PD1/-L1 relapsed or refractory with an overall response rate of 17% in an advanced-stage mixed tumor population (RECIST, all responses confirmed). The Phase 2a study cohorts were selected based on a translational research program and include several major solid tumor types identified in Catalym’s translation research program as potentially being GDF-15 influenced.

The emerging phase 2a efficacy data further extend the initial encouraging data from Phase 1 with durable, confirmed responses as per RECIST criteria in several major tumor indications. Furthermore, investigation of potentially response-predictive biomarkers identified during phase 1 dose-escalation are ongoing through tumor biopsy analyses. The cumulative safety and tolerability profile for the Phase 1/2a study confirmed, so far, a well-acceptable safety profile when treating advanced-stage cancer patients, an important aspect for combination therapy in this critically ill patient population and earlier treatment lines.

Dr. Phil L’Huillier, Chief Executive Officer at CatalYm added: "The data revealed in today’s presentation illustrate the strides we have made in developing a completely novel treatment option by neutralizing GDF-15 in a variety of indications. We will continue in our broad multi-arm Phase 2 development program (GDFATHER-2) in 2023 and anticipate sharing more data and an update on our late-stage clinical development strategy later this year. I am grateful for the study patients and dedicated clinicians who have been a part of our clinical development program to this stage."

The Phase 2a GDFATHER-2 program was initiated in March 2022. The ongoing study consists of two segments with up to seven cohorts, expected to enroll a total of over 200 patients in Simon-2-stage designs and in a biomarker-evaluation directed cohort.

Mature data readouts for efficacy and safety data of the core phase 2a program as well as main biomarker-correlations are expected to become available before the end of 2023.

About the GDFATHER-2 Trials

The GDFATHER-2a trial (GDF-15 Antibody-mediaTed Human Effector Cell Relocation Phase 2) (NCT04725474) is an ongoing Phase 2a trial with several cohorts investigating the effect of visugromab (CTL-002) as monotherapy and/or in combination with a PD-1 checkpoint inhibitor in patients in various advanced-stage, relapse/refractory solid tumor types and a biomarker-selected cohort. The study can enroll > 200 patients in Simon-2-stage designs and a biomarker-evaluation directed cohort to confirm certain response rates and potential biomarker-based responder patient selection.

About Visugromab (CTL-002)

Visugromab is a humanized monoclonal antibody that neutralizes the tumor-derived Growth Differentiation Factor-15 (GDF-15). GDF-15 is an essential player in feto-maternal tolerance, a powerful mechanism that cancer cells hijack to create an immunosuppressive environment to evade destruction. By neutralizing GDF-15, visugromab reverses the immunosuppressive effects that block an efficient anti-tumor immune response in the tumor microenvironment and the draining lymph nodes. Visugromab drives an activated and differentiated immune cell infiltration into the solid tumor as well as enables priming of T cells and enhances the tumor killing effects of T cells and NK cells. GDF-15 is currently investigated in an ongoing Phase 2 program that includes confirmatory studies in multiple solid tumor indications and the analysis of a predictive response biomarker to better identify the patients benefiting from this new class of immunotherapy.