On June 5, 2023 Elicio, a developer of immunotherapies for the treatment of cancer, reported positive interim clinical data from the ongoing Phase 1 study of its lead asset, ELI-002, an investigational therapeutic cancer immunotherapy (Press release, Elicio Therapeutics, JUN 5, 2023, View Source [SID1234632555]).

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Elicio engineers proteins that appear frequently in cancerous cells but less frequently in healthy cells, and presents these to the immune system, together with an adjuvant (immune response booster) that brings the antigen directly to the lymph nodes, part of the body’s immune system.

In the past, immunotherapies for cancer have yielded fairly weak responses, but Elicio hopes that its immunotherapy will be more effective, thanks to the mechanism whereby the antigen is presented directly to the lymph nodes, and because its product tackles several proteins at once.

The company’s first product, ELI-002 2P, targets mutant KRAS-driven cancers. It says that the seven KRAS driver mutations targeted by the ELI-002 7P formulation are present in 25% of all solid tumors (that is, not blood cancers). The trial is designed to assess the safety, immunogenicity and antitumor activity of ELI-002 2P as a monotherapy in patients with mutant KRAS-driven tumors who are at high risk for relapse due to detection of MRD ( minimal residual disease) following standard surgery and chemotherapy.

On June 5, 2023 Sermonix Pharmaceuticals Inc., a privately held biopharmaceutical company developing innovative therapeutics to specifically treat metastatic breast cancers harboring ESR1 mutations, reported a poster presentation detailing the results of its ELAINE-2 clinical study with longer patient follow-up (Press release, Sermonix Pharmaceuticals, JUN 5, 2023, View Source [SID1234632524]). The poster was initially presented yesterday at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting.

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ELAINE-2 (NCT04432454), an open-label, Phase 2 Evaluation of Lasofoxifene in ESR1 Mutations (ELAINE) study of Sermonix’s lead investigational drug, lasofoxifene, in combination with Eli Lilly and Company’s CDK4/6 inhibitor abemaciclib, evaluated 29 women with ER+/HER2- locally advanced or metastatic breast cancer and an ESR1 mutation. The primary endpoint was safety/tolerability, with secondary endpoints including progression-free survival (PFS) and overall response rate (ORR). Earlier ELAINE-2 results were shared at ASCO (Free ASCO Whitepaper) 2022.

With patient follow-up through Jan. 31, 2023, the combination of lasofoxifene and abemaciclib continued to be well-tolerated, with clinically meaningful efficacy in women with ER+/HER2- metastatic breast cancer and an ESR1 mutation. The PFS, a median of 13 months, and ORR of 56% were promising.

"No new safety signals were noted when looking at lasofoxifene and abemaciclib with longer patient follow-up," said Paul Plourde, M.D., vice president of oncology clinical development at Sermonix. "The combination demonstrated meaningful antitumor activity, and observed decreases in ESR1 ctDNA suggest potent target engagement. We look forward to ELAINE-3 and the continued investigation of this potentially practice-changing option for treating ESR1 mutations in women with metastatic breast cancer."

Noteworthy safety results:

Lasofoxifene/abemaciclib was well tolerated with primarily grade 1/2 treatment-emergent adverse events (TEAEs), most commonly diarrhea, nausea, fatigue, and vomiting.
Three patients (10.3%) had venous thromboembolic events, all occurring after patients had achieved clinical benefit.
One patient discontinued treatment due to grade 2 diarrhea, and no deaths on treatment occurred.
Abemaciclib underwent dose reduction once in 6 (20.7%) patients; there were no dose reductions for lasofoxifene.
There was no clinical evidence of any drug-drug interactions, and no pK impact of lasofoxifene on abemaciclib or abemaciclib on lasofoxifene exposure identified (data not shown).
Noteworthy efficacy results:

Median PFS was 56.0 wks (~13 mos), CBR was 65.5%, and ORR was 55.6%; median overall survival was not estimable at the time.
PFS rate (95% CI) was 76.1%, 56.1%, and 38.8% at 6, 12, and 18 mos respectively; 8 (27.6%) patients achieved PFS over 96 weeks.
Of the four patients who had prior abemaciclib exposure, two achieved clinical benefit, and one with RECIST progression at week 16 remained on study with stable disease until week 40.
In 26 patients with evaluable baseline and week 4 ctDNA, ESR1 mutant allele fractions (MAF) decreased at week 4 in 21 (80.8%) patients, including 14 (53.8%) whose ESR1 MAF were undetectable.
Antitumor activity of lasofoxifene/abemaciclib was not compromised by co-occurring alterations that confer endocrine resistance.
Sermonix in March initiated ELAINE-3, a registrational Phase 3 study of 400 patients assessing the efficacy of lasofoxifene and abemaciclib. Enrollment will begin soon.

The company also convened meetings of its ELAINE-3 Steering Committee and ELAINE-3 Translational Committee at ASCO (Free ASCO Whitepaper) 2023.

To learn more about Sermonix Pharmaceuticals and lasofoxifene, visit View Source To learn more about the ELAINE studies, visit View Source

About Lasofoxifene
Lasofoxifene is an investigational novel endocrine therapy in clinical development which has demonstrated robust target engagement as an ESR1 antagonist in the breast, particularly in the presence of ESR1 mutations. Lasofoxifene has demonstrated anti-tumor activity as monotherapy and in combination with a CDK4/6 inhibitor in Phase 2 studies and has unique tissue selectivity distinguishing it from other current and investigational endocrine therapies, with beneficial effects seen on vagina and bone in previous clinical studies. Lasofoxifene, which Sermonix licensed globally from Ligand Pharmaceuticals Inc. (NASDAQ:LGND), has been studied in previous comprehensive Phase 1-3 non-oncology clinical trials in more than 15,000 postmenopausal women worldwide. Lasofoxifene’s bioavailability and activity in mutations of the estrogen receptor could potentially hold promise for patients who have acquired endocrine resistance due to ESR1 mutations, a common finding in the metastatic setting and an area of high unmet medical need. Lasofoxifene’s novel activity in ESR1 mutations was discovered at Duke University and Sermonix has exclusive rights to develop and commercialize the product in this area. Lasofoxifene, a novel targeted and tissue selective oral endocrine therapy could, if approved, play a critical role in the precision medicine treatment of advanced ER+ breast cancer.

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