On November 12, 2021 Nkarta, Inc. (Nasdaq: NKTX), a biopharmaceutical company developing engineered natural killer (NK) cell therapies to treat cancer, reported the presentation of four preclinical data abstracts focused on its natural killer cell platform and pipeline at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 36TH Annual Meeting and Pre-Conference Programs (Press release, Nkarta, NOV 12, 2021, View Source [SID1234595340]).

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"The data we presented at this year’s SITC (Free SITC Whitepaper) meeting showcase the rapid and continuous advancement of our NK cell platform and its potential to deliver pioneering off-the-shelf cell therapies," noted James Trager, PhD, Chief Scientific Officer of Nkarta. "Nkarta’s ongoing research activities are designed to heighten the innate ability of NK cells to identify and kill tumor cells and to further build on our efficient and robust manufacturing process. Our findings reported at SITC (Free SITC Whitepaper) support further exploration of CISH gene-knockout CD70 CAR NK cells for clinical application, one focus of our ongoing collaboration with our partners at CRISPR Therapeutics."

Details of the preclinical poster presentations at SITC (Free SITC Whitepaper) follow. Each poster will be available for download shortly after the presentation at View Source

Title: A Combined Strategy of CD70 CAR Co-expression with Membrane-bound IL-15 and CISH Knockout Results in Enhanced NK Cytotoxicity and Persistence*
Abstract Number and Type:16439, oral
Poster Presentation Date and Time: November 10, 2021, 2:40 p.m. ET
This study illustrates multiple approaches to modify NK cells to target CD70, an antigen highly expressed in hematological malignancies and solid tumors, including renal cell carcinoma. Optimal CD70 chimeric antigen receptor (CAR) candidates were identified using high throughput screening approaches. Preclinical results showed that a combined editing and engineering strategy to armor primary NK cells via co-expression of the CD70 CAR and a membrane bound form of IL-15 (mbIL-15), together with knockout of CISH and CD70 genes using the CRISPR/Cas9 system enhanced the persistence in culture and the cytotoxicity of the cells against multiple tumor cell lines. The knockout of CISH also supported the resistance of primary NK cells to suppressive elements active in the tumor microenvironment.

Title: CISH Gene-knockout Anti-CD70-CAR NK Cells Demonstrate Potent Anti-tumor Activity Against Solid Tumor Cell Lines and Provide Partial Resistance to Tumor Microenvironment Inhibition*
Abstract Number and Type: 113, poster
Poster Presentation Date and Time:November 12, 2021, 7:00 am – 8:30 pm ET
Primary NK cells engineered with CD70 chimeric antigen receptor (CAR), membrane bound form of IL-15 (mbIL-15) and knockout of CISH and CD70 genes using the CRISPR/Cas9 system could be produced efficiently, demonstrating consistent knockout and transduction efficiency across donors. Memory like NK cell differentiation of the gene edited NK cells was achieved using a modified K562 stimulatory cell line expressing membrane-bound IL-15 and 4-1BBL with the addition of IL-12 and IL-18 during expansion. Various gene editing candidates were assessed; the knockout of CISH in particular enhanced not only tumor cell killing by CD70 CAR NK cells, but also their persistence in culture and resistance to suppressive molecules associated with the tumor microenvironment, such as TGFß and adenosine.

Title: Potentiating the Large-Scale Expansion and Engineering of Peripheral Blood-Derived CAR NK Cells for Off-the-Shelf Application
Abstract Number and Type: 151, poster
Poster Presentation Date and Time:November 12, 2021, 7:00 am – 8:30 pm ET
The study highlights novel methods for scaling the expansion of engineered NK cells to potentially supply a life cycle’s worth of commercial off-the-shelf product from a single donor. The methods entail sequential pulses with a proprietary K562 stimulatory cell line in the presence of IL-2 and use of IL-12 and IL-18 to achieve differentiation into memory-like NK cells. When these methods were used to achieve cell expansion greater than even 2 billion-fold, CAR expression was increased on the NK cell surface, engineered cells with CISH gene knockout, CAR and mbIL-15 were preferentially enriched during expansion, and the chromosomal integrity of the cells was well maintained.

Title: KIR Haplotype Can Inform Donor Selection in the Production of Allogeneic Memory-Like CAR NK Cells for Clinical Application
Abstract Number and Type: 128, poster
Poster Presentation Date and Time:November 13, 2021, 7:00 am – 8:30 pm ET
Study findings suggest that the profile of activating and inhibitory KIR genes expressed by healthy donors’ NK cells may serve as a future criterion for selecting donors whose NK cells can be engineered for enhanced cytotoxic activity. The optimal KIR profile may depend on the process used to generate NK cells. Engineered CD19 CAR NK cells whose expansion includes IL-12 and IL-18 added to a proprietary K562 stimulatory cell line containing mbIL-15 and 15-41BBL stimulatory cells showed enhanced potency and upregulation of NK memory associated cell surface markers and natural cytotoxicity markers. Finally, donor KIR haplotype correlated best with CAR NK activity in cells expanded in the presence of IL-12 and IL-18, showing that donor selection and expansion methods must be considered together for development of optimal CAR NK therapies.

* Presented jointly with CRISPR Therapeutics

On November 12, 2021 AstraZeneca reported that double-digit revenue growth from its Oncology, CVRM1 and R&I2 medicines, and established its Rare Disease capability with the acquisition of Alexion Pharmaceuticals Inc. (Alexion) (Press release, AstraZeneca, NOV 12, 2021, View Source [SID1234595380]). Rare disease is a high-growth area with rapid innovation and significant unmet medical need.

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Since June, AstraZeneca has made significant progress with its late-stage pipeline, reporting eight positive Phase III trial results and the approval of Saphnelo (anifrolumab) in the US for the treatment of systemic lupus erythematosus, and Ultomiris in the EU for children and adolescents with paroxysmal nocturnal haemoglobinuria.

Enhertu received a Breakthrough Therapy Designation from the US FDA3 following ground-breaking results from the DESTINY-Breast03 trial. The Company also announced positive results for Lynparza in prostate cancer, Imfinzi plus tremelimumab in liver cancer, Imfinzi in biliary tract cancer, PT027 in asthma, ALXN1840 in Wilson disease, and AZD7442 in COVID-19 prophylaxis and treatment. Pascal Soriot, Chief Executive Officer, commented: "AstraZeneca’s scientific leadership continues to provide strong revenue growth and exceptional pipeline delivery, with eight positive late-stage readouts across seven medicines since June, including our long acting antibody combination showing promise in both prevention and treatment of COVID-19.

The addition of Alexion furthers our commitment to bring transformative therapies to patients around the world, and I am proud of our colleagues’ ongoing dedication and focus. Our broad portfolio of medicines and diversified geographic exposure provides a robust platform for long-term sustainable growth. Following accelerated investment in upcoming launches after positive data flow, we expect a solid finish to the year and our earnings guidance is unchanged."

Key elements of Total Revenue performance in the year-to-date included:
-An increase in Product Sales of 33% (29% at CER) to $25,043m
-The first contribution from Rare Disease, which generated $1,311m of revenue in the period following completion of the Alexion acquisition on 21 July 2021-Oncology growth of 19% (16% at CER) to $9,744m, CVRM growth of 14% (10% at CER) to $6,028m and R&I growth of 16% (12% at CER) to $4,456m-An increase in Emerging Markets revenue of 33% (28% at CER) to $8,618m. In China, revenue increased 17% (8% CER) to $4,699m in the year to date and by 10% (2% CER) in the quarter. China revenues in the year to date were impacted by pricing pressure associated with NRDL11 and VBP12 programmes.
-Tagrisso’s sequential quarterly performance in China was impacted by inventory phasing and stock compensation relating to NRDL changes in March. In future periods, volume growth from increased patient access is expected to compensate for the lower NRDL price-Revenue in ex-China Emerging Markets increased 60% in the year to date to $3,919m. Excluding vaccine revenue of $1,139m, revenue in ex-China Emerging Markets increased by 13% in the year to date (14% at CER) to $2,780m and by 30% in the quarter to $1,018m, driven by Oncology medicines and Farxiga-In the US, Total Revenue increased by 29% to $8,305m and in Europe by 40% (31% at CER) to $5,178m, including pandemic COVID-19 vaccine revenue of $736m Guidance The Company provides further details on its FY 2021 guidance at CER.

Total revenue excluding the COVID-19 vaccine is expected to grow by a low-twenties percentage, in line with prior guidance. Including vaccine revenues in Q4 2021, revenue is expected to grow by a mid-to-high twenties percentage. Growth in Core EPS13 to $5.05 to $5.40, in line with prior guidance. Prior guidance excluded the revenue and profit impact of sales of the pandemic vaccine. The Company is now expecting to progressively transition the vaccine to modest profitability as new orders are received. COVID-19 vaccine sales in Q4 2021 are expected to be a blend of the original pandemic agreements and new orders, with the large majority coming from pandemic agreements. The limited profit contribution from the vaccine in Q4 2021 is expected to offset costs relating to the Company’s long acting antibody combination (AZD7442), resulting in no change to Core EPS guidance. Core Tax Rate guidance is unchanged at 18-22%.

In general, AstraZeneca continues to recognise the heightened risks and uncertainties from the effects of COVID-19. Variations in performance between quarters can be expected to continue. The Company is unable to provide guidance on a Reported basis because AstraZeneca cannot reliably forecast material elements of the Reported result, including any fair value adjustments arising on acquisition-related liabilities, intangible asset impairment charges and legal-settlement provisions.

Please refer to the cautionary statements section regarding forward-looking statements at the end of this announcement. Currency impact If foreign-exchange rates for October to December 2021 were to remain at the average of rates seen in the year to date, it is anticipated that there would be a low single-digit favourable impact on Total Revenue and an immaterial impact on Core EPS versus CER data. The Company’s foreign-exchange rate sensitivity analysis is contained within the operating and financial review.Financial summary-Variances across periods are based on a comparison of the Group’s performance in the year to date and the quarter, including Alexion from 21 July 2021, with the Group’s performance in the comparative prior periods, which do not include Alexion. Pro forma total revenue growth rates have been presented only for Q3 2021 Rare Disease and its constituent medicines, and do not impact any Group totals-Total Revenue, comprising Product Sales and Collaboration Revenue, increased by 32% in the year to date (28% at CER) to $25,406m.

Total Revenue included $2,219m from the pandemic COVID-19 vaccine-Reported Gross Profit14 Margin in the year to date declined eleven percentage points to 68.8%; Core Gross Profit Margin declined six percentage points in the year to date to 74.1%, predominantly reflecting the equitable supply, at no profit to AstraZeneca, of the pandemic COVID-19 vaccine, together with an increasing impact from profit-sharing arrangements (primarily Lynparza and roxadustat) and the impact of the NRDL and VBP programmes in China. These effects were partially offset by the contribution of Alexion from 21 July 2021, a higher proportion of Oncology sales, and increasing patient access in China. Reported Gross Profit Margin was also impacted by $1,044m due to the unwind of the fair value adjustment to Alexion inventories at the date of acquisition.

Variations in gross margin performance between periods can be expected to continue-Reported Total Operating Expense increased in the year to date by 39% (34% at CER) to $17,591m. Core Total Operating Expense increased by 24% (20% at CER) to $13,649m and represented 54% of Total Revenue (YTD 2020: 57%)-Reported R&D Expense increased in the year to date by 67% (63% at CER) to $7,152m including an impairment charge of $1,172m recognised in the quarter on an intangible asset related to the acquisition of Ardea Biosciences, Inc. in 2012, following the decision to discontinue the development of verinurad. Core R&D Expense increased in the year to date by 34% (30% at CER) to $5,591m with increases in both Reported and Core R&D Expense reflecting the Company’s continued investment in its COVID-19 vaccine and AZD7442, investment in several late-stage Oncology trials and the advancement of a number of Phase II clinical development programmes in BioPharmaceuticals-Reported SG&A Expense increased in the year to date by 25% (21% at CER) to $10,117m and includes the increased amortisation of intangible assets related to the Alexion acquisition.

Core SG&A Expense increased by 19% (14% at CER) to $7,736m, reflecting the addition of Alexion SG&A expenses from 21 July 2021, investment in Oncology-medicine launches, the launch of several new BioPharmaceuticals medicines, particularly in the US, AstraZeneca’s further expansion in Emerging Markets, and the existing infrastructure base in China-Reported and Core Other Operating Income and Expense 15 increased in the year to date by 51% (50% at CER) to $1,345m and $1,346m respectively, and included $776m income from the divestment of AstraZeneca’s 26.7% share of Viela Bio, Inc. (Viela) in March 2021-The Reported Operating Profit Margin declined fourteen percentage points (thirteen at CER) to 5.3%, reflecting the aforementioned intangible impairments and other factors. The Core Operating Profit Margin declined two percentage points (one percentage point at CER) in the year to date to 26.0% driven by the aforementioned increase in R&D and SG&A expenses-Reported EPS in the year to date declined 80% (65% at CER) to $0.33. Core EPS increased by 22% (23% at CER) to $3.59. Reported and Core EPS were adversely affected by $0.03 due to the pandemic COVID-19 vaccine

On November 12, 2021 Innate Pharma SA (Euronext Paris: IPH; Nasdaq: IPHA) ("Innate" or the "Company") reported that pre-clinical data from its proprietary, multi-specific NK cell engager platform, ANKETTM, will be presented at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting in collaboration with partner, Sanofi (poster #852) (Press release, Innate Pharma, NOV 12, 2021, View Source [SID1234595397]).

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Specifically, the companies will share new data on IPH6101/SAR443579, the first NKp46/CD16-based NK cell engager using Innate’s proprietary multi-specific antibody format1 that targets CD123 on acute myeloid leukemia (AML) cells and now co-engages NKp46 and CD16a on NK cells.

CD123 is an attractive target as it is expressed at high levels in the majority of AML patients2. However, overcoming resistance to antibody-dependent cellular cytotoxicity (ADCC) has been a challenge.

In pre-clinical studies, IPH6101/SAR443579 demonstrated potent antitumor activity against AML cell lines, including those resistant to ADCC by a comparator anti-CD123 antibody. IPH6101/SAR443579 also promoted strong and specific NK-cell activation and induced cytokine secretion only in the presence of AML target cells.

In addition, IPH6101/SAR443579 had sustained pharmacodynamic effects in non-human primates, combining efficient depletion of CD123-expressing cells with minor systemic cytokine release in comparison to T-cell engagers. As expected, it also had a favorable safety profile.

"There is a strong need to develop effective therapies to treat acute myeloid leukemia, the most common acute leukemia in adults," said Pr. Eric Vivier, Ph.D., DVM, Chief Scientific Officer at Innate Pharma. "We’re pleased to present pre-clinical data on IPH6101/SAR443579 that shows antitumor activity against AML, and more specifically, the potential of engaging NK cells through NKp46 and CD16 via our ANKETTM technology. We look forward to seeing Sanofi dose the first patient in the clinic with this molecule soon."

Innate will also present a second ANKETTM poster (poster #851) at SITC (Free SITC Whitepaper) entitled, "Harnessing Innate Immunity in Cancer Therapies: the Example of Natural Killer Cell Engagers." The data will highlight the induction of a unique NK cell activation pathway by its tetra-specific ANKETTM molecule. The abstract can be accessed here.

About ANKETTM:

ANKETTM (Antibody-based NK cell Engager Therapeutics) is Innate’s proprietary platform for developing next-generation, multi-specific natural killer (NK) cell engagers to treat certain types of cancer. The Company’s latest innovation, its tetra-specific ANKETTM molecule, is the first NK cell engager technology to engage activating receptors (NKp46 and CD16), a tumor antigen and an interleukin-2 receptor (via an IL-2 variant, IL-2v) via a single molecule. This leverages the advantages of harnessing NK cell effector functions against cancer cells and also provides proliferation and activation signals targeted to NK cells.

In pre-clinical studies, Innate’s tri-1 and tetra-specific ANKETTM technologies promote potent NK cell activation, cytotoxicity and efficient control of tumor growth in pre-clinical models. This versatile fit-for-purpose technology is creating an entirely new class of molecules to induce synthetic immunity against cancer.

About IPH6101/SAR443579:

In the first research program of the Sanofi collaboration, IPH6101/SAR443579, the first NKp46/CD16-based NK cell engager using Innate’s proprietary multi-specific antibody format1, has shown antitumor activity in pre-clinical models, including supportive pharmacokinetic/pharmacodynamic (PK/PD) and safety data in non-human primate studies leading to its selection as a drug candidate for development.

About the Innate-Sanofi agreement:

The Company has a research collaboration and licensing agreement with Sanofi to apply Innate’s proprietary technology to the development of innovative multi-specific antibody formats engaging NK cells through the activating receptors NKp46 and CD16 to kill tumor cells.

Under the terms of the license agreement, Sanofi will be responsible for the development, manufacturing and commercialization of products resulting from the research collaboration. Innate Pharma will be eligible to up to €400m in development and commercial milestone payments as well as royalties on net sales.

On November 12, 2021 Calithera Biosciences, Inc. (Nasdaq: CALA), a clinical-stage, precision oncology biopharmaceutical company, reported that Susan Molineaux, Ph.D., the company’s founder, president and chief executive officer, will present at the 2021 Jefferies London Healthcare Conference (Press release, Calithera Biosciences, NOV 12, 2021, View Source [SID1234595428]).

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The presentation will be available for on-demand viewing starting Thursday, November 18 at 3:00 a.m. Eastern Time, and can be accessed through the Investors section of the Company’s website at www.calithera.com. The replay of the webcast will be available on the Company’s website for 30 days.

On November 12, 2021 Candel Therapeutics, Inc. (Nasdaq: CADL), a late clinical stage biopharmaceutical company developing novel oncolytic viral immunotherapies, reported presentation of novel biomarker data from their ongoing phase 1 open-label, dose-escalation clinical trial of CAN-3110 in patients with recurrent high-grade glioma (HGG) (Press release, Candel Therapeutics, NOV 12, 2021, View Source [SID1234595450]). CAN-3110 is an HSV replication-competent oncolytic virus engineered to provide selective killing of cancer cells while sparing neighboring healthy cells. The presentation entitled "Detection of viral antigen and immune activation after intra-tumor injection of CAN-3110 (ICP-34.5 expressing HSV-1 oncolytic virus) in patients with recurrent high-grade glioma" was presented at the SITC (Free SITC Whitepaper) 36th Annual Meeting by Candel’s Vice President and Head of Research, Francesca Barone, MD, PhD.

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During the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in June 2021, Candel reported preliminary clinical data demonstrating an overall survival of 11.7 months in this difficult-to-treat patient population. The current presentation, focused on the biological findings of this study, showed the ability of CAN-3110 to induce immune activation both locally in the tumor microenvironment and systemically in peripheral blood.

Histologic analysis and molecular profiling of post-treatment brain samples demonstrated persistence of viral antigen associated with significant T-cell infiltration in the tumor parenchyma as well as a molecular signature consistent with local activation of innate and adaptive immunity. Analysis of post-treatment serum samples showed upregulation of pro-inflammatory cytokines and chemokines. These findings collectively indicate that CAN-3110 treatment can induce both local and systemic immune activation associated with an encouraging clinical response.

"There is a critical need for treatment options for patients with recurrent high-grade glioma. The data from this trial support the mechanistic approach of tumor cell-specific replication that was the intent of the CAN-3110 design," said Paul Peter Tak, MD, PhD, FMedSci, President and Chief Executive Officer of Candel Therapeutics. "The biomarker data presented at SITC (Free SITC Whitepaper), in conjunction with the overall survival data previously reported at ASCO (Free ASCO Whitepaper), are encouraging signals as we endeavor to bring novel oncolytic viral immunotherapies to patients with cancer."

Details from the presentations will be available on Candel’s company website at View Source

About CAN-3110

CAN-3110 is an HSV replication-competent oncolytic virus engineered to enhance selective killing of cancer cells while sparing neighboring healthy cells. CAN-3110 selectively expresses ICP34.5, a key gene in HSV replication, in tumor cells that overexpress nestin, a cytoskeletal protein. Nestin is highly expressed in high-grade glioma cells and other tumor tissues, but it is absent in healthy adult brain tissue.

Candel is evaluating the effects of treatment with CAN-3110 in recurrent high-grade glioma.

For more information on this clinical study, please visit View Source