On October 8, 2021 bluebird bio, Inc. (NASDAQ: BLUE) reported the filing by 2seventy bio of an updated Form 10 Registration Statement with the U.S. Securities and Exchange Commission (SEC) (Press release, 2seventy bio, OCT 8, 2021, View Source [SID1234594668]). This Form 10 reflects bluebird bio’s plans for a tax-free spin-off of its oncology programs and portfolio into 2seventy bio as a publicly traded company. The spin-off is on track to be completed by early November 2021. bluebird bio also announced the appointment of Najoh Tita-Reid and Sarah Glickman to the bluebird bio board of directors. Upon effectiveness of the Form 10, Ms. Glickman will also be a member of the board of directors of 2seventy bio and will step down from the bluebird bio board of directors upon completion of the spin-off.

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"As we approach separation, we have been strategic and diligent in setting up each business for success," said Nick Leschly, chief bluebird and expected chief kairos officer, 2seventy bio. "The first part of this year was largely directed toward focusing and shaping our internal operations and continuing to advance the transformative gene and cell therapy products that sit on both sides of the current business. Rounding out those necessary pillars for success is financial strength and leadership, and we’re extremely pleased to share today further detail on the balance sheet that each company is expected to launch with, as well as key members of each board of directors. This is another step forward and we remain on track to launch bluebird bio and 2seventy bio by early November with the right pieces in place to drive both entities toward delivering for patients with meaningful, value-creating milestones."

Upon separation, bluebird bio plans to distribute 100% of the outstanding shares of 2seventy bio common stock to bluebird’s shareholders in a 3:1 ratio. For every three shares of bluebird bio stock, current shareholders will receive one share of 2seventy bio stock.

The company anticipates that its cash, cash equivalents and marketable securities balance at separation will be approximately $1.0B, inclusive of proceeds from the recent sale of the company’s manufacturing facility in North Carolina and its private placement equity financing. bluebird bio expects to fund 2seventy bio with approximately $480M in cash upon separation, with the balance to be retained by bluebird bio. Together with existing and emerging sources of revenue and other anticipated cash inflows, which includes the potential sale of priority review vouchers that would be issued with anticipated U.S. regulatory approvals of BLAs for bluebird’s therapies in beta-thalassemia and cerebral adrenoleukodystrophy, the Company expects its cash, cash equivalents and marketable securities balance will be sufficient to fund operations for bluebird bio and 2seventy bio into 2023 under current business plans.

The company also announced the appointment of two new board members.

Najoh Tita-Reid was appointed to the bluebird bio board of directors. Najoh Tita-Reid is Chief Marketing Officer for Logitech, a global manufacturer of computer peripherals, software and services with headquarters in Switzerland and California. In her role, Ms. Tita-Reid is leading the transformation of the global marketing function and spearheading a strategic, digital-first and data-driven consumer and customer omnichannel experience. A multi-faceted executive with global marketing expertise, she has a record of strategic and operational ingenuity and transformation across complex organizations. Prior to her role at Logitech, Ms. Tita-Reid was Global Chief Marketing Officer and Executive Board Member for Hero-AG, a family-run healthy food company, and held leadership positions at Bayer PLC and Merck & Co, Inc. Ms. Tita-Reid spent 19 years at Procter & Gamble where she managed several multi-billion-dollar brands. She also led African American Marketing for P&G, the world’s largest advertiser, and created breakthrough marketing strategies, including "My Black is Beautiful," which stands as a template for multi-cultural campaigns across industry today. Ms. Tita-Reid graduated with a Bachelor of Arts from Spelman College and holds an MBA from Fuqua School of Business at Duke University.

"As we approach separation, we are in a strong financial and operational position and poised to unlock value both for our patients and our shareholders," said Andrew Obenshain, president, severe genetic diseases and expected chief executive officer, bluebird bio, post separation. "We are pleased to welcome Najoh to bluebird bio’s board of directors and look forward to benefiting from her expertise in multi-brand strategy and execution as we enter the next chapter for bluebird bio, focused on the commercialization of three transformational gene therapies for severe genetic diseases."

Sarah Glickman was also appointed to the bluebird bio board of directors and is expected to join the 2seventy bio board of directors as Audit Committee Chair upon separation. Ms. Glickman is the Chief Financial Officer for Criteo, a global technology company headquartered in Paris, France and listed on Nasdaq. She jointly leads Criteo’s strategy to drive profitable long-term growth and shareholder value through transformational change, including M&A. Key responsibilities include leading all aspects of financial planning and reporting, investor relations, treasury, tax, controllership and internal controls. She is also responsible for global IT, procurement and real estate. Prior to Criteo, she was the acting Chief Financial Officer and Chief Transformation Officer of XPO Logistics in Greenwich, CT. Prior to XPO, she was the Chief Financial Officer for the Novartis Business Services division of Novartis AG, a global pharmaceutical company. Ms. Glickman spent ten years at Honeywell, Inc. and before held finance roles at Bristol-Myers Squibb and PricewaterhouseCoopers. She is a Certified Public Accountant (US) and Fellow Chartered Accountant (UK) and graduated with a Bachelor of Arts in Economics and History, with honors, from the University of York in England.

"We’re excited that Sarah will join the board of 2seventy bio in this crucial launch phase," said Nick Leschly. "Her financial leadership experience at several successful companies will be a tremendous asset as we focus on shoring up our balance sheet and setting up 2seventy bio with a healthy foundation to enable the continued advancement of our cell therapy platform."

On October 8, 2021, Adhera Therapeutics, Inc. (the "Company") reported that entered into a Securities Purchase Agreement ("SPA") with an institutional investor (the "Buyer"), pursuant to which the Company issued the Buyer a 10% Convertible Redeemable Note in the principal amount of $131,250 (the "Note") and a three-year warrant to purchase 476,190 shares of common stock of the Company (the "Warrant") for which the Company received consideration of $110,000 (Filing, 8-K, Adhera Therapeutics, OCT 8, 2021, View Source [SID1234591173]).

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The Note is due October 5, 2022. The Note provides for guaranteed interest at the rate of 10% per annum, payable at maturity. The Note is convertible into shares of common stock at any time following the date of cash payment at the Buyer’s option at a conversion price of $0.075 per share, subject to certain adjustments. Furthermore, the Buyer will not be allowed to effect a conversion if such conversion, along with all other shares of the Company’s common stock beneficially owned by the Buyer and its affiliates would exceed 4.99% of the outstanding shares of common stock of the Company, which may be increased up to 9.9% upon 60 days’ prior written notice by the Buyer.

The Warrants are exercisable for three-years from October 5, 2021 at an exercise price of $0.095 per share, subject to certain adjustments, which exercise price may be paid on a cashless basis. The aggregate exercise price is $45,238.05.

Pursuant to the SPA, the Company shall have filed a registration statement within 90 days providing for the registration of all shares issuable upon conversion of the Note and exercise of the Warrant.

For services rendered in connection with the SPA, the Company paid Carter, Terry & Company a fee of $10,000. In addition, the Company reimbursed the Buyer $5,000 for legal expenses incurred in connection with the transaction.

The foregoing description of the terms of the SPA, the Note, the Warrant and the transactions contemplated thereby does not purport to be complete and is qualified in its entirety by reference to the form of SPA, the form of Note, and the form of Warrant, a copy which is filed as Exhibits 10.1, 10.2, and 10.3, respectively, to this Current Report on Form 8-K and is incorporated herein by reference.

On October 8, 2021 Shanghai Medicilon reported that The direction of tumor immunity is undoubtedly one of the most popular directions in the field of cancer research ,but for researchers who are new to this field, the results of using only the mouse tumor model used in the previous tumor research will not be convincing (Press release, Shanghai Medicilon, OCT 8, 2021, View Source [SID1234591042]). For example, The most common human tumor cell line is the tumorigenesis model on immunodeficient mice. The deficiency of the immune system leads to partial or complete loss of the tumor immune microenvironment. It is used to evaluate PD-L1/PD-1 inhibition. The effect of the drug and CAR-T solid tumors is not rigorous enough.

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Syngeneic Tumor Mouse Model
Syngeneic tumor model refers to a model that uses tumor cell lines of the same species to inoculate and form tumors on that species. Common mouse strains can be C57BL/6, BALB/c and FVB, etc. The inoculation method is usually subcutaneous tumor formation or Tail vein tumor formation and in situ tumor formation, this model is characterized by fast tumor formation time, usually only about 4 weeks (see the figure below).

From the perspective of the degree of simulation of the immune microenvironment, the final tumor microenvironment is still different from the native tumor microenvironment, and will be affected by the number of inoculations, the method of inoculation, the site of inoculation, and even the inflammation caused by the injection itself. It will also affect the formation of TME. Relatively speaking, tumor formation in situ usually better mimics the tumor microenvironment, but it also requires more difficulty in operation. One problem with the mouse model of homologous tumors is that the formed tumors are not heterogeneous enough, because they are all derived from the same cell line, the level of tumor heterogeneity will also have an impact on the effect of tumor immunotherapy.

Genetically Engineered Mouse Models
Gene-edited tumor mouse models are usually spontaneous tumor models. Through systemic or tissue-specific overexpression of oncogenes, or knockout of tumor suppressor genes, tumors are formed in mice, such as KRAS, MYC overexpressing breast cancer Mouse models, P53 or PTEN knockout mouse models of prostate cancer, tamoxifen-induced Cre-loxP specific knockout tumor mouse models. The advantage of these models is that the growth process of tumors undergoes immune tolerance, immune editing, and immunity In the process of suppression, the final TME will be closer to the native state. However, due to the long time of tumor formation, differences in heterogeneity will lead to large differences in experimental results between mice, and the repetition rate is lower than that of homologous tumor models.

Carcinogen-Induced Tumor Models
Common carcinogen-induced tumor mouse models include DEN-induced liver cancer, MCA-induced fibrosarcoma, ultravolet B-induced skin cancer, NHK-induced lung cancer models, etc. These tumor models have obvious genomic instability and tumor formation time It is also about half a year to 1 year. Compared with the gene-edited tumor mouse model, it has a richer gene mutation spectrum. These mutations are involved in immune remodeling in the neoantigen process for a long time in the tumorigenesis process, and can more naturally simulate tumor immune microbes. The formation of the environment, and therefore, the tumor heterogeneity between mice is greater, and the results will be quite different.

PDX model (Patient-Derived Xenograft Models)
The PDX model refers to the direct inoculation of patient-derived tumor mass into mice subcutaneously or orthotopic transplantation. The advantage of this model is that it can retain the cellular composition of the patient’s tumor, the tumor immune microenvironment, and the genetic heterogeneity. Compared with the previous tumor formation methods, the results of immunotherapy are closer to the actual clinical treatment situation.

Before tumorigenesis, mice will undergo humanized remodeling of the immune system, usually in two ways:

One is to transplant the patient’s CD34+ HSC cells 10-14 weeks before vaccination. Hematopoietic stem cells will differentiate into the human immune cell lineage during this time. The advantage of this method is that there is no GVHR, but the waiting cycle after transplantation will be biased. Long, the evaluation of the effects of vaccination and subsequent immunotherapy cannot be carried out immediately, but the results will be more realistic.

Another way is to transplant the patient’s PBMC for immune remodeling, but because the T cells in PBMC are already mature T cells, there will be a certain degree of GVHR response after transplantation into mice, which will have a certain impact on the treatment results, but The advantage is that mice can be inoculated immediately after transplantation and the experiment can be started.

Summary
The above are several tumor mouse models commonly used in evaluating tumor immunotherapy. These models have their own advantages and disadvantages. If there are clinical sample resources, the PDX model is recommended first. This model can simulate the real immune microenvironment to the greatest extent; if the sample resources are not easy to obtain, from the experimental cycle and experimental risk From a perspective, we can give priority to a mouse model of a homologous tumor or a mouse model of a heterogeneous tumor. The preliminary results are obtained first, and the results are good, and there is ample time. If you need to get data closer to the clinical results, you can do gene-edited tumor mice. Model or carcinogen-induced tumor mouse model verification, or find clinical resources to make PDX models.

On October 8, 2021 The Childhood Cancer STAR Act and Childhood Cancer Data Initiative (CCDI) reported that are major federal government-led initiatives that exist in part because of years of advocacy work by members of the brain tumor and childhood cancer communities (Press release, National Brain Tumor Society, OCT 8, 2021, View Source [SID1234591041]). As we reflect back on Childhood Cancer Awareness Month (CCAM) this past September, we want to share updates on these initiatives as a reminder of the ongoing impact that advocacy makes possible.

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"The progress of the STAR Act and CCDI illustrate the commitment and increase in focus on research in childhood cancer," says Danielle Leach, chief of government and community relations at NBTS. "Cancer is the number one cause of death by disease among children, and pediatric brain tumors are the leading cause of cancer-related death in this population. Therefore, seeing this increased collaboration and commitment is promising. Now is the time for advocates to continue to work together to support increases in federal research funding so this critical work can create the change we so desperately need to find cures and quality of life."

Childhood Cancer Data Initiative

In late 2020, following extensive input from NBTS and advocates, Congress approved funding for CCDI at $50 million per year for 10 years. Once that funding was secured, the CCDI steering committee, which includes NBTS CEO David Arons, delivered a report to the National Cancer Institute on the goals of the initiative:

Gather data from every child, adolescent, and young adult diagnosed with pediatric cancer, regardless of where they receive their care.
Create a national strategy of appropriate clinical and molecular characterization to speed diagnosis and inform treatment for all types of pediatric cancers.
Develop a platform and tools to bring together clinical care and research data that will improve preventive measures, treatment, quality of life, and survivorship for pediatric cancers.
Based on these goals, the National Cancer Institute (NCI) is currently building the National Childhood Cancer Registry, which will centralize all existing data on cancer patients from birth to 39 years old and include information on their treatments, tumor types, outcomes, and post-care experiences. This registry will make it easier for researchers to collaborate and build on each others’ work, and hopefully, increase the pace of progress.

Danielle Leach

Also leveraging funding from the STAR Act, the NCI is working with Children’s Oncology Group (COG) to build a "biobank" of tumor tissue samples— a national "Molecular Characterization Protocol"— that will make it easier for researchers leading studies to acquire samples of tissue for their work. According to the NCI, this biobank will focus on cancers for which existing treatments are limited or ineffective and tissue for research is lacking and therefore will help fill a gap in the current research landscape.

As NCI Director Dr. Ned Sharpless wrote in a recent blog, these initiatives will "provide unprecedented insights into the drivers of childhood cancers and how they become resistant to treatment, as well as factors that influence the risk of treatment-related side effects…Collecting comprehensive data from as many children as possible will give researchers a more thorough understanding of how well treatments work…[and] make it easier for researchers to monitor the health of survivors of childhood cancer throughout their lives, providing further insights into the impact of cancer and its treatments."

STAR ACT

The STAR Act is the most comprehensive childhood cancer bill in history. It expands opportunities for childhood cancer research, improves efforts to identify and track childhood cancer incidences, and enhances the quality of life for childhood cancer survivors.

Since the bill was signed into law in 2018, NBTS advocates have played an active role in ensuring that the STAR Act has been fully funded at $30 million every year by asking for funding through activities like Head to the Hill and our online action alerts. Additionally, Danielle Leach sits on the Centers for Disease Control and Prevention Childhood Cancer STAR Act advisory group.

To date, funding from the STAR Act has led to:

Seven new research grants for "Improving Outcomes for Pediatric, Adolescent, and Young Adult Cancer Survivors."
Ten new research grants for "Research to Reduce Morbidity and Improve Care for Pediatric, and Adolescent and Young Adult (AYA) Cancer Survivors."
Additional funding for the CDC to expand the capacity of state cancer registries and their abilities to collect data on childhood cancer cases and trends.
More details related to these and other updates were included in a comprehensive overview put together by the Alliance for Childhood Cancer, for which NBTS serves as the co-chair of the policy committee.

On October 8, 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 issued the following statement about the safety of its allogeneic CAR T cell therapies (Press release, Precision Biosciences, OCT 8, 2021, View Source [SID1234591036]).

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1) Precision BioSciences’ allogeneic CAR T cells are made using its proprietary ARCUS genome editing platform designed for precision, specificity, and safety.

2) Precision BioSciences’ CAR T cells are the only allogeneic CAR T cells in human clinical trials made with a single gene editing step to specifically avoid the potentially deleterious effects of making multiple edits to T cells.

It is known in the field that making multiple edits in T cells can result in chromosomal abnormalities. Specifically, it has been shown to be an issue in TCR/CD52 edited cells. As published in Cancer Research[1], "Translocation frequencies ranged from 10-4 to 2×10-2 with translocations resulting in acentromeric or dicentromeric chromosomes occurring the least frequently."
Precision’s lymphodepletion strategy does not include an anti-CD52 monoclonal antibody, and therefore does not require editing CD52 in the CAR T cells.
3) In addition, Precision BioSciences believes the oligo-capture method is the most sensitive method available for off-target detection allowing for superior product characterization with respect to gene editing safety. Importantly, this method is used to engineer out off-target editing of the ARCUS nucleases during the research phase of product development.

4) As part of product release testing, Precision BioSciences evaluates chromosomal abnormalities and confirms that the CAR T cells are not transformed.

5) Across four clinical programs in more than 100 patients treated with PBCAR T cells, Precision BioSciences has seen no evidence of chromosomal abnormalities.

Precision BioSciences is actively recruiting patients in ongoing clinical studies of PBCAR0191 (NCT03666000) for patients with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) and R/R B-cell acute lymphoblastic leukemia, PBCAR19B (NCT04649112) for patients with R/R NHL, and PBCAR269 (NCT04171843) for patients with R/R multiple myeloma.