jondoeuk
6 월 전
Discovery of Novel CARs for Solid Tumors Using Senti REVEAL™, a Massively Parallel Technology Platform Comprising Pooled Screening, Machine Learning, and Lab Automation
Introduction. CAR-T and CAR-NK therapies have limited efficacy in solid tumors due to multiple factors including the immunosuppressive tumor microenvironment and the limited potency of the signaling domains of current approved CAR therapies. More potent CAR signaling domains may address this limitation by activating different pathways (or combinations) that increase robustness to the immunosuppressive tumor microenvironment. FDA-approved CAR therapies for liquid tumors tend to use a limited set of intracellular domains, highlighting a need for new signaling domains for solid tumors. Conventional approaches of screening and optimizing CAR designs are manual labor intensive, low throughput, and can suffer from operator and batch error.
Methods. We developed a massively parallel technology platform, REVEAL™ (Research Engine for Validation of Engineered Asset Libraries), comprising (1) pooled screens of CAR libraries of 10,000s to 100,000s of signaling domains, (2) machine learning models to predict performance, and (3) parallel clonal validation of 100s to 1,000s of candidates using a purpose-built automated liquid handler. Here we used CAR-NK cells, but we anticipate that this framework can be used for other types of effector cells such as CAR-T. We designed libraries of CARs with a fixed extracellular domain targeting CEA, an antigen expressed on a range of solid tumors including colorectal cancer, and over 50,000 combinatorial signaling domains consisting of arrays of subdomains derived from native receptors. High-performing CARs in the libraries were discovered using a sort-seq approach: cells expressing CARs driving robust degranulation (CD107a+) were sorted, and CARs enriched in these cells were identified via NGS. We used these data to train machine learning models mapping CAR structure (i.e., the position and identity of constituent subdomains) to performance. In addition to reproducing experimental CAR performance, these models were used to predict CAR structures not present in the dataset due to cloning or coverage constraints. The highest performing library CARs and model-predicted CARs were then clonally validated in parallel using a liquid handler-based workflow that automated viral production, NK transduction, co-culture assay setup, and imaging-based readout of target killing.
Results. Our library screens and modeling indicate, and our clonal validations confirm, that signaling domains enriched for TRAF-binding motifs have high performance in the context of anti-CEA CAR-NK cells. Among highest performing CARs, however, TRAF domains are typically accompanied by other functional motifs, constituting a more diverse signaling array than would be found in a single native immune receptor. Successful CARs often comprised multiple canonical immune signaling types, i.e., signal 1 (CD3z), signal 2 (one or more costimulatory motifs) and signal 3 (cytokine signaling), demonstrating that a variety of signaling features can be successfully packaged into a single compact CAR. Additionally, these CARs contained sequences from a wide variety of sources outside of canonical CAR domains such as CD3z, CD28, 4-1BB, indicating the untapped potential for designing new CARs for solid tumors.
Conclusion. The REVEAL™ framework described here is capable of extensive optimization of CAR structures, and could potentially be applied to development of potent CAR cell therapies targeting solid tumors and hematologic malignancies beyond B cell cancers.
https://annualmeeting.asgct.org/abstracts/abstract-details?abstractId=60213
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11 월 전
NEWS
Senti Bio Announces FDA Clearance of IND Application for SENTI-202 for the Treatment of Relapsed or Refractory Hematologic Malignancies Including Acute Myeloid Leukemia
– First patient in Phase 1 clinical trial expected to be treated in Q2 2024 –
– Initial clinical efficacy data expected by year-end 2024 and durability data expected in 2025 –
– SENTI-202 is a potential first-in-class off-the-shelf CAR-NK cell therapy using Logic Gated Gene Circuits to selectively target cancer cells while sparing healthy bone marrow cells –
SOUTH SAN FRANCISCO, Calif., Dec. 22, 2023 (GLOBE NEWSWIRE) -- Senti Biosciences, Inc. (Nasdaq: SNTI) (“Senti Bio”), a clinical stage biotechnology company developing next-generation cell and gene therapies using its proprietary Gene Circuit platform, today announced that it received clearance of its Investigational New Drug (IND) application from the U.S. Food and Drug Administration (FDA) for SENTI-202, an off-the-shelf chimeric antigen receptor natural killer (CAR-NK) cell therapy product candidate designed to selectively target and eliminate CD33 and/or FLT3 expressing hematologic malignancies while sparing healthy bone marrow cells.
The Company plans to initiate a Phase 1 clinical trial of SENTI-202 in 2024 in multiple sites in the United States and Australia, and expects to treat the first patient in the second quarter of 2024. The dose finding trial will evaluate two dose levels, either 1 or 1.5 billion SENTI-202 cells, administered after lymphodepleting conditioning in adult patients with relapsed or refractory (r/r) CD33 and/or FLT3 expressing hematologic malignancies, including acute myeloid leukemia (AML). Initial dosing will consist of three doses administered weekly following lymphodepletion, with the option to receive continuation cycles of lymphodepletion and SENTI-202 cells based on safety and efficacy data.
“Clearance of our IND application for SENTI-202 is a tremendous milestone and marks an important achievement for Senti as we transition to a clinical-stage therapeutics company,” said Timothy Lu, MD, PhD, Chief Executive Officer and Co-Founder of Senti Bio. “Our team has dedicated immense time and resources to developing our Gene Circuit technology from an initial synthetic biology hypothesis to what is now a tangible product for cancer patients. We look forward to initiating Senti’s first clinical trial and continuing our strong momentum into next year.”
A limitation of many existing cancer therapies, according to the Company, is that current treatments cannot precisely distinguish cancer cells from healthy cells, leading to side effects and limited efficacy due to dosing limitations from these safety events. Furthermore, AML is polyclonal and heterogenous, and requires multiple antigens to be targeted in order to achieve deep and durable responses. SENTI-202 utilizes proprietary Logic Gating technology designed to overcome AML disease heterogeneity by targeting both the cancer cells and leukemic stem cells through its OR GATE, which can kill cancer cells that express either CD33 and/or FLT3. SENTI-202 also incorporates the NOT GATE that recognizes healthy cells through a protective antigen, and spares healthy bone marrow cells even if they express CD33 and/or FLT3. Finally, SENTI-202 expresses a proprietary calibrated release IL15, which has the ability to enhance both the CAR-NK cells, as well as patient immune cell function in the leukemic milieu to further enhance activity. Senti Bio believes this approach can lead to more effective and durable responses in patients.
“SENTI-202 has been systematically engineered to potentially overcome the key limitations of current AML therapies, namely the need to address AML heterogeneity and to protect healthy marrow cells from on-target and off-tumor killing,” said Kanya Rajangam, MD, PhD, Head of Research & Development and Chief Medical Officer of Senti Bio. “Our trial design incorporates lessons learnt from clinical experiences with other AML cell therapies and includes disease-specific lymphodepletion, multiple high doses of CAR-NK cells, as well as multiple treatment cycles. We are excited to begin this trial and deliver a potential treatment to patients who currently have no approved therapies and very poor prognosis.”
The Company expects to disclose initial efficacy data from the Phase 1 trial by year-end 2024 and durability data in 2025. Through Senti Bio’s previously announced agreement with GeneFab, the Company has prepaid the majority of manufacturing-related expenses through the completion of the Phase 1 trial.
About SENTI-202
SENTI-202 is a Logic Gated off-the-shelf CAR-NK cell therapy product candidate designed to selectively target and eliminate CD33 and/or FLT3 expressing hematologic malignancies, such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), while sparing healthy bone marrow cells. SENTI-202 has three main components. First, the OR GATE, which is an activating CAR that targets CD33 and FLT3. By targeting either or both of these antigens, SENTI-202 could effectively kill both the leukemic blasts and leukemic stem cells that form an important basis for AML disease. Second, the NOT GATE, which is designed to recognize the healthy cells and protect those healthy cells from being killed. Third, the calibrated-release IL-15 technology, which is designed to significantly increase cell persistence, expansion and activity of both the CAR- NK cells and the host immune cells. The NK cells used to construct SENTI-202 are sourced from healthy adult donors, which have been screened based on a set of criteria that reflect manufacturability and product quality, and are then cryopreserved prior to use in manufacturing to minimize variability. Senti Bio is currently enrolling adult patients with r/r CD33 and/or FLT3 expressing heme malignancies in a Phase 1 clinical trial for SENTI-202, which can be a potential first-in-class allogenic treatment for AML/MDS patients.
About Acute Myeloid Leukemia
Acute myeloid leukemia is a cancer of the blood and bone marrow and is the most common type of acute leukemia in adults. It is estimated there will be 20,380 new cases of AML in the United States in 2023. The five-year survival rate for these patients is approximately 30%. AML is currently treated with chemotherapy, targeted therapies, and/or allogeneic or autologous stem cell transplant. For patients with relapsed or refractory AML, there are few treatment options and median overall survival is typically less than seven months.
About Senti Bio
Senti Biosciences is a biotechnology company developing a new generation of cell and gene therapies for patients living with incurable diseases. To achieve this, Senti Bio is leveraging a synthetic biology platform called Gene Circuits to create therapies with enhanced precision and control. These Gene Circuits are designed to precisely kill cancer cells, spare healthy cells, increase specificity to target cells and control the expression of drugs even after administration. These Gene Circuits work in many different genetic medicine modalities, including T cells, NK cells, induced pluripotent stem cells (iPSCs), and gene
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1 년 전
NEWS
Senti Bio Announces New Strategic Collaboration with Celest Therapeutics for Clinical Development of SENTI-301A in China
– Celest to lead clinical development with technical support from Senti Bio –
– First patient expected to be enrolled in China in 1H 2024 –
– Senti Bio eligible to receive up to $156 million in milestones and royalties –
SOUTH SAN FRANCISCO, Calif., Nov. 06, 2023 (GLOBE NEWSWIRE) -- Senti Biosciences, Inc. (Nasdaq: SNTI) (“Senti Bio”), a biotechnology company developing next-generation cell and gene therapies using its proprietary Gene Circuit platform, today announced a new strategic collaboration with Celest Therapeutics (Shanghai) Co. Ltd (“Celest”), a China-based biotechnology company, for the clinical development of SENTI-301A to treat solid tumors in China.
Through this collaboration, Celest will lead clinical development, operations, and manufacturing for the advancement of SENTI-301A with technical support from Senti Bio. Celest plans to enroll patients initially through a pilot trial in mainland China and expects to enroll the first patient in the first half of 2024. Celest and Senti Bio have the option to expand clinical development of SENTI-301A to Hong Kong, Macau and Taiwan. Senti Bio will retain all commercialization rights outside of mainland China, Hong Kong, Macau, and Taiwan for SENTI-301A.
Under the terms of the collaboration, Senti Bio will be eligible to receive up to $156 million in certain milestone payments, in addition to potential tiered royalty payments. Other terms of the transaction were not disclosed.
The planned dose finding trial will include 9 patients with advanced glypican 3 (“GPC3”)-expressing hepatocellular carcinoma (“HCC”) across two dose cohorts. Endpoints will include safety assessments for adverse events and dose limiting toxicities, as well as efficacy analyses using standard response criteria for liver cancer.
“We are pleased to have established a strategic partnership with Celest to advance the clinical development of SENTI-301A, an objective we set earlier this year,” said Timothy Lu, MD, PhD, Chief Executive Officer and Co-Founder of Senti Bio. “By leveraging Celest’s strength to accelerate clinical development, manufacturing, and regulatory activities in China, we are one step closer to bringing Senti’s Gene Circuit technology to patients who have limited therapeutic options. We look forward to collaborating with the experienced team at Celest, a company committed to the clinical development of innovative drugs in China.”
“Our partnership with Senti Bio provides multiple synergies in our mission to develop next-generation cell therapies in China to fulfill the tremendous unmet medical need in combating cancer,” said Erdong Hua, Chairman at Celest Therapeutics. “We are excited to combine Senti’s novel Gene Circuit technology with Celest’s clinical expertise to drive SENTI-301A into the clinic and begin treating patients.”
The Company has previously highlighted the significant prevalence of HCC and market opportunities for HCC treatments in Asia. HCC remains the predominant histological type of primary liver cancer in Asia.
SENTI-301A is a multi-armed off-the-shelf healthy donor derived CAR-NK cell therapy designed for the treatment of GPC3 expressing tumors. The engineered NK cells target the GPC3 antigen, which is highly expressed in 70% to 90% of HCCs and has low or no expression on normal adult tissues. Additionally, SENTI-301A incorporates the calibrated release interleukin-15 (crIL-15), a multi-functional immuno-stimulatory payload designed to simultaneously stimulate surrounding immune cells and promote CAR-NK cell expansion, persistence and tumor killing. Senti Bio has shown comprehensive preclinical data demonstrating robust in vitro and in vivo killing of relevant tumor cells with SENTI-301A.
About Senti Bio
Senti Biosciences is a biotechnology company developing a new generation of cell and gene therapies for patients living with incurable diseases. To achieve this, Senti Bio is leveraging a synthetic biology platform called Gene Circuits to create therapies with enhanced precision and control. These Gene Circuits are designed to precisely kill cancer cells, spare healthy cells, increase specificity to target cells and control the expression of drugs even after administration. Senti Bio’s wholly-owned pipeline utilizes off-the-shelf chimeric antigen receptor natural killer (CAR-NK) cells, outfitted with Gene Circuits, to target challenging liquid and solid tumor indications. Senti Bio has also preclinically demonstrated the potential breadth Gene Circuits in other modalities, diseases outside of oncology, and continues to advance these capabilities through partnerships with Spark Therapeutics and BlueRock Therapeutics.
About Celest Therapeutics
Celest Therapeutics LLC was founded to develop intelligent CAR-immune cell therapy for effective treatment of challenging solid tumors. Celest technology platforms employ a suite of immunological technologies, including screens for tumor microenvironment (TME) induced immune cell enrichment, trafficking and persistence. In parallel, the platforms also iden
INFINITI
1 년 전
Hedge Funds Weigh In On Senti Biosciences
Several institutional investors and hedge funds have recently added to or reduced their stakes in the stock. Renaissance Technologies LLC bought a new position in Senti Biosciences in the 4th quarter valued at approximately $25,000. Virtu Financial LLC bought a new position in shares of Senti Biosciences during the second quarter valued at $43,000. Geode Capital Management LLC raised its stake in shares of Senti Biosciences by 19.7% during the fourth quarter. Geode Capital Management LLC now owns 200,187 shares of the company’s stock valued at $282,000 after acquiring an additional 32,912 shares during the last quarter. Millennium Management LLC bought a new position in shares of Senti Biosciences during the second quarter valued at $71,000. Finally, Triatomic Management LP raised its stake in shares of Senti Biosciences by 39.0% during the first quarter. Triatomic Management LP now owns 210,883 shares of the company’s stock valued at $249,000 after acquiring an additional 59,208 shares during the last quarter. Institutional investors own 27.37% of the company’s stock.
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