On December 10, 2022 Gracell Biotechnologies Inc. ("Gracell" or the "Company", NASDAQ: GRCL), a global clinical-stage biopharmaceutical company dedicated to developing highly efficacious and affordable cell therapies for the treatment of cancer, reported that the clinical data from its ongoing Phase 1, investigator-initiated trial (IIT) in China evaluating FasTCAR-enabled GC012F as first-line therapy in transplant-eligible, high-risk, newly diagnosed multiple myeloma (NDMM) patients (Press release, Gracell Biotechnologies, DEC 11, 2022, View Source [SID1234625037]). Data has been presented in an oral session at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition, held Dec. 10-13 in New Orleans. Patients in the study achieved a 100% overall response rate (ORR) and 100% minimal residual disease (MRD) negativity in all dose levels.

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GC012F is an autologous CAR-T therapeutic candidate dual-targeting B cell maturation antigen (BCMA) and CD19, and utilizes Gracell’s proprietary FasTCAR next-day manufacturing platform.

As of the Oct. 14, 2022 data cutoff date, 16 transplant-eligible NDMM patients had received GC012F infusion in the clinical trial. All patients had multiple high-risk features. After receiving a conditioning lymphodepletion regimen of cyclophosphamide and fludarabine, patients were treated with GC012F as a single infusion with one of three dose levels: 1×105 cells/kg, 2×105 cells/kg and 3×105 cells/kg.

As of Oct. 14, 2022, among the 16 evaluable patients with the median follow-up time of eight months (ranging from 1.3 to 15.4 months):

ORR was 100%
87.5% (14/16) of patients achieved stringent complete response (sCR). Patients continue to be followed for deepening responses
100% of evaluable patients achieved MRD negativity in all dose levels
100% of evaluable patients achieved MRD negativity at months 1, 6 and 12
100% of patients experienced robust CAR-T cell expansion with long persistence in all dose levels
The clinical data also demonstrated an excellent safety profile:

Only 25% (4/16) of patients experienced Grade 1-2 cytokine release syndrome (CRS); no patients experienced Grade 3-5 CRS
No immune effector cell-associated neurotoxicity syndrome (ICANS) or other neurotoxicity of any grade had been observed
"This clinical data brings us great optimism. GC012F has demonstrated an impressive 100% ORR, 100% MRD negativity and 87.5% sCR, as well as an outstanding safety profile, among newly-diagnosed multiple myeloma patients, showing tremendous potential for substantial improvement over currently available therapies," said Dr. Wendy Li, Gracell’s Chief Medical Officer. "We are pleased to share this data with the leading experts in hematology and oncology at ASH (Free ASH Whitepaper) 2022. We believe that the data underscores GC012F’s significant potential as a safe and effective therapy for NDMM patients. In addition, GC012F is developed using our proprietary FasTCAR next-day manufacturing platform, which could greatly expedite the delivery of this much-needed therapy to patients."

About GC012F

GC012F is a FasTCAR-enabled BCMA/CD19 dual-targeting CAR-T product candidate that is currently being evaluated in IIT studies in China for the treatment of multiple myeloma and B-cell non-Hodgkin’s lymphoma. GC012F simultaneously targets CD19 and BCMA to drive fast, deep and durable responses, which can potentially improve efficacy and reduce relapse in multiple myeloma and B-NHL patients.

About FasTCAR

CAR-T cells manufactured on Gracell’s proprietary FasTCAR platform appear younger, less exhausted and show enhanced proliferation, persistence, bone marrow migration and tumor cell clearance activities as demonstrated in preclinical studies. With next-day manufacturing, FasTCAR is able to significantly improve cell production efficiency which may result in meaningful cost savings, and, together with fast release time, enables enhanced accessibility of cell therapies for cancer patients.

On December 11, 2022 Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in developing novel therapies for cancers, chronic hepatitis B (CHB), and age-related diseases, reported that it has released preliminary results of olverembatinib (HQP1351) in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), in an Oral Presentation at the American Society of Hematology (ASH) (Free ASH Whitepaper) 64th Annual Meeting and Exposition (New Orleans, LA), marking the first data readout from the US study (Press release, Ascentage Pharma, DEC 11, 2022, View Source;ascentage-pharma-delivers-oral-report-on-the-first-dataset-from-the-us-study-of-olverembatinib-hqp1351-with-promising-efficacy-observed-in-patients-who-failed-prior-treatment-with-ponatinib-301699947.html [SID1234625036]).

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The ASH (Free ASH Whitepaper) Annual Meeting is one of the largest gatherings of the international hematology field, featuring world-class advances on cutting-edge scientific and clinical research in hematology. As a leading member of the Chinese hematology and oncology research community that has been increasingly active on the global stage, Ascentage Pharma had results from 5 of its clinical trials selected for 4 Oral Presentations at this year’s ASH (Free ASH Whitepaper) Annual Meeting, attracting widespread interest at the event. In total, Ascentage Pharma will have 8 presentations at ASH (Free ASH Whitepaper) 2022, including 4 Oral and 4 Poster Presentations (with 3 poster presentations submitted independently by investigators based on real-world evidence).

Preliminary results announced at this year’s meeting suggested that olverembatinib has favorable efficacy and a manageable safety profile in US patients with drug-resistant CML and Ph+ ALL, and showed the drug’s potential as a "salvage" therapy in patients with prior resistance to third-generation tyrosine kinase inhibitor (TKI) ponatinib and allosteric STAMP inhibitor asciminib. These data showed that close to 80% patients with CML had received at least three lines of treatment, and over 50% had failed prior treatment with ponatinib. Even in heavily pre-treated patients with drug-resistant CML, those with chronic-phase CML (CML-CP) achieved complete cytogenetic response (CCyR) and major molecular response (MMR) rates of 77.8% and 43.5%, respectively; while patients with CML-CP who had failed prior treatment with ponatinib have achieved a CCyR and an MMR rate of 83.3% and 42.9%, respectively.

In addition, olverembatinib was well-tolerated. The safety data from this US study were similar to previously published results from Chinese studies and showed no new safety signals. In particular, olverembatinib demonstrated excellent tolerability in patients who were intolerant of ponatinib, which also exemplifies olverembatinib’s positive safety profile.

Developed by Ascentage Pharma, olverembatinib is a potential best-in-class novel drug that has been designated a Major New Drug Project by China’s Ministry of Science and Technology. As the first approved third-generation BCR-ABL inhibitor in China and the second in any country globally, olverembatinib is recommended by both the Guidelines of the Chinese Society of Clinical Oncology (CSCO) and the China Anti-Cancer Association’s (CACA) Guidelines for the Holistic Integrative Management of Cancers, for the treatment of patients with TKI-resistant CML harboring the T315I mutation (while the CACA Guidelines also recommend olverembatinib for the treatment of patients with CML intolerant/resistant to at least two TKIs).

Globally, despite approvals for ponatinib and asciminib, patients with CML still have enormous unmet medical needs because of limited accessibility as well as adverse events of these two drugs. Taken together, these limitations have recently stimulated strong interest in clinical progress with olverembatinib among the global hematology community. At present, olverembatinib is being evaluated in a US Phase Ib study for the treatment of drug-resistant CML. Furthermore, olverembatinib has been granted one Fast Track designation and three Orphan Drug designations by the US Food and Drug Administration (FDA), and one Orphan Drug designation by the European Medicines Agency (EMA).

As olverembatinib is not yet approved anywhere outside China, Ascentage Pharma is pressing ahead with global clinical development of olverembatinib and advancing the drug toward approvals in a number of countries to help address the unmet medical needs of patients with CML globally. Driven by a sense of urgency to facilitate early access by patients with malignancies that currently lack treatment options, Ascentage Pharma and Tanner Pharma Group (a global pharmaceutical services provider of specialty access solutions) jointly launched an innovative Named Patient Program (NPP) for olverembatinib in July 2022. This collaboration will allow access to olverembatinib on a named patient basis in more than 140 countries and regions where the drug is not yet commercially accessible, in a manner that is reliable, responsible, ethical, and in accordance with all country-specific regulatory requirements.

"These findings suggest that olverembatinib is a potentially effective ‘salvage’ therapy for patients with prior CML treatment failure," according to Prof. Elias Jabbour, MD, Department of Leukemia, The University of Texas MD Anderson Cancer Center (Houston, TX). "The favorable safety and tolerability profile of olverembatinib are important because many patients with CML experience intolerance, including potentially concerning cardiovascular events, when using certain other BCR-ABL1 inhibitors."

"The first batch of data from the first US study of olverembatinib released at ASH (Free ASH Whitepaper) 2022 are very promising, indeed, as they show olverembatinib’s exciting potential as a best-in-class drug that can overcome resistance to ponatinib and asciminib in patients with CML and Ph⁺ ALL. We are encouraged by these results because they further validate that olverembatinib can potentially bring a long-awaited change to the treatment paradigm for CML and Ph⁺ ALL globally." according to Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma.

"At this year’s ASH (Free ASH Whitepaper) Annual Meeting, we released data of olverembatinib and our Bcl-2 inhibitor for CLL/SLL, lisaftoclax, in four Oral Presentations. We are very proud of this achievement, which underscores our robust capabilities in global innovation," she remarked. "Moving forward, we will remain committed to the mission of addressing unmet clinical needs in China and around the world, and continue to accelerate our clinical development programs with the hope of bringing more safe and effective therapeutics to patients in need," Dr. Zhai noted.

Data from the US studies of olverembatinib reported in Oral Presentations at this year’s ASH (Free ASH Whitepaper) Annual Meeting are as follows (for detailed results from the study of lisaftoclax and the China study of olverembatinib, please refer to other two press releases to be published during ASH (Free ASH Whitepaper) 2022):

Olverembatinib (HQP1351) Overcomes Ponatinib Resistance in Patients with Heavily Pretreated/Refractory Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL)

Format: Oral Presentation
Abstract: #162387
Session: 632. Chronic Myeloid Leukemia: Clinical and Epidemiological: Novel Agents
Time: Saturday, December 10, 2022, 10:15 AM (Eastern Time) / Saturday, December 10, 2022, 11:15 PM (Beijing Time)
Highlights
– Olverembatinib is a novel third-generation BCR-ABL1 TKI with antitumor activity against CML and Ph+ ALL and a favorable safety profile.

– This multicenter, open-label, randomized trial is the first to report on the safety, efficacy, and pharmacokinetics (PK) of olverembatinib in patients with CML and Ph+ ALL outside China, who were intolerant or resistant to at least 2 BCR-ABL1 inhibitors, including ponatinib and asciminib, except for those whose disease harbors the T315I mutation, for whom the number of prior lines of therapy was not limited. Study participants were randomized in a ratio of 3:3:2 to receive olverembatinib 30, 40, or 50 mg QOD in 28-day cycles.

– As of Dec 5, 2022, a total of 51 patients have been enrolled, including 38 with CML-CP, and 13 with CML-AP, CML blast phase (-BP), or Ph+ ALL. The median treatment duration was 32.4 (range, 0-119) weeks. 54.9% (28/51) of patients were men, and the median age was 51 (range, 21-79). In all, 7 (13.7%), 14 (27.5%), and 25 (49%) patients received 2, 3, and ≥ 4 prior lines of treatment, respectively. A total of 28 (54.9%) patients were pretreated with the third-generation TKI ponatinib, including 21 (75.0%) with resistance and 7 (25.0%) with intolerance; a total of 19 (37.3%) had T315I mutations; 28 (54.9%) had cardiovascular diseases at baseline, and 18 (35.3%) had hypertension.

– PK analysis indicated a dose-proportional increase in olverembatinib plasma exposure from 30 to 50 mg QOD and comparable plasma exposures between the Chinese and US CML populations.

– Safety: Olverembatinib was well tolerated. 34 patients experienced treatment related adverse events (TRAEs) of any grade, the incidence of which tended to be dose-dependent. Most of the nonhematologic TRAEs were grade 1/2. Common grade 3/4 nonhematologic TRAEs included thrombocytopenia (18.9%), neutropenia (16.2%), and decreased leukopenia counts (13.5%). 8 olverembatinib-related serious adverse events (SAEs) were observed in 6 patients, and none of these SAEs led to treatment discontinuation.

– Preliminary efficacy: Olverembatinib conferred potent antileukemic activity in patients with CML and Ph+ ALL. Of 23 efficacy-evaluable patients with CML-CP, 14/18 (77.8%) had a CCyR; 10/23 (43.5%) had a MMR. Olverembatinib was effective in patients with either the T315I-mutant (87.5%, CCyR; 55.6%, MMR) or T315I un-mutant (70.0%, CCyR; 35.7%, MMR), and its effectiveness was not compromised by prior use of ponatinib or asciminib. Among patients who were previously treated with ponatinib, 10/12 (83.3%) experienced CCyR and 6/14 (42.9%) experienced MMR. In particular, among patients with diseases resistant to ponatinib, 7/9 (77.8%) experienced CCyR, and 5/10 (50%) experienced MMR. In patients who were previously treated with asciminib, 1 experienced CCyR and MMR. In the 7 efficacy-evaluable patients with Ph+ leukemia in progressive phase (including CML-AP, CML-BP, and Ph+ ALL), 2 experienced CCyR and MMR. Both patients were resistant to ponatinib and neither harbored the T315I mutation. Of them, 1 patient with Ph+ ALL achieved CCyR after just one cycle of treatment with olverembatinib.

– Conclusions: Olverembatinib monotherapy is efficacious and well tolerated in patients with TKI-refractory CML and Ph+ ALL. Even in patients with CML who were ponatinib or asciminib resistant, or who had T315I mutations, olverembatinib also showed strong efficacy.

On December 11, 2022 Wugen, Inc., a clinical-stage biotechnology company developing a pipeline of allogeneic cell therapies to treat a broad range of hematological and solid tumor malignancies, reported data on WU-NK-101, the company’s lead memory natural killer (NK) cell therapy product, at the 64th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) taking place December 10 – 13, 2022 in New Orleans, Louisiana (Press release, Wugen, DEC 11, 2022, View Source [SID1234625035]).

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"Conventional NK cells (cNK) have proven dysfunctional in the harsh, acute myeloid leukemia (AML) tumor microenvironment (TME), and attempts to improve anti-tumor performance prior to adoptive transfer have proven limited in their success," said Sergio Rutella, M.D., Ph.D., FRCPath, FRSB, Professor of Cancer Immunotherapy at Nottingham Trent University and presenting author. "These data functionally characterizing the anti-tumor properties of WU-NK-101 are highly encouraging and support the potential for WU-NK-101 as a treatment for relapsed/refractory (r/r) AML. Further, the identification of a TME immune signature highly predictive of response may be an impactful tool to support future clinical studies."

"These data further validate our approach deploying WU-NK-101 for AML," said Jan Davidson-Moncada, M.D., Ph.D., Chief Medical Officer of Wugen. "In early clinical studies, memory NK cells have already demonstrated impressive efficacy against AML. We look forward to building on those promising signals and advancing WU-NK-101 into the clinic as a novel, off-the-shelf therapy for this indication."

Today’s presentation highlighted the following:

An 8-gene TME immune signature showed excellent predictive ability for response to cytokine-induced memory-like (CIML) NK cells in patients with r/r AML. Responders exhibited TME modulation via innate and immune cell presence as well as metabolic re-programming reflected by enhanced glucose and amino acid consumption.
Compared to cNK cells, WU-NK-101 had enhanced anti-tumor activity, trafficked to the bone marrow, and showed metabolic flexibility, potentially mitigating the adverse effects of the highly immuno-suppressive AML TME.
WU-NK-101 may represent an effective treatment modality for r/r AML. A Phase 1 study evaluating WU-NK-101 in patients with r/r AML is expected to begin enrollment in the first half of 2023.
The details of Wugen’s presentation at ASH (Free ASH Whitepaper) are as follows:

Title: Putative Predictors of Response to WU-NK-101, an Allogeneic, Enhanced Memory (ML)

Natural Killer (NK) Cell Therapy Product, for Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML)

Publication Number: 3294

Session Name: 703. Cellular Immunotherapies: Basic and Translational: Poster II

Session Date and Time: Sunday, December 11, 2022 from 6:00 p.m. – 8:00 p.m. CT

Location: Ernest N. Morial Convention Center, Hall D

Presenting Author: Sergio Rutella, M.D., Ph.D., FRCPath, FRSB, Nottingham Trent University

Additional meeting information can be found at View Source

About WU-NK-101

WU-NK-101 is a novel immunotherapy harnessing the power of memory natural killer (NK) cells to treat liquid and solid tumors. Memory NK cells are hyper-functional, long-lasting immune cells that exhibit enhanced anti-tumor activity and a cytokine-induced memory-like (CIML) phenotype. This rare cell population has a superior phenotype, proliferation capacity, and metabolic fitness that makes it better suited for cancer therapy than other NK cell therapies. Wugen is applying its proprietary MonetaTM platform to advance WU-NK-101 as a commercially scalable, off-the-shelf cell therapy for cancer. WU-NK-101 is currently in development for acute myelogenous leukemia (AML) and solid tumors.

About the MonetaTM Platform

Wugen’s proprietary MonetaTM platform is a robust, scalable process to manufacture off-the-shelf memory natural killer (NK) cell therapies with enhanced anti-tumor functionality. The MonetaTM platform uses cytokine fusion complexes for streamlined and consistent manufacturing, is free of feeder cells for enhanced safety, and integrates cryopreservation to allow convenient dosing options for cancer patients.

On December 11, 2022 Vincerx Pharma, Inc. (Nasdaq: VINC), a biopharmaceutical company aspiring to address the unmet medical needs of patients with cancer through paradigm-shifting therapeutics, reported that a poster presentation of preclinical data of Vincerx’s proprietary payload and linker technology and VIP943, the Company’s internalizing ADC targeting CD123, at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting 2022 (Press release, Vincerx Pharma, DEC 11, 2022, View Source [SID1234625034]).

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VIP943 is a novel ADC, which binds to the IL3-receptor alpha chain (CD123). VIP943 combines the unique payload class of kinesin spindle protein inhibitors (KSPi) with a proprietary legumain-cleavable linker. Vincerx’s CellTrapper modification of the KSPi prevents diffusion out of the cell, allowing intracellular accumulation. The nonpermeability of the payload prevents off-target toxicities, leading to favorable efficacy and safety profiles.

"I am truly excited about the preclinical results for VIP943 and our proprietary payload and linker technology presented at ASH (Free ASH Whitepaper)," said Ahmed Hamdy, M.D., Chief Executive Officer of Vincerx. "For the first time, we showed a significant improvement in safety over an approved ADC, demonstrating in non-human primates the benefit of our KSPi payload and CellTrapper technology specifically designed to address some of the well-known challenges of ADCs on the market. The in vivo AML mouse model results also showed improved efficacy and survival for VIP943 in combination with venetoclax and azacitidine. This triple combination resulted in significant tumor regression as demonstrated by five complete responses and significantly prolonged survival time without increased toxicity," added Dr. Hamdy.

Dr. Anthony Tolcher, M.D., Chief Executive Officer, Founder and Director of Clinical Research at NEXT Oncology, added, "This ADC is innovative and exciting. The target is well understood and the novel payload that targets myeloid cells suggests this could be a valuable agent for patients with AML."

"Current standard of care for AML patients is combination therapy with venetoclax and azacitidine, yet most patients eventually relapse with progressive disease. The efficacy and safety data for VIP943 we see in our studies suggest it may be a promising option for treating AML as a monotherapy in relapse/refractory elderly, unfit and high-risk patients as well as in combination with venetoclax and azacitidine. Our results also provide compelling evidence that VIP943 represents a substantial advancement and potential paradigm-shift in ADC technology. We look forward to continuing to advance the IND-enabling studies for VIP943 and expect to file our IND in mid-2023," concluded Dr. Hamdy.

Key Presentation Highlights:

Poster presentation titled, "VIP943 is a Novel CD123 Antibody Drug Conjugate with In Vitro and In Vivo Efficacy in Acute Myeloid Leukemia (AML) Models", presented by Beatrix Stelte-Ludwig, Ph.D., Vincerx Pharma GmbH, Monheim, Germany, includes:

Bone marrow samples derived from patients with AML were used to evaluate VIP943 monotherapy at different concentrations (0.1 pM to 1µM) in a depletion (without cytokine addition) and a proliferation assay. Combination treatment of VIP943 (using 8 different doses) and venetoclax (one fixed dose of 16.5 nM) was evaluated. All patient samples were analyzed by flow cytometry and were positive for CD123 cell surface expression. In the depletion assay, only the samples which showed spontaneous proliferation were sensitive to VIP943 treatment in accordance with the mode of action of the KSPi payload.

In a patient-derived AML xenograft model, the triple combination of VIP943 with venetoclax and azacitidine increased the number of complete responses (56% vs 22%) and the overall survival (>107 vs 83 days) compared with venetoclax and azacitidine.

VIP943 did not induce cytokine release in a human cytokine release assay when compared with positive controls. One dose of VIP943 in an immunophenotyping study in NHP resulted in a reversible reduction in CD123+ basophils.
In a NHP safety study, a newly generated ADC using a gemtuzumab biosimilar as the targeting antibody conjugated to our effector chemistry comprised of a proprietary linker and payload (Gem-KSPi ADC) and VIP943 (anti-CD123-KSPi ADC) were directly compared with Mylotarg.

CD33+/CD123+ basophils showed an expected decrease across treatments; however, the VIP943 and Gem-KSPi ADC groups demonstrated a full recovery over the observation period, whereas Mylotarg showed an increased severity. Over time, a significant deleterious effect was seen with a single dose of Mylotarg on platelets, WBC count, reticulocytes, hemoglobin, hematocrit and lymphocytes. In contrast, a single dose of Gem-KSPi ADC and VIP943 showed no effects on hematology parameters other than the aforementioned transient reduction of CD123+ basophils.

Evaluation of serum chemistry showed increases in liver function enzymes, bilirubin and urea nitrogen in the Mylotarg group. The female monkey treated with Mylotarg died before the end of the observation period and the male monkey had to be euthanized. All monkeys from the Gem-KSPi ADC and VIP943 groups were healthy and returned to the colony with no remarkable changes in serum chemistry.
Overall, these results demonstrate the substantial advancement in ADC technology with the development of VIP943. Further IND-enabling studies are ongoing, and the Company expects to file an IND in mid-2023.
A copy of this presentation can now be accessed on the Investors section of the Company’s website at www.vincerx.com. Other Vincerx presentations related to enitociclib will be available on the company website on Monday, December 12 at 9:00AM CST.

On December 11, 2022 Sana Biotechnology, Inc. (NASDAQ: SANA), a company focused on creating and delivering engineered cells as medicines, reported data in six presentations at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition, taking place from Saturday, December 10 to Tuesday, December 13, 2022 in New Orleans, LA, which highlighted further progress with key technologies supporting Sana’s ex vivo allogeneic CAR T cell programs and in vivo platform (Press release, Sana Biotechnology, DEC 11, 2022, View Source [SID1234625030]).

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"Our HIP platform has the potential to transform the CAR T space, and with it, the treatment of hematologic malignancies, and we are pleased to share data from several drug candidates before our planned entry into the clinic in 2023," said Terry Fry, M.D., Sana’s Senior Vice President and Head of T Cell Therapeutics. "Separate oral presentations show that our HIP-modified allogeneic CD19-targeted CAR T cells can evade immune detection and kill tumor cells in a fully immunocompetent preclinical model, including with serial in vivo tumor stimulation, and that our manufacturing process is able to produce HIP-modified allogeneic CAR T cells reproducibly at scale with high gene editing efficiency and yield. We intend to develop this platform broadly to treat patients with lymphoma, leukemia, and multiple myeloma with a goal of three INDs over the next several years, including one this year for SC291 targeting CD19 positive cancers and one next year for SC263 for patients who have failed a CD19-directed CAR T therapy."

Transplanting cells or tissues from a donor to a different recipient currently requires intense immunosuppression to prevent rejection of the transplant. The goal of Sana’s hypoimmune (HIP) platform is to eliminate the need for immunosuppression by cloaking cells from immune recognition while at the same time generating the manufacturing scale and reproducibility of allogeneic cells. The challenge for the field to date in generating immune cloaked cells has been turning off both the adaptive and innate immune system concurrently. Sana’s platform includes disruption of major histocompatibility (MHC) class I and MHC class II expression to hide cells from the adaptive immune system, which includes antibody and T cell responses, as well as overexpression of CD47 to inhibit activation of the innate immune cell system, in particular macrophages and natural killer (NK) cells. The company has presented data across multiple preclinical models highlighting the potential of this platform to cloak cells from immune recognition. Sana’s goal is to use these HIP-modified cells to replace damaged or missing cells in the body in a number of different diseases, including, among others, cancer and type 1 diabetes.

On Sunday, December 11, Sonja Schrepfer, M.D., Ph.D., Sana’s Senior Vice President and Head of Hypoimmune Platform, gave an oral presentation (Abstract 485) titled "Engineered Hypoimmune CAR T Cells Provide Lasting Tumor Control in Fully Immunocompetent Allogeneic Humanized Mice." This presentation demonstrated that CD47 is an important mechanism to avoid innate immune rejection. CD47 overexpression comprehensively inhibits macrophage and NK cell killing after the disruption of MHC class I and MHC class II expression, making it a more complete approach against innate immune cell killing compared to other strategies. A single dose of HIP-modified CD19-targeted CAR T cells was able to eliminate CD19+ tumors in immune competent animals, including after tumor rechallenge, indicating that these cells may be able to persist and maintain anti-tumor efficacy without immunosuppression.

On Sunday, December 11, Christina Chaivorapol, Ph.D., Sana’s Vice President, Translational Technologies, gave an oral presentation (Abstract 663) titled "Efficient and Specific Multi-Locus Editing of Allogeneic CAR T Cells for Hypoimmunity during Large Scale Manufacture Using Cas12b." The presentation outlined the use of a novel of CRISPR enzyme, Cas12b, to engineer allogeneic hypoimmune CAR T cells at large scale in order to prevent recognition and clearance by the host immune system while maintaining anti-tumor efficacy. Cas12b has been highlighted in prior studies as exhibiting a high level of on-target editing specificity. Assessment of genome integrity of T cells manufactured using Cas12b demonstrated highly specific editing with no significant off-target editing and no evidence for editing-associated structural modifications beyond those expected from on-target cleavage. These data indicate that this scaled manufacturing process can produce fully engineered HIP-modified CD19-targeted allogeneic CAR T cells with high editing efficiency and specificity.

On Saturday, December 10, Sana scientist Darin Salloum, Ph.D., presented a poster (Abstract 1974) titled "Functional T Cell Assays Are Predictive of Pre-Clinical Potency to Generate Allogeneic, Hypoimmune CD19 CAR T Cells." The presentation highlighted the use of several in vitro and in vivo assays to categorize T cells derived from healthy, allogeneic donors into excellent-, good-, or poor-performing T cells. These "stress test" assays may be used to identify T cell quality differences which may be used to select donors and reduce batch variability for allogeneic, HIP-modified CAR T manufacturing. Sana’s manufacturing process appears to create, in a replicable fashion, high quality T cells at a scale with the potential for hundreds of doses per batch.

On Saturday, December 10, Sana scientist Adam Johnson, Ph.D., presented a poster (Abstract 1988) titled "A Dual-Antigen Targeting, Hypoimmune Allogeneic CAR T to Evade Innate and Adaptive Immune Rejection and Overcome Antigen Escape." The presentation showed that a dual-transduction method using lentivirus encoding CD47-CD19CAR and CD47-CD22CAR could reproducibly generate dual-targeted hypoimmune CAR T cells, maintain CD47 overexpression for HIP function, and eliminate both CD19 and CD22 knockout tumor cell lines. Sana is developing SC263, a HIP-modified, CD22-directed CAR T with a clinically-validated CAR with the potential to treat patients with B cell malignancies who have not responded, relapsed, or are refractory to previous CD19-targeted CAR T therapies. The company expects to file an IND in 2023.

On Sunday, December 11, Sana scientist Jeremy Kinder, Ph.D., presented a poster (Abstract 3168) titled "BCMA-Targeted, Hypoimmune Allogeneic CAR T Cells Exhibit Potent Anti-Tumor Activity Together with the Ability to Evade Innate and Adaptive Immune Rejection in Pre-Clinical Tumor Models." The presentation showed that, in pre-clinical tumor models, HIP-modified BCMA-directed CAR T cells with the clinically-validated CT103A CAR construct licensed by Sana in January 2022 controlled myeloma tumor cells equivalently to HIP-modified CAR T cells with approved BCMA CAR constructs. In addition, HIP-modified BCMA CAR T cells showed equal in vitro efficacy and cytokine production against BCMA+ target cells compared to non-HIP BCMA CAR T cells. These data support advancing an allogeneic, HIP-modified BCMA-directed CAR T product to treat myeloma. Sana expects to file an IND for product candidate SC255 as early as 2024 to treat multiple myeloma.

On Sunday, December 11, Sana scientist Jesse Green, Ph.D., presented a poster (Abstract 3457) titled "CD8-Targeted, Integrating Viral Vectors Transduce Resting T Cells and Enable Extracorporeal Delivery (ECD) for Rapid CAR T Cell Therapies." The presentation highlighted that CD8-targeted CD19 CAR fusosomes are able to specifically transduce primary, non-activated CD8+ T cells to generate highly functional CAR T cells capable of eliminating CD19+ tumor cells in animal models. This result was accomplished by both a short-term ex vivo incubation with T cells followed by infusion, termed extracorporeal delivery (ECD), or by direct IV injection of fusosomes into animals engrafted with peripheral blood mononuclear cells. Data generated demonstrate ECD and direct IV are potential dosing options for patients with this fusosome for the in vivo production of CAR T cells. The company expects to study SG295, an in vivo CAR T with CD8-targeted fusosome delivery of a CD19-targeted CAR, in patients with B cell malignancies. With increased potency from a second-generation manufacturing process, SG295 has the potential to generate a comparable number of CAR T cells to current ex vivo manufacturing processes. The company remains on track to file an IND in 2023.