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Scientists used a new method to screen 10,000 combinations of gene edits in immune cells engineered to fight cancer SAN FRANCISCO, Sept. 14, 2023 /PRNewswire/ -- In recent years, scientists have used gene modification technologies to reprogram immune cells into therapeutics that can attack cancers. But such immunotherapies don't work for all patients or all cancer types, and screening through every possible combination of genetic changes that might improve these reprogrammed immune cells is a daunting and slow task. Continue Reading Researchers at Gladstone Institutes and UC San Francisco—including Theodore Roth (left) and Franziska Blaeschke (center)—used a new method to screen 10,000 combinations of gene edits in immune cells engineered to fight cancer. Photo: Michael Short/Gladstone Institutes Now, scientists at Gladstone Institutes and UC San Francisco (UCSF) have developed a technology that lets them rapidly "snap" together thousands of different combinations of genetic edits to test in immune cells. They used their screening technology, called Modular Pooled Knockin Screening (ModPoKI), to identify a new combination of genes that, when added to immune cells, makes the cells last longer and become more effective at fighting cancers. "This is a major step forward in our ability to ask questions about how we put pieces of genetic programs together into cells and test how they may be advantageous for patients," says Alex Marson, MD, PhD, director of the Gladstone-UCSF Institute of Genomic Immunology and senior author of the new study published in Cell. "I think this is going to accelerate the development of better cellular therapies." "This study demonstrates the power of using high-throughput genomics to discover and engineer novel molecular programs in cell therapies, and further, to understand the impact of these programs on the T cell state that is required for cancer killing," adds Ansuman Satpathy, MD, PhD, affiliate investigator at Gladstone, assistant professor in the Department of Pathology at the Stanford School of Medicine, and co-author of the study. Mixing and Matching Parts The immune system's T cells play a key role in fighting cancer. When a T cell recognizes a cancer cell as foreign, through a receptor on its surface, it targets the cancer cell for destruction. Scientists have discovered how to alter receptor proteins on T cells—often done by adding DNA sequences for an artificial chimeric antigen receptor (CAR)—so the T cells can more easily recognize and eliminate cancer cells. With CAR T-cell therapy, cancer patients' T cells are removed with a blood draw, reprogrammed genetically in the lab to introduce these new CAR receptors, and infused back into the patients' blood. Many CAR T-cell therapies, however, still have limitations: they often don't work against solid tumors, they can wear out over time, and some CARs don't elicit strong enough immune responses to kill cancer cells. "CAR T cells have been incredibly successful in the treatment of blood cancers like leukemia and lymphoma, but we're still searching for ways to optimize them and apply them to other cancers," says Franziska Blaeschke, MD, PhD, a postdoctoral fellow in Marson's lab and first author of the new paper. "Until now, what we've been lacking is a systematic way to discover what genetic changes in a T cell will be most effective at improving CAR T cells." To fill that gap, the team of scientists developed ModPoKI. The technology combines multiple genes into long stretches of DNA for use in a CRISPR gene editing platform. The group used this tool to create approximately 10,000 possible combinations of these DNA stretches by mixing hundreds of genes with DNA for a specific CAR. Then, they pasted the stitched-together DNA sequences into a defined location in the T cell genome using CRISPR. Each T cell took up a different DNA sequence, and the researchers then raced the cells against each other to see which ones performed best in various tests that could predict anti-tumor activity. An easy-to-read DNA barcode on each ModPoKI-generated set of genes let them track which gene combination led to improved T cells. The Lego-like ability to combine genes in new ways before adding them to the cells is what allowed them to rapidly discover combinations that might improve CAR T cells—without having to manually choose and engineer each combination. "Rather than having to make individual guesses about what might improve the function of cells and work through them one by one, we can click these pieces together and very rapidly test many of them in succession," says Theodore Roth, MD, PhD, a former member of Marson's lab now working with Satpathy's group, and co-senior author of the study. "It's a really useful piece of molecular biology." Toward Better Therapeutics The genes that Marson's team added to cells in the new study were surface receptors (both natural and engineered receptors designed to send boosting signals to CAR T cells) and transcription factors (which turn other genes on and off). When they analyzed test results from the hundreds of surface receptors and transcription factors, the researchers discovered that different CARs can be optimized by different factors. "It turns out it's not a one-transcription-factor-fits-all approach," says Blaeschke. "So, when researchers are developing new CAR T cells, it makes sense to check what other factors will be best to engineer at the same time. Our work produced a kind of atlas scientists can use to combine different transcription factors with different T cell receptors or CARs." They also pinpointed a combination of two transcription factors that often seemed to improve CAR T cells. These two transcription factors—known as BATF and TFAP4—boosted the fitness of a CAR T cell that had previously been developed to treat childhood brain tumors. "In the lab, the ModPoKI sequence with BATF and TFAP4 made CAR T cells show potential to improve anti-tumor activity," says Marson. "Next, we need to do more work to determine whether adding these transcription factors will make CAR T cells more effective in human cancer patients." About the Study The paper, "Modular Pooled Discovery of Synthetic Knockin Sequences to Program Durable Cell Therapies," was published in the journal Cell on September 14, 2023. Other authors are: Yan Yi Chen, Ryan Apathy, Bence Daniel, Andy Y. Chen, Peixin Amy Chen, Katalin Sandor, Wenxi Zhang, Zhongmei Li, Cody Mowery, Tori N. Yamamoto, William A. Nyberg, Angela To, Ruby Yu, Ralf Schmidt, and Daniel B. Goodman of Gladstone; Raymund Bueno, Min Cheol Kim, Justin Eyquem, Julia Carnevale, Eric Shifrut, and Chun Jimmie Ye of UCSF; and Tobias Feuchtinger of Ludwig Maximilian University of Munich. The work was supported by the National Institutes of Health (S10 RR028962, P30 DK063720, S10 1S10OD021822-01, F30DK120213), the National Cancer Institute (1R01CA276368-01, 5T32CA108462, 1K08CA252605-01), the Parker Institute for Cancer Immunotherapy, the Cancer League, the James B. Pendleton Charitable Trust, the UCSF Medical Scientist Training Program (T32GM007618), UCSF Endocrinology Training Grant (T32 DK007418), the Burroughs Wellcome Fund, the Lydia Preisler Shorenstein Donor Advised Fund, the Care-for-Rare Foundation, the German Research Foundation (SFB-TRR338/1 2021–452881907), an Emerging Investigators EHA-EBMT Joint Fellowship Award, Lloyd J. Old STAR Awards (Cancer Research Institute), a Pew-Stewart Scholars in Cancer Research Award, the Simons Foundation, Innovative Genomics Institute, the Chan Zuckerberg Biohub, the Byers family, Barbara Bakar, Karen Jordan, Elena Radutzky, the Austrian Exchange Service, the Austrian Society of Laboratory Medicine, and the Max Kade Foundation. About Gladstone Institutes Gladstone Institutes is an independent, nonprofit life science research organization that uses visionary science and technology to overcome disease. Established in 1979, it is located in the epicenter of biomedical and technological innovation, in the Mission Bay neighborhood of San Francisco. Gladstone has created a research model that disrupts how science is done, funds big ideas, and attracts the brightest minds. About UCSF The University of California, San Francisco (UCSF) is exclusively focused on the health sciences and is dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. UCSF Health, which serves as UCSF's primary academic medical center, includes top-ranked specialty hospitals and other clinical programs, and has affiliations throughout the Bay Area. Learn more at ucsf.edu, or see our Fact Sheet. Sources Gladstone Institutes: Julie Langelier | [email protected] | 415.734.2019 UCSF: Robin Marks | [email protected] | 628.399.0370 SOURCE Gladstone Institutes

Novel Technology Identified Genes that Promote T Cell Exhaustion, and which are Unique from PD-1/PD-L1 Checkpoint Pathway Engineered CAR-T Cells Lacking Exhaustion-Associated Genes Mediate Improved Tumor Killing and Sustained CAR-T Proliferation With Additive Benefit to PD-1/PD-L1 Inhibition Additional Presentation Reports Latest Preclinical Data for EV-104, First-in-Category Multifunctional T Cell Redirecting Antibody for Select Solid Tumors BRANFORD, Conn., April 18, 2023 (GLOBE NEWSWIRE) -- EvolveImmune Therapeutics, Inc. an immuno-oncology company developing first-in-category, multifunctional biotherapeutics to overcome cancer-driven immunodeficiency, today announced the presentation of the first data highlighting the company’s proprietary CRISPR-Cas9 T cell exhaustion screening platform. Additionally, the company presented the latest preclinical data for EV-104, the company’s first-in-category lead solid tumor program which was created using the company’s proprietary costimulatory T cell engager platform, known as EVOLVE. These presentations were delivered at the American Association for Cancer Research (AACR) Annual Meeting 2023, which is being held April 14-19, 2023, in Orlando, Florida. In a poster presentation, the company introduced a novel CRISPR-Cas9 T cell exhaustion screen that it designed to identify molecular targets that regulate T cell exhaustion following chronic T cell receptor and CD28 costimulatory receptor activation. EvolveImmune scientists utilized this screen to identify specific genes that promote T cell exhaustion, which are associated with different signaling and regulatory pathways than the PD-1/PD-L1 checkpoint pathway. The company then identified the optimal guide RNAs for CRISPR-Cas9 knock-out, engineered anti-CD19 and anti-mesothelin CAR-T cells that lacked the exhaustion-associated genes, and evaluated their effector function in tumor co-culture assays. Presented data highlighted that highly efficient knockout of the exhaustion-associated genes, such as BATF, CD70 and FAS, via CRISPR gene editing resulted in significantly improved tumor killing and sustained proliferation of both anti-CD19 and anti-mesothelin CAR-T cells. Combinations of gene knockouts showed better tumor killing than individual knockouts and this activity was additive to PD-1 and PD-L1 inhibition. Ongoing studies will evaluate the in vivo efficacy of anti-CD19 CAR-T cells engineered with exhaustion-associated gene knockouts in humanized mouse models of B cell lymphoma. “We are excited to unveil our T cell exhaustion screening platform for the first time. Our initial data suggest the potential of this technology to unlock the development of novel CAR-T therapeutics engineered to overcome the significant therapeutic challenge of T cell exhaustion. Importantly, we also demonstrated that these engineered T cells drove increased tumor killing and CAR-T cell proliferation when combined with checkpoint inhibition,” said Jeremy Myers, Ph.D., senior vice president, research and development at EvolveImmune. “This initial research produced important discoveries of differentiated cellular pathways that promote T cell exhaustion and illuminated opportunities for manipulating these pathways to facilitate novel cancer treatments. We are eager to complete our ongoing in vivo studies with our engineered T cells in humanized mouse models of B cell lymphoma and continue to advance this exciting area of research.” In a second poster presentation at AACR, EvolveImmune reported new data on EV-104, the company’s lead solid tumor program which targets an antigen present in a significant portion of bladder cancers and other solid tumors. EV-104 was derived from the EVOLVE platform, which is designed to unleash potent, selective, and integrated T cell costimulation to bypass low tumor immunogenicity, conditionally activate adaptive immunity, and reduce T cell dysfunction, to address unmet needs for the treatment of solid and hematologic tumors. This is achieved through finely tuned T cell receptor and CD2 costimulation optimized for CD8 T cells. New data demonstrated the potential of EV-104 to rejuvenate exhausted T cells to drive more potent tumor cell killing than matched CD3 bispecific antibody controls that lack costimulatory activity. Researchers observed a 100% complete response rate for EV-104 treated animals in a CORL105 lung cancer xenograft model expressing high levels of the EV-104 tumor antigen, whereas the matched CD3 control showed limited anti-tumor efficacy. Additionally, EV-104 was well tolerated at efficacious dose levels in non-human primate studies and demonstrated acceptable pharmacokinetics. “We continue to generate promising preclinical data which are pinpointing exciting opportunities for differentiation for multiple EVOLVE-based programs,” said Jay Fine, Ph.D., president of research and development at EvolveImmune. “Both EV-104 and our lead hematological tumor program, EV-105, are progressing well and we expect to nominate development candidates for these programs in the coming months.” Additional information on the AACR Annual Meeting 2023 is available through the conference website at: About EvolveImmune Therapeutics EvolveImmune Therapeutics, Inc. is an immunotherapy platform company developing first-in-category, multifunctional biotherapeutics designed to overcome cancer-driven immunodeficiency in a range of solid tumors and hematological cancers. The company is rapidly advancing two first-in-category programs, with first-in-human clinical trials anticipated in 18 months. The company is supported by a syndicate of top-tier life science industry investors including Pfizer Ventures, Solasta Ventures, Takeda Ventures, Yonjin Ventures and Elm Street Ventures. For more information, please visit: Contacts: EvolveImmune Therapeutics Stephen Bloch, M.D. Chief Executive Officer 860-856-7104 info@evolveimmune.com Vida Strategic Partners (on behalf of EvolveImmune Therapeutics) Tim Brons (Media) 415-675-7402 tbrons@vidasp.com

LONDON, UK I November 22, 2022 I GSK plc (LSE/NYSE: GSK) today announced it has initiated the process for withdrawal of the US marketing authorisation for Blenrep (belantamab mafodotin-blmf) following the request of the US Food and Drug Administration (FDA). This request was based on the previously announced outcome of the DREAMM-3 phase III confirmatory trial, which did not meet the requirements of the FDA Accelerated Approval regulations. Blenrep is a monotherapy treatment for adult patients with relapsed or refractory multiple myeloma (RRMM) who have received at least four prior therapies including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent. As part of the Company’s efforts to ensure physicians and patients are supported during this important time, patients already enrolled in the Blenrep Risk Evaluation and Mitigation Strategy (REMS) programme will have the option to enrol in a compassionate use programme to continue to access treatment. Further information on how to enrol patients into the compassionate use program will be provided directly to REMS enrolled prescribers. Patients currently being treated with Blenrep should consult their healthcare provider. GSK continues to believe, based on the totality of data available from the DREAMM (DRiving Excellence in Approaches to Multiple Myeloma) development programme, that the benefit-risk profile of belantamab mafodotin remains favourable in this hard-to-treat RRMM patient population. Patients responding to belantamab mafodotin experienced durable clinical benefit, and safety remains consistent with the known safety profile. Sabine Luik, Chief Medical Officer, said, “We respect the Agency’s approach to the accelerated approval regulations and associated process. Multiple myeloma is a challenging disease, with poor outcomes for patients whose disease has become resistant to standard-of-care treatments. We will continue the DREAMM clinical trial programme and work with the US FDA on a path forward for this important treatment option for patients with multiple myeloma.” Additional trials within the DREAMM clinical trial programme are designed to determine the benefit of belantamab mafodotin in combination treatment with novel therapies and standard-of-care treatments in earlier lines of therapy and dosing optimisation to maintain efficacy while reducing corneal events. Data from the DREAMM-7 and DREAMM-8 phase III trials are event-driven, and results are anticipated in the first half of 2023. Results of these trials will be shared with health authorities and inform future regulatory pathways. About DREAMM-3 The DREAMM-3 phase III trial is an open-label, randomised head-to-head superiority trial evaluating the efficacy and safety of single-agent belantamab mafodotin compared to pomalidomide in combination with low-dose dexamethasone (PomDex) in patients with RRMM. A total of 325 participants were randomised in a 2:1 ratio to receive either single-agent belantamab mafodotin administered as a 2.5 mg/kg dose every three weeks or PomDex. Pomalidomide was administered daily on days 1 to 21 of each 28-day cycle, with dexamethasone administered once weekly (days 1, 8, 15, and 22 of each cycle). The primary endpoint was PFS. Secondary endpoints include overall survival, safety, ORR, duration of response and assessment of minimal residual disease. About DREAMM-7 DREAMM-7 is evaluating the safety and efficacy of belantamab mafodotin in combination with bortezomib and dexamethasone versus daratumumab in combination with bortezomib and dexamethasone. About DREAMM-8 DREAMM-8 is assessing the efficacy and safety of belantamab mafodotin in combination with pomalidomide and dexamethasone compared with that of a combination of pomalidomide, bortezomib and dexamethasone in participants with relapsed/refractory multiple myeloma. About multiple myeloma Multiple myeloma is the second most common blood cancer in the US and is generally considered treatable but not curable. 1 , 2 In the US, more than 32,000 people are estimated to be diagnosed with multiple myeloma this year, and nearly 13,000 people will die from the disease. 3 Research into new therapies is needed as multiple myeloma commonly becomes refractory to available treatments. 4 About B-cell maturation antigen (BCMA) The normal function of BCMA is to promote plasma cell survival by transduction of signals from two known ligands, BAFF (B-cell activating factor) and APRIL (a proliferation-inducing ligand). This pathway is important for myeloma cell growth and survival. BCMA expression is limited to B cells at later stages of development. BCMA is expressed at varying levels in myeloma patients, and BCMA membrane expression is universally detected in myeloma cell lines. 5 About Blenrep Blenrep is an antibody-drug conjugate comprising a humanised BCMA monoclonal antibody conjugated to the cytotoxic agent auristatin F via a non-cleavable linker. The drug linker technology is licensed from Seagen Inc.; the monoclonal antibody is produced using POTELLIGENT Technology licensed from BioWa Inc., a member of the Kyowa Kirin Group. Refer to the BLENREP Prescribing Information for a full list of adverse events and the complete important safety information in the US. GSK in oncology GSK is focused on maximising patient survival through transformational medicines. GSK’s pipeline is focused on immuno-oncology, tumour cell targeting therapies and synthetic lethality. Our goal is to achieve a sustainable flow of new treatments based on a diversified portfolio of investigational medicines utilising modalities such as small molecules, antibodies, and antibody-drug conjugates, either alone or in combination. About GSK GSK is a global biopharma company with a purpose to unite science, technology, and talent to get ahead of disease together. Find out more at gsk.com/company References [1] CA: A Cancer Journal for Clinicians , Vol. 70, Issue 1, Jan/Feb 2020 Pages 7-30. [2] Kazandjian D. Multiple myeloma epidemiology and survival: A unique malignancy. Semin Oncol . 2016;43(6):676–681. doi:10.1053/j.seminoncol.2016.11.004. [3] SEER Cancer Facts & Figures 2019. Available at: https://seer.cancer.gov/statfacts/html/mulmy.html. Accessed October 2021. [4] Nooka AK, Kastritis E, Dimopoulos MA. Treatment options for relapsed and refractory multiple myeloma. Blood . 2015;125(20). [5] Lonial, S, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study. Lancet Oncol . 2020; 21(2):207–21. SOURCE: GlaxoSmithKline