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Cell therapy has broken new therapeutic ground, but the progress of this drug class in blood cancers has yet to be realized in solid tumors. Big pharmaceutical companies and upstart biotechs are trying various approaches to broaden the scope of these cancer treatments and AstraZeneca is now joining them by buying a startup with technology for developing a new type of personalized cell therapy. AstraZeneca said Tuesday it has agreed to pay $200 million up front to acquire Neogene Therapeutics, a company that earlier this year received the regulatory green light to begin the first human test of its cell therapy. Another $120 million is tied to the achievement of milestones. The companies expect to close the deal in the first quarter of 2023. The first cell therapies were made by harvesting a patient’s own T cells and engineering them in a lab to address a target on cancer cells. The cell therapies of Neogene are also highly personalized. The biotech takes a patient’s T cells and engineers them to target neoantigens, novel targets found exclusively on cancer cells due to cancer-associated DNA mutations. Whereas the first generation of cell therapies go after targets on the tumor surface, Neogene, which maintains operations in Amsterdam and Santa Monica, California, claims its T cell receptor-therapies (TCR-Ts) can recognize targets inside a tumor. By addressing previously inaccessible targets, Neogene says its cell therapies can address solid tumors. A Neogene TCR-T starts with a biopsy of a patient’s tumor. DNA sequencing along with other genomics tools are used to identify the neoantigens of a tumor as well as the genes that code for their receptors. Those genes are introduced into a patient’s T cells, enabling them to recognize a patient’s tumors. But rather than addressing a single target, a Neogene TCR-T will span multiple tumor neoantigens to spark a broader T cell response against the cancer. In a prepared statement, Susan Galbraith, AstraZeneca’s executive vice president of oncology R&D, said the Neogene’s capability to discover TCRs complements the cell therapy capability it has built over the last three years. Neogene’s founders have deep cell therapy experience. The company was founded in 2018 by Ton Schumacher and Carsten Linneman. The duo had previously founded T-Cell Factory, a company that developed technology that discovers tumor-specific T cell receptors. Kite Pharma acquired T-Cell Factory in 2015. Kite’s Yescarta became the second CAR T cell therapy to win FDA approval in 2017, the same year that Gilead Sciences struck an $11.9 billion deal to acquire Kite. Neogene has Kite connections. The startup’s investors include Kite founder and former CEO Arie Belldegrun; David Chang, another former Kite executive, is also a Neogene investor. Neogene disclosed more details about pedigree and its technology in 2020, when it unveiled a $110 million Series A round of financing. At that time, Linneman told me he estimated clinical testing was two years away. AstraZeneca’s deal to acquire Neogene comes as the biotech moves its research into clinical testing with its lead program, NT-125. This cell therapy is designed to carry up to five neoantigen-specific TCRs, reducing the opportunity for a tumor to develop mutations that enable it to escape the treatment. Dutch authorities cleared Neogene’s application to begin a Phase 1 test in May. That study, which will be done in partnership with the Netherlands Cancer Institute, is designed to enroll adults with various types of solid tumors. The broader field of TCR therapies is making progress and growing. Adaptimmune’s work in TCRs has led to alliances with GSK, Astellas, and Roche. In August, startup 3T Biosciences emerged with $40 million and technology licensed from Stanford that screens for TCRs that are specific to cancer cells. South San Francisco-based 3T aims to reach the clinic by 2024.

AstraZeneca will take control of Neogene’s TCR-T pipeline and operations in Amsterdam and California. AstraZeneca is stepping up its pitch for a slice of the cell therapy space, paying $200 million upfront for a solid tumor player that recently hustled an autologous, fully individualized, multispecific prospect into the clinic. The biotech, Neogene Therapeutics, is part of a clutch of companies that see T-cell receptor therapies (TCR-Ts) as the key to expanding the modality into solid tumors. Using its neoantigen TCR discovery and T-cell engineering platform, Neogene aims to find neoantigens, plus TCRs that target them, for each patient and then create T cells with the neoantigen-specific TCRs. Neogene’s lead candidate, NT-125, is designed to contain up to five distinct neoantigen-specific TCRs per patient in a single cell product. The approach could, in theory, cut the risk of antigen escape and trigger deep, durable clinical responses.   The biotech is also working on TCR-Ts targeting shared neoantigens, including mutated KRAS and mutated TP53. The company licensed a portfolio of TCRs targeting KRAS and TP53 mutations from the National Cancer Institute at the start of the year. Some of these candidates are "close to the clinic," AstraZeneca's executive vice president of oncology R&D Susan Galbraith, Ph.D., told Fierce Biotech in an interview. But rather than the specific assets, AstraZeneca is most enthused by Neogene's platform and how it fits into the Big Pharma's recent attempts to move into the CAR-T space. "What Neogene bring is this T-cell receptor screening capability which they've developed," Galbraith said. "We put that together with what we're able to build and, of course, the global scale that we can bring—I think that produces a complementary capability overall, which we're excited about." The company is backing up its warm words with cold cash. In return for $200 million upfront, plus up to $120 million in future paydays, the Big Pharma will take control of Neogene’s TCR-T pipeline and operations in Amsterdam and California. The biotech will operate as a subsidiary of AstraZeneca.  The deal comes early in the validation of the technology. Neogene only disclosed the authorization to take its lead program into phase 1 in May, suggesting some limited clinical data may be available, but key questions about the pipeline and platform remain unanswered.  Targeting solid tumors is a key goal of many players in the cell therapy space, and Galbraith said Neogene's platform offers another avenue to reach this destination in addition to CAR-Ts. "If you're going to bring cell therapy effectively to a large number of patients with solid tumors, then you really need this TCR-based capability to complement the cell surface-targeted therapies," she said. Having built a growing commercial oncology portfolio around products such as Enhertu, Lynparza and Tagrisso, AstraZeneca has decided the early-phase bet on a novel technology has a favorable risk-reward profile. The calculation is potentially informed by the credentials of the people behind Neogene, which was founded by Carsten Linnemann, Ph.D., and Ton Schumacher, Ph.D. The pair previously teamed up to establish T-Cell Factory, a startup Kite Pharma acquired in 2015. And, when they came to set up Neogene, they leveraged their connections to Kite and brought Arie Belldegrun, M.D., on board. Belldegrun’s Vida Ventures was among the VC shops that powered Neogene to its $110 million series A round in 2020.  "With the history of many of the team at Neogene coming from the Kite background, they've also got manufacturing capability, which we're excited about because then we think that can accelerate our own programs as well," Galbraith said. "It's about the quality of their science and the quality of their team."

Scientists at St. Jude Children's Research Hospital have developed a method that may be able to improve CAR T-cell therapies by identifying the early cells that become effective at killing cancer. MEMPHIS, Tenn., July 6, 2022 /PRNewswire/ -- St. Jude Children's Research Hospital scientists have demonstrated that the long-term performance of cancer-killing chimeric antigen receptor (CAR) T cells can, in some cases, be predicted before treatment. The research provides a unique cell sequencing-based framework to measure and improve CAR T–cell immunotherapy performance. The report appears online early today in Cancer Discovery, a journal of the American Association for Cancer Research. From left, Stephen Gottschalk, M.D. of the Department of Bone Marrow Transplantation and Cell Therapy, Jeremy Chase Crawford, Ph.D., Taylor Wilson and Paul Thomas, Ph.D., of the Department of Immunology at St. Jude Children's Research Hospital are coauthors on a new article that appeared in the journal Cancer Discovery. The article discusses a new cell sequencing-based framework to measure and improve CAR T–cell immunotherapy performance St. Jude scientists develop a method to identify early cells that effectively kill cancer in CAR T-cell therapy Tweet this CAR T cells work by harnessing a patient's immune system to identify and kill cancer cells. The immunotherapy has proven effective for treating children and adults with leukemia and lymphoma, but the therapy sometimes fails or falters over time. Using advanced technologies in the lab, St. Jude researchers identified a small subset of CAR T cells, among the total group of CAR T cells prepared for therapy, produced most of the enduring anti-cancer activity when infused into children with acute lymphoblastic leukemia (ALL). The methodological framework the scientists created serves as a template to improve other CAR T–cell therapies by providing a guide to navigate the complexities of these immunotherapies. "It was a surprising finding," said co-corresponding author Paul Thomas, Ph.D., St. Jude Department of Immunology. "It appears that a very small proportion, certainly the minority of CAR positive T cells in the pre-infusion product, are actually contributing to the anti-tumor response in the patient." Before the study, researchers assumed most CAR T cells created in a single preparation are similar, with cancer clearance activity representing the average activity of those prepared cells. "We showed that, in this case, a small group of cells is the driving force of cancer clearance," said co-corresponding author Jeremy Chase Crawford, Ph.D., St. Jude Department of Immunology. "The ability to find the therapy-driving cells was important to demonstrate because in the future a refined version of this method could be used to identify and enrich for infused cells that are going to be helpful to a patient, as opposed to cells that aren't." A signature of potential success The scientists found a distinct gene expression "signature" in the pre-infusion CAR T cells that became effector T cells, the type of immune cell that killed cancer cells. The team found three genes within that signature that encoded proteins expressed on the T–cell surface. Cells that carried a particular combination of the surface proteins became effector T cells; the other CAR T cells became dysfunctional. The technology to sort cells by surface markers exists and could be used to enrich CAR T–cell preparations to include only cells fated to become effective cancer killers. The researchers clarified that the cell surface markers identified in this study may be unique to this combination of CAR T cell, ALL and patient population. But the method the researchers pioneered serves as a proof-of-principle of how other CAR T–cell therapies could be improved. To find the signature, researchers collected CAR T cells in the laboratory before they were given to patients (pre-infusion). The investigators later collected blood samples from the patients, weeks and months into the study. They were able to track the fate of the infused CAR T cells using single-cell RNA sequencing. "Right now," Thomas said, "almost everything for CAR products is assessed at a bulk level. We showed that you need to look at the single-cell level to define the phenotypes of those cells that are going to be the critical effectors in the patient." A barcode to identify CAR T-cell descendants The researchers' novel approach combines a T-cell "barcode" with single-cell gene expression sequencing in pediatric cancer patients. This allows them to follow T–cell lineages. Each original T–cell lineage taken from the patient has a unique protein, called the T–cell receptor (TCR). In a patient, an activated CAR T cell will divide and proliferate after encountering cancer cells. So, every T cell from a patient with an identical TCR is descended from the same original T–cell lineage, which was modified in the laboratory prior to infusion. Thus, the TCR can act as a barcode for a specific lineage of CAR T cells. The scientists sequenced the TCRs in the pre-infusion cells and in patient samples after therapy. Using machine learning, the researchers compared genetic transcripts from single cell sequencing to see if cells became effectors. From this tracing, the investigators found that a small proportion of pre-infusion cells, specifically those with the pre-effector signature, become effectors and proliferate in the patient. The first of its kind study was made possible due to a cross-departmental collaborative effort at St. Jude aimed at integrating clinical trials and basic immunological research, called the Center for Translational Immunology and Immunotherapy (CeTI2). Scientist obtained samples from a clinical trial called SJCAR19, the first investigator-initiated CAR T–cell therapy study at St. Jude, led by study co-author Aimee Talleur, MD, St. Jude Department of Bone Marrow Transplantation and Cellular Therapy. "The study illustrates a huge team effort and brought together investigators from basic science and the clinic," said co-corresponding author Stephen Gottschalk, M.D., St. Jude Department of Bone Marrow Transplantation and Cellular Therapy chair, "It highlights the virtue of team science and the promise of single-cell technologies combined with big data analytics to develop effective cellular immunotherapies for cancer." Authors and funding The study's co-first authors are Taylor Wilson of St. Jude, and Hyunjin Kim, formerly of St. Jude. The other authors are Ching-Heng Chou, formerly of St. Jude, Deanna Langfitt, Robert Mettelman, Anastasia Minervina, E. Kaitlynn Allen, Jean-Yves Métais, Mikhail Pogorelyy, Janice Riberdy, M. Paulina Velasquez, Pratibha Kottapalli, Sanchit Trivedi, Scott Olsen, Timothy Lockey, Catherine Willis, Michael Meagher and Brandon Triplett, all of St. Jude. The study was supported by grants from by the National Cancer Institute (P30CA021765); the National Institutes of Health (U01AI150747 and R01AI136514); the American Society of Transplantation and Cellular Therapy; the American Society of Hematology; the Key for a Cure Foundation; the Mark Foundation ASPIRE Award; NRSA-NIAID (F32AI157296) and ALSAC, the fundraising and awareness organization of St. Jude. St. Jude Children's Research Hospital St. Jude Children's Research Hospital is leading the way the world understands, treats and cures childhood cancer and other life-threatening diseases. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 60 years ago. St. Jude freely shares the breakthroughs it makes, and every child saved at St. Jude means doctors and scientists worldwide can use that knowledge to save thousands more children. To learn more, visit stjude.org or follow St. Jude on social media at @stjuderesearch. SOURCE St. Jude Children's Research Hospital