体内免疫细胞工程

Executive Summary...........................................................................................................3Overview of In Vivo CAR Engineering...............................................................................7Learnings From the Last Two Years..................................................................................9Remaining Questions and Future Outlooks...................................................................10Financing Landscape and Partnerships..........................................................................15 In ourCELLect Horizonsseries, we examine cell and gene therapy platforms that we believe are onthe cusp of generating data that could transform the therapeutic landscape. Ina2023 editionofthis report, we detailed in situ engineering of CAR-T therapies, which were still an immature butpromising concept at the time. Following the advancement of several candidates into the clinic andfour high-profile acquisitions this year, in this edition ofCELLect Horizons,we revisit the in vivo Since our 2023 report, the number of companies developing in vivo CAR-T therapies has nearlytripled (exhibit 1, on the following page), with a quarter of companies now in early clinical devel-opment. We highlight that the majority of the growth in the field is attributable to new companiespursuing lipid nanoparticle (LNP)-based delivery, which has more than quadrupled in the pasttwo years. We believe the increase in LNP-delivered in vivo CAR-T therapies has been driven by Of the 12 companies that currently have an asset in clinical development, only one is initially pur-suing clinical development in the U.S., while 7 are initially evaluating their assets in investigator-initiated trials (IITs) in China, and 4 have started their clinical trials in Australia. We believe thispattern is indicative of the reduced bureaucratic barriers, increased regulatory flexibility, and Early clinical data from both lentiviral (LV) and LNP-based approaches have demonstrated thatCAR-T cells generated in vivo are capable of expanding without the use of lymphodepletion andfully depleting peripheral B cells, which has translated into clinical responses in oncology andautoimmune patients. However, the clinical safety profile of in situ CAR-T approaches has beenmixed, with some exhibiting benign safety profiles and others demonstrating high-grade CRSevents similar to ex vivo CAR-Ts (exhibit 2, on page 5). Given each approach bears its own meritsand drawbacks, we believe additional clinical data are needed to better determine which technol-ogy and/or cell targeting method will yield the optimal safety/efficacy profile. It also remains to beseen whether technologies that enable CAR transgene integration into the host genome (e.g., LV), In contrast to investor sentiment for public cell and gene therapy companies, which has largelydeclined over the last 24 months, private companies developing in vivo CAR therapies have raisedover $427 million year-to-date, up 76% year-over-year. In addition, four companies developing invivo CAR-Ts were acquired this year, with the deal values totaling $5 billion in aggregate. Although We expect additional clinical data from several companies in late 2025 and early 2026 could provideincreased insight into the risk/benefit profiles of various candidates and drive further business de-velopment activity. The successful development of in situ CAR-T has broad implications for oncology,immunology, and the genetic medicine fields. However, since the majority of in situ CAR-Ts in devel-opment target validated and approved antigen targets (e.g., CD19, BCMA, and CD20), their success-ful development could impact CAR-Ts that are commercially available or in late-stage developmentfor oncology indications, including: Gilead’s Yescarta and Tecartus, Bristol Myers’s Breyanzi andAbecma, Novartis’s Kymriah, Johnson & Johnson/Legend’s Carvykti, Autolus’s obe-cel, Allogene’scema-cel, and Arcellx’s anito-cel. Similarly, the advancement of these approaches could negatively af-fect companies that are developing CAR-Ts for autoimmune diseases, including: Cabaletta’s rese-cel,Kyverna’s KYV-101, Novartis’s YTB323, AstraZeneca’s GCO12F, Bristol Myers’s CC-97540, Autolus’sobe-cel, Allogene’s ALLO-329, CRISPR’s CTX112, and Nkarta’s NKX019. Advances in gene therapy have ushered in a reimagining of CAR-T engineering in which ex vivomanufacturing is not necessary and instead T-cell programming could occur in vivo through thetransient delivery of mRNA encoding the CAR or the permanent integration of the CAR transgene Source: William Blair Equity Research However, various approaches to in vivo CAR delivery are being investigated, and each possessesunique advantages and disadvantages from safety, efficacy, and manufacturing perspectives (ex-hibit 5). While we broadly refer to this evolving field as in vivo CAR-T, we highlight that compa-nies are taking different approaches with cell target