The next frontier of cell therapy: CAR-T that can be "ready-made"
The next frontier of cell therapy: CAR-T that can be "ready-made" April 04, 2019 Source: Sina Pharmaceutical Just a year and a half ago, the US FDA approved two revolutionary CAR-T cell therapies: Novartis's Kymriah and Gilead's Yescarta. Both products are autologous, which means they are patient-specific. The preparation and treatment process is: separating T cells from the blood of the patient, storing and transporting them to the manufacturer, genetically modifying the T cells of the patient to express a chimeric antigen receptor (CAR), and modifying The latter T cells return to the patient, identify and attack the cancer cells of the patient, thereby achieving the purpose of treating cancer. Although this personalized treatment is revolutionizing cancer treatment and healthcare, it also has some obvious limitations. Limitations of current autologous CAR-T therapy Because autologous CAR-T is patient-specific, each treatment can only be used for one patient; if patient B receives treatment from patient A, then patient A's CAR-T cells attack all cells of patient B (and Not just cancer cells, they are identified as "foreign." This patient-specific treatment characteristic also means labor-intensive work and increased product production time (usually 3-4 weeks to produce), but also runs counter to the concept of cancer treatment. Although weeks don't sound as long as you think, it's longer than many non-personalized treatments, and most treatments are available to patients almost immediately. The labor-intensive work of personalizing T cells has also greatly pushed up the price of the product – in the US market, the price tag for Kymriah disposable treatment is $475,000 and Yescarta is $73,000. To address these issues, several research institutes and pharmaceutical companies are driving the next generation of CAR-T therapies – the development of the same or “off-the-shelf†therapies, which can be made by healthy donor cells. Mass production and use in multiple patients. Research progress on "ready-made" CAR-T therapy Researchers from the University of California, Los Angeles (UCLA) are able to convert pluripotent stem cells (almostable into any cell type) into T cells through artificial thymus organs. These organoids (a miniature simplified version of the three-dimensional organ derived from stem cells) mimic the thymus, an organ that converts hematopoietic stem cells into T cells in the human body. In a study published in the Cell Stem Cell in January 2019, the researchers demonstrated that the three-dimensional environment of artificial thymus organs can successfully mature T cells. Importantly, they created mature T cells from two pluripotent stem cells used for research: human embryonic stem cells (from donor pre-transplant human embryos) and induced pluripotent stem cells (IPSC, from healthy adult donors) Tissues such as skin or blood cells are reprogrammed). Gay Crooks, co-author of the study and head of the Cancer and Stem Cell Biology Program at the UCLA Jensen Comprehensive Cancer Center, said in a press release that "excitingly, we are able to create mature T cells from pluripotent stem cells. My hope for the future of this technology is that we can combine it with genetic editing tools to create 'ready-to-use' T cell therapies that are easier for patients to access." Researchers have shown that they can genetically engineer pluripotent stem cells to express a specific cancer-targeting T cell receptor, thereby creating T cells that can target and kill mouse tumors. Amelie Montel Hagen, the lead author of the study and a laboratory assistant project scientist at Crooks, said, "Once we have created a gene-edited pluripotent stem cell line that produces tumor-specific T cells in artificial thymus organs, then we can be infinite. Expand these stem cell lines." Although this technology is promising, there are still some issues that need to be addressed. T cells produced by artificial thymus organs still express surface molecules that do not meet each patient, causing patients to reject these T cells. Christopher Seet, another co-first author of the study and clinical instructor of the UCLA hematology department, said, "Our next step will be to create a T cell that has a receptor against cancer but does not cause cell rejection. The molecule, which will be an important step in the development of 'universal' T cell therapy." In July 2016, their artificial thymus organ technology was licensed to Gilead's Kite Pharma. In April 2017, they published their technology for the first time in Nature Methods, proving that artificial thymus organs allow mature human hematopoietic stem cells to mature into T cells. Currently, Kate has not released any further updates on their use of organ-like technology. Current status of “off-the-shelf†CAR-T therapy in biopharmaceuticals Currently, "off the shelf" therapy is also a hot topic in the field of biotechnology, and several companies are working on the next breakthrough therapy, including UCLA/Kate Pharma's artificial thymus organ technology. In addition, Cellectis is also investigating gene editing (using TALEN technology) and allogeneic CAR-T therapy (also known as universal CAR-T cell therapy, UCART). The company is developing a series of UCARTs. Currently, UCART123 targeting CD123+ leukemia cells in acute myeloid leukemia (AML) is being evaluated in two open-label Phase I studies: AML123 study assesses the efficacy and safety of 156 AML patients; ABC123 study To evaluate the efficacy and safety of 72 patients with parental plasmacytoid dendritic cell tumor (BPDCN). UCART22 is designed to develop treatment for CD22+ B cell acute lymphoblastic leukemia (B-ALL) and CD22+ B cell non-Hodgkin's lymphoma (NHL), which is currently being evaluated in an open-label, dose-increasing phase I study. The efficacy and safety of patients with relapsed or refractory CD22+B-ALL. UCARTCS1 is being developed to treat hematological malignancies that express CS1, such as multiple myeloma (MM). UCARTCLL1 is preclinically developed for the treatment of hematological malignancies that express CLL1, such as AML. In addition, Cellectis has partnered with another CAR-T-focused biotechnology company, Allogene Therapeutics, to develop allogeneic CAR-T therapy. The latter ALLO-501 targets CD19 and is currently being developed for the treatment of relapsed or refractory NHL. In January 2019, the US FDA approved a research-based new drug application (IND) for the drug, and Phase I clinical trials are expected to be launched in the next few months. Cellectis also licensed two therapies to Allogene: ALLO-715 targeting B cell maturation antigen (BCMA) for the treatment of relapsed or refractory MM; ALLO-819 targeting CD135 (also known as FLT3) For the treatment of relapsed or refractory AML. Allogene has teamed up with Cellectis and Pfizer to launch three open-label, one-arm Phase I studies to evaluate allogeneic CAR-T therapy UCART19 in patients with relapsed or refractory CD19+B-All: PALL study involving 18 children The CALM study was a dose escalation study involving 40 adult patients; another long-term safety and efficacy follow-up study involved 200 patients with advanced lymphoid malignancies. Allogene reported some exciting proof-of-concept results at the American Society of Hematology (ASH) meeting in December 2018. Of the 17 patients treated with UCART19, fludarabine/cyclophosphamide, and anti-CD52 monoclonal antibodies, 14 patients (82%) achieved complete remission and UCART19 cells were significantly expanded. In stark contrast, 4 patients who received only UCART19 and fludarabine/cyclophosphamide (no anti-CD52 antibody) did not respond, with minimal expansion of UCART19. This highlights the apparent importance of anti-CD52 antibodies for the efficacy of allogeneic CAR-T therapy. Safety data also appears to be promising: there are no grade 3 or 4 neurotoxic cases, only 2 grade 1 graft-versus-host disease (10%), and 3 grade 3 or 4 cytokine release syndromes. Control (14%), 5 cases of grade 3 or 4 viral infection (24%), and 6 cases of grade 4 long-term cytopenia (29%). Although this allogeneic CAR-T technology is still under development, its focus has been on its production efficiency and on the production efficiency of autologous CAR-T therapy. For example, Allogene noted that it is possible to treat 100 patients per batch of allogeneic CAR-T cell therapy. This has significant advantages over the two CAR-T cell therapies currently on the market. (Sina Pharmaceutical Compilation/newborn) Article, picture reference source: 1. 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