1981 Apr;21(4):195-7. doi: 10.1002/j.1552-4604.1981.tb05699.x. These jobs have a median annual salary of $128,090. We found that pharmacologic archetype, combined with variability in CAR-T cell dose and initial tumor burden, fully accounts for the inter-patient variability in exposure observed in clinical trials of Kymriah. Sometimes therapeutic equivalence is possible despite differences in bioavailability. Clin. Rev. What Is a Doctor of Medical Science Degree? The best clinical pharmacology drug development services are built for flexibility. Correspondence. Andreatta, M. et al. Nat. 4, 4457 (2009). 2016 Dec;38(6):1445-1456. doi: 10.1007/s11096-016-0385-3. During developmental age, differences in pharmacodynamic reactions to several drugs may reflect polymorphisms of genes encoding drug-transporting proteins, receptors, drug targets, and gene products, whose disturbed activity sometimes plays an important role in certain diseases. BREYANZI (FDA, 2020); https://www.fda.gov/media/146424/download. 4). 2e,f), indicating that the CR cell products may show heightened sensitivity to the correspondent cytokines. a,cf, ssGSEA reveals differences in cell populations and signaling pathways between populations for selected cell signatures and signaling pathways (panel titles). T effectors can expand through N population doublings but lack the capacity for self-renewal. Med. These parameters correspond to cytotoxic potency, tumor cell lysis rate, memory cell proliferation and death rates, respectively. J. Pharmacol. We observed many differences between the treatment and comparison groups before matching. . ISSN 1546-1696 (online) Shah, N. N. & Fry, T. J. Mechanisms of resistance to CAR T cell therapy. 4b). Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article. They are responsible for managing Toxbase, an evidence-based toxicology database. Therapeutics noun. Creating a positive study experience attracts repeat participation and generates referrals. 10, 362376 (2021). In particular, the CAR-T dysfunction signature is consistently heightened. Google Scholar. Conceptually, the idea of an antigen sensing, saturable function regulating T cell proliferation was first described by de Boer et al.48, extended to differentiation control between memory and effector T cell fates49 and applied to CAR-T pharmacokinetics by Martinez-Rubio et al.50. PubMed CAR-T products resulting in non-durable response show deficits in proliferative and functional capacity characteristic of T cell exhaustion and terminal differentiation, even within immunophenotypically indistinguishable memory and effector cell populations. Clinical pharmacokinetics is the application of pharmacokinetic principles to the safe and effective therapeutic management of drugs in an individual patient. The same result was reported for overall survival in B-ALL38, indicating that this is a conserved feature across indications. To compute distributions of exposure (AUC and Cmax), we simulated pharmacokinetic profiles for 1,000 virtual patients. However, inability to predictively control this pharmacology limits their clinical utility. Mathematical modeling of tumorimmune cell interactions. This formulation has proven applicable to multiple other CAR-T therapies in a variety of indications6 and has been adopted by the FDA for benchmarking7,8. 2a), consistent with simulations, wherein the fraction of non-exhausted cells at day 60 (peak of anti-tumor effects) is significantly higher in the CR group (Fig. Transl. de Claro, R. A., George, B. PubMed Central Pharmacy students typically pursue jobs in drugstores, hospitals, clinics, and other traditional pharmacy settings. CPT Pharmacometrics Syst. Comparing cell populations from the CR versus NR/PR/RL categories reveals a consistent pattern across datasets. This control population did not reproduce the same findings, emphasizing the need for appropriate training data to make accurate predictions. Sci. Qualied clinical pharmacologists often work as researchers. Correspondence to Biol. The equivalent logistic curves from Yescarta were digitized and overlaid by normalizing the x axes. Tips for Taking Online Classes: 8 Strategies for Success. In addition to completing a doctorate in pharmacy (PharmD), students must also complete 1,500 training hours and pass the North American Pharmacist Licensure Exam. Starting with the 28 pathways that were differentially expressed between the CR versus NR groups (false discovery rate (FDR)-adjusted P<0.05; Supplementary Information), we trained a logistic regression-based classifier using a genetic algorithm for feature selection (Methods). Both have been shown to mediate CAR-T expansion and tumor response, as cytokine-mediated interactions among CAR-Ts, host T cells and tumors14 likely mediate cell-intrinsic differences. Int. 60, S147S159 (2020). Pharmacy is the science or practice of the preparation, formulation, and dispensing of medicinal drugs. b, CAR-T AUC distributions. The resulting accuracies were either slightly better or indistinguishable from chance (the null model), and all were significantly less accurate than predictions arising from the 28-gene signature panel. Clinical pharmacology provides the link between preclinical data and new treatments for patients. Differential expression analysis was implemented with Seurat using a Wilcoxon rank-sum test, followed by GSEA. The group of box plots labeled Model shows the AUC distribution obtained for the 12 best-fitting parameter sets for each population (CR, blue; PR, gray; NR, pink) with the colored background the range of AUCs obtained from the clinical pharmacokinetics data. We made this division for mathematical simplicity: the non-tumor killing subgroup differentiates from the memory cells and forms the initial pool of effector cells that further differentiates (with rate parameter E) to cytotoxic effector cells (TE2). Our team of scientists and clinicians put principles into action by closely monitoring testing, including preliminary evaluation of drug safety, tolerance and . Epub 2016 Nov 5. Their core goal is to improve patient care through the safe and effective use of medicines. That is, at an insufficient Cmax:tumor burden ratio, due either to low dose or expansion capacity, the infused CAR-T population will exhaust before clearing tumor. Curr. Notably, IL2 and IL7 are common components of CAR-T expansion media29, and peak serum IL7 concentration is predictive of CD19 CAR-T exposure and progression-free survival30. Although the pharmacokinetics are moderately under-predicted, the tumor dynamics are predicted with reasonable accuracy. After elimination of the pathogen, effector cells undergo a precipitous contraction phase, and a small percentage survive to form long-term memory T cells capable of self-renewal and recall responses. Although they both require similar education and can expect comparable salaries, the demands of their role and the working environment are quite different. Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. Our Madison clinical research unit is the global leader in the conductof radiolabeled clinical studies. Trimmed mean of M-values (TMM) normalization was implemented with edgeR (3.34.1), and normalized data were converted to log(counts per million) by applying Voom transformation. Kirouac, D.C., Zmurchok, C., Deyati, A. et al. Science 367, eaay3224 (2020). The parameter fmax describes the fraction of memory cells that self-renew versus differentiate to become effector cells. Why partner with the British Pharmacological Society? Rev. Pharmacologist vs. pharmacist: similarities and differences. 20, 6223 (2019). Gesztelyi, R. et al. 14). ce, Model analysis: we compared the fraction of the total T cell population across doses in the memory, effector and exhausted groups by plotting the mean across parameter sets. Biol. Memory cells are regenerated (with rate parameter rM) from the TE2 population. 17), and simulations recapitulate the relationship between Cmax/Bo and tumor response identified in Fig. Pharmacists have a deep understanding of medications and their effects on the human body, disease management, and immunology. ISSN 1087-0156 (print). Clinical pharmacology is the link between the preclinical data and the targeted population. 22, 6371 (2021). j, GSEA for select pathways, comparing both exhausted versus non-exhausted and CR versus PR/RL/NR categories within cells annotated as T effector memory (Tem via ProjecTILs) or early memory (Tmem; CD8+CD45ROCD27+ via CITE-seq). 5f for Kyrmiah and Yescarta (Supplementary Fig. Current perceptions of the term Clinical Pharmacy and its relationship to Pharmaceutical Care: a survey of members of the European Society of Clinical Pharmacy. Pharmacol. Invest. Median accuracy of the transcriptome classifier was 80%, less (as expected) than before but better than that achieved by T cell immunophenotyping (47%, P<1015; Fig. For our purposes, we define product-intrinsic to mean that clinical response is predictable by properties of the infusion product. PubMed 1. ORIGINAL ARTICLE. That is, in responding patients, CAR-T effectors lyse target tumor cells much more efficiently, and both memory and effector cells cycle at a higher rate. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Article Clinical pharmacologists will continue to dominate clinical research, but clinical pharmacists will continue to expand their contributions in all types of research. This toggle switch coordinately regulates rates of T memory cell self-renewal versus differentiation, proliferation and exhaustion of T effectors and regeneration of T memory cells from T effectors. This multidisciplinary, research-heavy field combines medicinal chemistry, drug delivery, and biomedical research. We found that CRs are differentially enriched in both CD8+ and CD4+ memory T cell signatures (Fig. Singh, A. P. et al. Article PubMed Northeastern offers both a masters degree and PhD in pharmacology. Sign up for the Nature Briefing newsletter what matters in science, free to your inbox daily. If CAR-T response is product-intrinsic rather than host-intrinsic, we reasoned that the differences in pre-infusion product transcriptomes could be predictive of response. Notch Therapeutics, Vancouver, BC, Canada, Daniel C. Kirouac,Cole Zmurchok,Avisek Deyati,Jordan Sicherman,Chris Bond&Peter W. Zandstra, School of Biomedical Engineering and Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada, You can also search for this author in Note that the toggle switch, encoded as a Hill function in B cell antigen BA, has the same half-maximum parameter B50 across all T cell populations but different exponents (km, kr, km, ke and kx) to account for presumed differential doseresponse relationships. Thus, although variability in CAR-T dose and tumor burden is sufficient to explain the observed variance in exposure, the inclusion of additional host-intrinsic factors may extend the models utility. PubMed Central Chimeric antigen receptor T cell therapies: a review of cellular kineticpharmacodynamic modeling approaches. Google Scholar. Kagawa Y, Noguchi H, Namiki N, Hayashi H, Kosuge K. Yakugaku Zasshi. Multiple clinical studies have confirmed that robust cell expansion after CAR-T infusion is a prerequisite for clinical efficacy3,20,27,38,40,41. If material is not included in the articles Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. Perturbation-response genes reveal signaling footprints in cancer gene expression. government site. We have deep experience with special populations such as Type 1 and 2 diabetics, healthy elderly, high cholesterol, obese and postmenopausal women. Differential expression analysis on the CR versus NR populations revealed biological features (gene signatures) consistent with inferred functional differences (Supplementary Figs. 4, 560572 (2020). Securing one of these jobs, however, can be a challenge. It is an intimidating but inexpensive reference book detailing the pharmacology of drugs used in dogs and cats. 18). At each timestep (0.1days for 1year), 199 percentiles were computed, and AUC and Cmax were calculated from these percentiles. Professor Asbjrn Mohr Drewes, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Mlleparkvej, DK-9000 Aalborg, Denmark. . 66, 427438 (2012). The resultant pharmacology is different from that of small molecules or biologics, as there is little relationship between administered dose and exposure2. the differences between similar drugs Clayton's Basic Pharmacology for Nurses - Binder Ready - Michelle J. Willihnganz 2022-03-07 Learn safe, effective nursing care for patients receiving drug therapy! The images or other third party material in this article are included in the articles Creative Commons license, unless indicated otherwise in a credit line to the material. We describe this control of T cell fates via a system of non-linear ordinary differential equations: Here, the self-renewal and differentiation of memory cells occurs at rate M and is regulated through Hill equation switches that depend on the B cell antigen BA. Examining the coefficients of PC1 (Fig. . In AcoP10 (ISOP, 2019); https://drive.google.com/file/d/1Uz69ZXIVLp_9RPaBBhex7fLxRPk7og8e/view. Chimeric antigen receptor T cell (CAR-T) expansion and persistence vary widely among patients and predict both efficacy and toxicity. Whether you choose to study pharmacology or pharmacy, Northeastern offers a wide range of experience-based learning opportunities that can expand your education. Details of the career pathways, entry requirements and training, 2023 British Pharmacological Society, The Schild Plot, 16 Angel Gate, City Road, London EC1V 2PT, United Kingdom. Our team of scientists and clinicians put principles into action by closely monitoring testing, including preliminary evaluation of drug safety, tolerance and pharmacokinetics. Nature Biotechnology thanks Luciana Barros and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. In addition to completing a doctorate in pharmacy (PharmD), students must also complete 1,500 training hours and pass the, These jobs have a median annual salary of. Unauthorized use of these marks is strictly prohibited. However, T cells bring unique challenges to therapeutic development. 56). *NR=NR/RL or NR/PR. 5df). Single-sample gene set enrichment analysis (ssGSEA) was subsequently used to examine distribution of the pathway and cell signatures in individual samples. A review of published CAR-T mathematical models, model structural analyses and Supplementary Figs. Others work in sales and explain drug compositions and benefits to hospitals and insurers. 1d) suggest that cell-intrinsic differences in memory cell function (M and dM) rather than frequency (fTm) are more important determinants of response. Google Scholar. It is one critical element of the drug development process. 37, 139 (2015). To discern the importance of memory cell frequency versus function, we preformed two experiments. Our strategy for model-based integration of the disparate datasets was to (1) fit the pharmacokinetics/pharmacodynamics model independently to the Fraietta et al.18 CR, PR and NR profiles; (2) create virtual populations from this model and compare the predicted population pharmacokinetic variance against Kymriah data from Stein et al.5 and covariates of response against Yescarta data from Locke et al.20; and (3) fit the pharmacokinetics/pharmacodynamics model to Abecma doseresponse data from Raje et al.39 to understand mechanisms underlying the response covariates. Provided by the Springer Nature SharedIt content-sharing initiative, Nature Biotechnology (Nat Biotechnol) History of clinical pharmacy and clinical pharmacology. The cellular kinetics (pharmacokinetics) of circulating CAR-Ts are characterized by three distinct phases: initial expansion, followed by a rapid contraction and then slow, long-term decay3. Note, however, that bulk sequencing data cannot resolve cell population frequencies nor discern between transcriptionally similar versus co-varying cell types (Supplementary Fig. The mission of the Office of Clinical Pharmacology is two-fold: 1) play a pivotal role in advancing development of innovative new medicines by applying state-of-the-art scientific principles; and . What is the difference between clinical pharmacology and pharmacology? Although efforts are underway to improve CAR constructs and cell culture media, results are constrained by the autologous starting material. Pharmacology is a more distinct and particular department that focuses on the impact and purposes of different types of drugs. 50, D687D692 (2021). 8600 Rockville Pike Tumor immune contexture is a determinant of anti-CD19 CAR T cell efficacy in large B cell lymphoma. Nat. Drug Intell Clin Pharm. performed the mathematical modellng and subsequent analysis. a, Shaded areas show the clinical variability of exposure to Kymriah5 with median model simulations overlaid for the CR, PR and NR populations. In-Demand Biotechnology Careers Shaping Our Future, The Benefits of Online Learning: 7 Advantages of Online Degrees, How to Write a Statement of Purpose for Graduate School, Online Learning Tips, Strategies & Advice, Northeasterns Online DMSc Program: What To Expect. Clinical pharmacology is the link between the preclinical data and the targeted population. Let us manage complexity with you. P values were calculated by KolmogorovSmirnov tests implemented in GSEA. For parameter estimation routines, we encode N population doublings in a single source term in the TE2 equation instead of using a hierarchy of ordinary differential equations (ODEs), each tracking the number of cells that have undergone n divisions. The remaining 10 percent enter alternative career paths within the pharmacy industry. The lowest dose (50 million cells) was incapable of tumor reduction and resulted in a predominance of exhausted T cells and gradual loss of memory cells. This was one of the primary conclusions of Fraietta et. Oncol. Mahlbacher, G. E., Reihmer, K. & Frieboes, H. B. Cell-intrinsic differences inferred by the model and highlighted in this scorecard may emanate from the variable quality of patient T cells at harvest42. MAbs 12, 1688616 (2019). Therapeutic nonequivalence (eg, more adverse effects, less efficacy) is usually discovered during long-term treatment when patients who are stabilized on one formulation are given a nonequivalent substitute. https://www.fda.gov/files/vaccines%2C%20blood%20%26%20biologics/published/Clinical-Review---KYMRIAH.pdf, https://maayanlab.cloud/Harmonizome/dataset/Biocarta+Pathways, https://www.fda.gov/files/vaccines%2C%20blood%20%26%20biologics/published/BLA-Clinical-Review-Memorandum--October-5--2017---YESCARTA.pdf, https://www.fda.gov/media/146424/download, https://drive.google.com/file/d/1Uz69ZXIVLp_9RPaBBhex7fLxRPk7og8e/view, http://creativecommons.org/licenses/by/4.0/. Google Scholar. The tumor dynamics out to 1year fall within the bounds predicted for the 150450 million cell doses. A positive normalized enrichment score (NES, blue) indicates higher enrichment in CR/non-exhausted cells. The group of box plots labeled +Dose shows the AUC distributions for each population when doses are randomized within reported ranges in the virtual population (n=1,000); +B0 shows the distributions when initial tumor burdens are randomized; and +Dose/B0 shows the distribution when both dose and initial tumor burdens are randomized. In order words why should you study this course you have registered for? Clinical pharmacology of tisagenlecleucel in B-cell acute lymphoblastic leukemia. That is, if any cell population had a fractional number (<1), that cell population was set to 0. Nucleic Acids Res. The site is secure. Hist. Protoc. Tools. We confirmed findings from the original report and additionally found that the CR population is enriched in CD4+ and CD8+ memory cell gene signatures (defined by single-cell sequencing of thymic tissue21) and display heightened expression of signatures characterizing T cell proliferation, effector cytokine (interferon) signaling and IL2RB, IL7 and JAK/STAT signaling (defined by curated pathway databases22,23,24). Tumor size data were reported as B cells per microliter and were, hence, used directly in model fitting (assuming an initial tumor burden of 1010 total cells). *** indicates P<1015, two-sided rank-sum test. Closely related T-memory stem cells correlate with in vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15. Examination of uniform manifold approximation and projection (UMAP) projections of the three datasets (Kymriah in ALL, Kymriah in LBCL and Yescarta in LBCL) reveals some separation of response categories in transcriptome space, particularly in ALL (Fig. Finally, some pharmacy professionals open specialty compounding facilities for non-standard drugs, many of which are formulated according to individual patients specific needs. Pharmacology and pharmacy may sound like similar terms, but in reality, theyre two very distinct areas of drug development and distribution. the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in 2007 Feb;127(2):285-90. doi: 10.1248/yakushi.127.285. Benchtobedside translation of chimeric antigen receptor (CAR) T cells using a multiscale systems pharmacokineticpharmacodynamic model: a case study with antiBCMA CART. Transl. A simple, easily implemented molecular signature for efficacious (CR-like) CAR-T products would be highly valuable for guiding optimization studies. These include: Formal training in clinical trial research is invaluable to the pharmaceutical industry. 7, 303ra139 (2015). a,b, Model training: we fit the toggle switch model to phase 1 doseresponse data and observed good fits, with Pearson correlation coefficients from the goodness-of-fit plots (Supplementary Fig. 6). Mol. performed the bioinformatics and machine learning analyses. A., Zheng, D., Graham, N. A., Wang, P. & Finley, S. D. Computational model of chimeric antigen receptors explains site-specific phosphorylation kinetics. Red, CR enriched; blue, NR/PR/RL enriched. J. Clin. CAS The majority of pharmacology students go on to become bench scientists at biotechnology and pharmaceutical companies. 8). It is a diverse discipline that both sustains and advances best healthcare. Opin. Gene signatures are annotated by source. 12). That is, CR products may have higher frequencies of CD4+ and CD8+ memory cells or may contain cells with more memory-like transcriptomes at similar frequencies. We next assessed the effect of variability in dose and tumor burden using a virtual population approach9. 2. Model simulations and analysis were performed using MATLAB R2021a and the SimBiology toolbox (6.1). Clinical pharmacologists enjoy a great deal of diversity throughout their careers. A cell atlas of human thymic development defines T cell repertoire formation. As a team, well work together to transform your preclinical safety data into robust protocols for Phase I safety and signals of target engagement and pharmacodynamics in healthy subjects and patients. That is, CAR-T cell composition as defined by memory and exhausted cell frequencies alone is insufficient to explain the variance in clinical activity. Albert, S. et al. c,d, Bivariate classifiers based on T effector memory and exhausted cell frequencies from ProjecTILs annotations of Haradhvala et al.32. A pharmacist is in the best position to explain a drug, Booth says. 43, e47 (2015). As a control, we first assessed differences between cells annotated as exhausted versus non-exhausted. Kaech, S. M. & Cui, W. Transcriptional control of effector and memory CD8+ T cell differentiation. For the genetic algorithm, we used a population size of 100 with a mutation rate of 0.001, an immigration rate of 0.3 and a reproduction rate of 0.1. The non-linear mixed effects model of Kymriah cellular kinetics, as reported in the BLA4 and described in a subsequent publication5, was used to simulate population pharmacokinetics in refractory B-ALL. To assess whether these predictions emanate directly from the model structure or necessitate model training, we created a control virtual population by random sampling of parameter space (n=1,000). Northeastern's pharmaceutical programs allow students to focus on more than one area in biomedical science to prepare them to work in an evolving and interdisciplinary field. Transient compartments are commonly employed in pharmacokinetics/pharmacodynamics modeling51 to connect drug concentration to measured pharmacodynamic response. Using bulk gene expression data, we found that enrichment of memory cell signatures, heightened proliferative and inflammatory signaling and lack of exhaustion markers in pre-infusion CAR-T products correlate with response, consistent with previous work and model-predicted functional differences. It is one critical element of the drug development process. Huang, D. W., Sherman, B. T. & Lempicki, R. A. Second, the definitions are blurred as many of the model parameters integrate some aspects of both. To condense the inner workings of the transcriptome classifier into interpretable patterns, we created a CAR-T response scorecard (Fig. In summary, response to two separate CD19 CAR-T therapy products (Kymriah and Yescarta) in three indications (CLL, ALL and LBCL) is at least partially predetermined by functional attributes of the CAR-T infusion product. That is, although the model was fit to population mean data assuming fixed tumor burden and dose, relaxing either of these input assumptions is sufficient to account for reported variance. Notably, the memory/exhaustion phenotypes identified as predictive of response in CLL did not translate to ALL, whereas the gene signature panel did. 13d,e). Clinical Pharmacy and Pharmacology; Complementary and Alternative Medicine; Consensus Statements; Coronavirus (COVID-19) Critical Care Medicine . However, the magnitude of differences between the populations cannot be fully explained by this hypothesis. Normalized ssGSEA scores were calculated as: wherein A is the matrix of ssGSEA signature scores (i) samples (j). Rohrs, J. Their core goal is to improve patient care through the safe and effective use of medicines. D.C.K. Daniel C. Kirouac. In both cases, the model described the data with good accuracy. To estimate a scaling factor between transgene counts and cell numbers, we used data from Kalos et al.45 wherein both counts per microgram and total circulating CD19+ cells were reported, estimated as ~104. This lesson will summarize the drug approval process, the pre-clinical phase, the clinical phase, the NDA . As more information on your molecule becomes available, well scrutinize development progress and deliver unique insights for decisions. Med. BioCarta pathways. It is also concerned with the effects of different drugs on the body and vice versa. , and pharmacology jobs in other areas tend to offer high salaries, as well. National Institute for Clinical Excellence (NICE), The Medicines and Healthcare products Regulatory Agency (MHRA), pharmacovigilance schemes such as Yellow Card Centres, keep a strong research emphasis in their work, play an important role in undergraduate teaching. and C.B. Kalos, M. et al. Owing to the stochastic nature of genetic algorithms, this was repeated 2,500 times, wherein each iteration produced a list of N pathways to be used as features for logistic regression. Impaired death receptor signaling in leukemia causes antigen-independent resistance by inducing CAR T-cell dysfunction. Upon viral antigen encounter, antigen-specific T cells clonally expand and differentiate into cytotoxic effectors, which clear infected cells. 1d), the lowest value (associated with NR) is TK50 (cytotoxic potency of effectors), and the largest positive contributions (associated with CR) is memory and effector cell turnover (proliferation and death rates; M, dM and dE2). As you perform an increasing number of clinical Phase I studies in patient populations, it helps to have an ally with deep hospital partnerships. To deconvolute the role of cell frequency versus function in mediating response, we leveraged two recently published clinical studies containing scRNA-seq data of pre-infusion, autologous CD19 CAR-T products matched with clinical outcomes.
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