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Development timeline of axicabtagene ciloleucel and tisagenlecleucel The spaces between the lines are not to scale. EMA=European Medicines Agency. FDA=US Food and Drug Administration. NICE=National Institute for Health and Care Excellence. UPenn=University of Pennsylvania. NCI=National Cancer Institute. DLBCL=diffuse large B-cell lymphoma. PRIME scheme=Priority Medicines scheme. PMBCL=primary mediastinal B-cell lymphoma. FL=follicular lymphoma. ALL=acute lymphoblastic leukaemia. NHL=non-Hodgkin lymphoma. *Points on the same line represent the events arranged chronologically from top to bottom.

Development timeline of axicabtagene ciloleucel and tisagenlecleucel The spaces between the lines are not to scale. EMA=European Medicines Agency. FDA=US Food and Drug Administration. NICE=National Institute for Health and Care Excellence. UPenn=University of Pennsylvania. NCI=National Cancer Institute. DLBCL=diffuse large B-cell lymphoma. PRIME scheme=Priority Medicines scheme. PMBCL=primary mediastinal B-cell lymphoma. FL=follicular lymphoma. ALL=acute lymphoblastic leukaemia. NHL=non-Hodgkin lymphoma. *Points on the same line represent the events arranged chronologically from top to bottom.

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Chimeric antigen receptor (CAR) T cells represent a potent new approach to treat haematological malignancies. Two CAR T-cell therapies, tisagenlecleucel and axicabtagene ciloleucel, have been approved in Europe and the USA, as well as several other countries, for the treatment of leukaemia and lymphoma. These approvals marked a major milestone in t...

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... on axicabtagene ciloleucel pharmacology were generated by the phase 1-2 ZUMA­1 trial 20 and the supportive National Cancer Institute 09­C­00082 study 21 ( figure 1, table 2), whereas tisagenlecleucel relied on the pivotal phase 2 ELIANA trial 22 and supportive studies (Pedi CART19 23 [NCT01626495] and ENSIGN 22 [NCT02228096]) for the acute lymphoblastic leukaemia indication, and the JULIET study 24 for the DLBCL indication ( figure 1, table 2). In these trials, proliferation, distribution, and persistence of anti­CD19 CAR T cells were measured in peripheral blood and bone marrow by qPCR and flow cytometry. ...
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... on axicabtagene ciloleucel pharmacology were generated by the phase 1-2 ZUMA­1 trial 20 and the supportive National Cancer Institute 09­C­00082 study 21 ( figure 1, table 2), whereas tisagenlecleucel relied on the pivotal phase 2 ELIANA trial 22 and supportive studies (Pedi CART19 23 [NCT01626495] and ENSIGN 22 [NCT02228096]) for the acute lymphoblastic leukaemia indication, and the JULIET study 24 for the DLBCL indication ( figure 1, table 2). In these trials, proliferation, distribution, and persistence of anti­CD19 CAR T cells were measured in peripheral blood and bone marrow by qPCR and flow cytometry. ...
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... on axicabtagene ciloleucel pharmacology were generated by the phase 1-2 ZUMA­1 trial 20 and the supportive National Cancer Institute 09­C­00082 study 21 ( figure 1, table 2), whereas tisagenlecleucel relied on the pivotal phase 2 ELIANA trial 22 and supportive studies (Pedi CART19 23 [NCT01626495] and ENSIGN 22 [NCT02228096]) for the acute lymphoblastic leukaemia indication, and the JULIET study 24 for the DLBCL indication ( figure 1, table 2). In these trials, proliferation, distribution, and persistence of anti­CD19 CAR T cells were measured in peripheral blood and bone marrow by qPCR and flow cytometry. ...
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... on axicabtagene ciloleucel pharmacology were generated by the phase 1-2 ZUMA­1 trial 20 and the supportive National Cancer Institute 09­C­00082 study 21 ( figure 1, table 2), whereas tisagenlecleucel relied on the pivotal phase 2 ELIANA trial 22 and supportive studies (Pedi CART19 23 [NCT01626495] and ENSIGN 22 [NCT02228096]) for the acute lymphoblastic leukaemia indication, and the JULIET study 24 for the DLBCL indication ( figure 1, table 2). In these trials, proliferation, distribution, and persistence of anti­CD19 CAR T cells were measured in peripheral blood and bone marrow by qPCR and flow cytometry. ...
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... on axicabtagene ciloleucel pharmacology were generated by the phase 1-2 ZUMA­1 trial 20 and the supportive National Cancer Institute 09­C­00082 study 21 ( figure 1, table 2), whereas tisagenlecleucel relied on the pivotal phase 2 ELIANA trial 22 and supportive studies (Pedi CART19 23 [NCT01626495] and ENSIGN 22 [NCT02228096]) for the acute lymphoblastic leukaemia indication, and the JULIET study 24 for the DLBCL indication ( figure 1, table 2). In these trials, proliferation, distribution, and persistence of anti­CD19 CAR T cells were measured in peripheral blood and bone marrow by qPCR and flow cytometry. ...
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... on axicabtagene ciloleucel pharmacology were generated by the phase 1-2 ZUMA­1 trial 20 and the supportive National Cancer Institute 09­C­00082 study 21 ( figure 1, table 2), whereas tisagenlecleucel relied on the pivotal phase 2 ELIANA trial 22 and supportive studies (Pedi CART19 23 [NCT01626495] and ENSIGN 22 [NCT02228096]) for the acute lymphoblastic leukaemia indication, and the JULIET study 24 for the DLBCL indication ( figure 1, table 2). In these trials, proliferation, distribution, and persistence of anti­CD19 CAR T cells were measured in peripheral blood and bone marrow by qPCR and flow cytometry. ...

Citations

... Based on the pre-marketing assessment of their safety profile, in 2017, CAR-T cells were approved by the US Food and Drug Administration (FDA) with a Risk Evaluation and Mitigation Strategy, a program required for medications associated with serious safety concerns, as a risk minimization measure ensuring that benefits outweigh risks. In Europe, an accelerated assessment application through the Priority Medicines (PRIME) scheme for orphan diseases has been granted for CAR-T cells and additional monitoring and post-authorization safety studies have been required by the European Medicines Agency [12] after marketing authorization. Increasing post-marketing data have been recorded for CAR-T-cell safety profile monitoring in a real-world setting, where a significantly larger and heterogeneous population of patients has been treated [13][14][15][16]. ...
Article
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Introduction: As chimeric antigen receptor T-cell therapies are becoming increasingly available in the armamentarium of the hematologist, there is an emerging need to monitor post-marketing safety. Objective: We aimed to better characterize their safety profile by focusing on cytokine release syndrome and identifying emerging signals. Methods: We queried the US Food and Drug Administration Adverse Event Reporting System (October 2017-September 2020) to analyze suspected adverse drug reactions to tisagenlecleucel (tisa-cel) and axicabtagene ciloleucel (axi-cel). Disproportionality analyses (reporting odds ratio) were performed by comparing chimeric antigen receptor T-cell therapies with (a) all other drugs (reference group 1) and (b) other onco-hematological drugs with a similar indication, irrespective of age (reference group 2), or (c) restricted to adults (reference group 3). Notoriety was assessed through package inserts and risk management plans. Adverse drug reaction time to onset and cytokine release syndrome features were investigated. Results: Overall, 3225 reports (1793 axi-cel; 1433 tisa-cel) were identified. The reported toxicities were mainly: cytokine release syndrome (52.2%), febrile disorders (27.7%), and neurotoxicity (27.2%). Cytokine release syndrome and neurotoxicity were often co-reported and 75% of the events occurred in the first 10 days. Disproportionalities confirmed known adverse drug reactions and showed unexpected associations: for example, axi-cel with cardiomyopathies (reporting odds ratio = 2.3; 95% confidence interval 1.2-4.4) and gastrointestinal perforations (2.9; 1.2-7.3), tisa-cel with hepatotoxicity (2.5; 1.1-5.7) and pupil disorders (15.3; 6-39.1). Conclusions: Our study confirms the well-known adverse drug reactions and detects potentially emerging safety issues specific for each chimeric antigen receptor T-cell therapy, also providing insights into a stronger role for tisa-cel in inducing some immunodeficiency-related events (e.g., hypogammaglobulinemia, infections) and coagulopathies, and for axi-cel in neurotoxicity.
... They provide a new therapeutic approach for patients with r/r DLBCL and acute lymphoblastic leukemia (r/r ALL) after ≥2 lines of therapy. 11 After extracting and reproducing the patient's T cells in a laboratory, CARs are integrated into the T-cell membrane and reinfused as CAR T-cells into the patient's body. Upon binding to the antigen CD19+ at the surface of malignant cells, a specific immune reaction can be induced, activating a cytotoxic mechanism to destroy the CD19+ cancer cells. ...
Article
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The aim was to assess the incremental costs of chimeric antigen receptor (CAR) T-cell therapy (axicabtagene ciloleucel, tisagenlecleucel) compared with standard of care in adult patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) from the German third-party payer perspective. A budget impact model was established over a 6-year period. Estimation of the third-line population: partitioned survival model based on outcome data from peer-reviewed literature, a top-down approach based on population forecasts, and age-standardized incidences. Cost data were derived from the controlling department of a tertiary hospital and a German cost-of-illness study. In the scenario analysis, the budget impact of treating second-line DLBCL patients was calculated. One-way deterministic sensitivity analyses were conducted to test the robustness of the model. For the period 2021-2026, 788-867 (minimum population, min) and 1,068-1,177 (maximum population, max) adult third-line r/r DLBCL patients were estimated. The budget impact ranged from €39,419,562; €53,426,514 (min; max) in year 0 to €122,104,097; €165,763,001 (min; max) in year 5. The scenario analysis resulted in a budget impact of €65,987,823; €89,558,611 (min; max) and €204,485,031; €277,567,601 (min; max) for years 0 and 5, respectively. This budget impact analysis showed a significant but reasonable financial burden associated with CAR T-cell therapy for a limited number of patients requiring individualized care. Further, this study presents challenges and future needs in data acquisition associated with cost analysis in personalized medicine. For comprehensive economic discussions, complementary cost-effectiveness analyses are required to determine the value of innovative therapies for r/r DLBCL.
... CAR is composed of three parts: the intracellular region, which is the signaling molecule that mediates T cell activation, transmembrane region, and extracellular region, which is the variable region of mAb that can bind specific tumor antigens. As an innovative and promising therapeutic strategy, CAR-T therapy has remarkable efficacy and safety in the treatment of hematological tumors (114). It has also shed new light on solid cancer treatment, including lung cancer. ...
Article
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Cancer stem cells, a relatively small group of self-renewing cancer cells, were first isolated from acute myeloid leukemia. These cells can play a crucial role in tumor metastasis, relapse, and therapy resistance. The cancer stem cell theory may be applied to lung cancer and explain the inefficiency of traditional treatments and eventual recurrence. However, because of the unclear accuracy and illusive biological function of cancer stem cells, some researchers remain cautious about this theory. Despite the ongoing controversy, cancer stem cells are still being investigated, and their biomarkers are being discovered for application in cancer diagnosis, targeted therapy, and prognosis prediction. Potential lung cancer stem cell markers mainly include surface biomarkers such as CD44, CD133, epithelial cell adhesion molecule, and ATP-binding cassette subfamily G member 2, along with intracellular biomarkers such as aldehyde dehydrogenase, sex-determining region Y-box 2, NANOG, and octamer-binding transcription factor 4. These markers have different structures and functions but are closely associated with the stem potential and uncontrollable proliferation of tumor cells. The aberrant activation of major signaling pathways, such as Notch, Hedgehog, and Wnt, may be associated with the expression and regulation of certain lung cancer stem cell markers, thus leading to lung cancer stem cell maintenance, chemotherapy resistance, and cancer promotion. Treatments targeting lung cancer stem cell markers, including antibody drugs, nanoparticle drugs, chimeric antigen receptor T-cell therapy, and other natural or synthetic specific inhibitors, may provide new hope for patients who are resistant to conventional lung cancer therapies. This review provides comprehensive and updated data on lung cancer stem cell markers with regard to their structures, functions, signaling pathways, and promising therapeutic target approaches, aiming to elucidate potential new therapies for lung cancer.
... Chimeric antigen receptor (CAR)-expressing T-cells have indeed shown a remarkable potential for the treatment of various B-cell related malignancies, which has led to the approval of several CAR T-cell products such as Kymriah TM , Yescarta TM and others [1][2][3]. However, clinical experience has shown that targeting single antigens, such as CD19, on leukemic cells can result in relapse with antigen-negative leukemic clones following the treatment [4][5][6]. ...
Article
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Chimeric antigen receptor (CAR)-expressing T-cells are without a doubt a breakthrough therapy for hematological malignancies. Despite their success, clinical experience has revealed several challenges, which include relapse after targeting single antigens such as CD19 in the case of B-cell acute lymphoblastic leukemia (B-ALL), and the occurrence of side effects that could be severe in some cases. Therefore, it became clear that improved safety approaches, and targeting multiple antigens, should be considered to further improve CAR T-cell therapy for B-ALL. In this paper, we address both issues by investigating the use of CD10 as a therapeutic target for B-ALL with our switchable UniCAR system. The UniCAR platform is a modular platform that depends on the presence of two elements to function. These include UniCAR T-cells and the target modules (TMs), which cross-link the T-cells to their respective targets on tumor cells. The TMs function as keys that control the switchability of UniCAR T-cells. Here, we demonstrate that UniCAR T-cells, armed with anti-CD10 TM, can efficiently kill B-ALL cell lines, as well as patient-derived B-ALL blasts, thereby highlighting the exciting possibility for using CD10 as an emerging therapeutic target for B-cell malignancies.
... For instance, for Kymriah in refractory ALL indication, external control was used for comparison with data pooled from the three main Kymriah trials, despite confounding patient populations and matching on few variables. 33,68 For Kymriah and Yescarta in DLBCL indication, the treatment effect was compared with SCHOLAR-1 sponsored by Kite Pharma (MA holder of Yescarta). 57 The acceptance of comparison between Yescarta pivotal results and the SCHOLAR-1 study was attributed to the availability of individual patient data, enabling the company to match patients in both trials. ...
... 57 The acceptance of comparison between Yescarta pivotal results and the SCHOLAR-1 study was attributed to the availability of individual patient data, enabling the company to match patients in both trials. 68,69 However, for Kymriah given that only published data of SCHOLAR-1 was available for comparisons, the data from the pooled CORAL extensions study was accepted by the agency as a more suitable comparator than SCHOLAR-1 due to similarities in the populations enrolled and the objective response rate results obtained. 33,57,68 ...
Article
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Advanced therapy medicinal products (ATMPs) are innovative therapies that mainly target orphan diseases and high unmet medical needs. The uncertainty about the product’s benefit-risk balance at the time of approval, the limitations of nonclinical development and the complex quality aspects of those highly individualized advanced therapies are playing a key role in the clinical development, approval and post-marketing setting for these therapies. This article reviews the current landscape of clinical development of advanced therapies, its challenges and some of the efforts several stakeholders are conducting to move forward within this field. Progressive iteration of the science, methodologically sound clinical developments, establishing new standards for ATMPs development with the aim to ensure consistency in clinical development and the reproducibility of knowledge is required, not only to increase the evidence generation for approval but to set principles to achieve translational success in this field.
... Approved gene therapy products demonstrate the real-world efficacy of gene therapy using viral vectors. Autologous chimeric antigen receptor (CAR) T cell products achieve response rates not seen for previous benchmark therapies in patients with advanced hematological cancer, 1,2 and in vivo delivery of the SMN1 gene with vectors based on adeno-associated virus 9 (AAV9) improves the quality of life of children with spinal muscular atrophy. 3 In addition to these and other approved gene therapy medicinal products, many clinical trials are ongoing worldwide that promise benefit for patients suffering from severe diseases. ...
Article
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Preclinical studies on gene delivery into mouse lymphocytes are often hampered by insufficient activity of lentiviral (LV) and adeno-associated vectors (AAVs) as well as missing tools for cell type selectivity when considering in vivo gene therapy. Here, we selected designed ankyrin repeat proteins (DARPins) binding to murine CD8. The top-performing DARPin was displayed as targeting ligand on both vector systems. When used on engineered measles virus glycoproteins, the resulting mCD8-LV transduced CD8+ mouse lymphocytes with near-absolute (>99%) selectivity. Despite its lower functional titer, mCD8-LV achieved fourfold higher gene delivery to CD8+ cells than conventional VSV-LV when added to whole mouse blood. Addition of mCD8-LV encoding a chimeric antigen receptor specific for mouse CD19 to splenocytes resulted in elimination of B lymphocytes and lymphoma cells. For display on AAV, the DARPin was inserted into the GH2-GH3 loop of the AAV2 capsid protein VP1, resulting in a DARPin-targeted AAV we termed DART-AAV. Stocks of mCD8-AAV contained similar genome copies as AAV2, but were >20-fold more active in gene delivery in mouse splenocytes, while exhibiting >99% specificity for CD8+ cells. These results suggest that receptor targeting can overcome blocks in transduction of mouse splenocytes.
... Chimeric antigen receptor (CAR) T-cell therapy has proved to be effective in patients for whom few therapeutic options otherwise remain, such as those with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) and B-cell lymphomas (1)(2)(3)(4). These results have led to clinical approval of commercially available treatments (1). ...
... Chimeric antigen receptor (CAR) T-cell therapy has proved to be effective in patients for whom few therapeutic options otherwise remain, such as those with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) and B-cell lymphomas (1)(2)(3)(4). These results have led to clinical approval of commercially available treatments (1). Despite the great hopes that CAR T cells directed against CD19 (CART19) cells has raised, treatment failure is not uncommon. ...
... The use of CART19 therapy has improved the clinical outcome of patients with relapsed/refractory B-cell malignancies (1)(2)(3)(4). Despite the promising initial results, however, a not-negligible proportion of cases does not show CR or does not achieve longterm remission (1)(2)(3)(4). ...
Article
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Background Chimeric antigen receptor (CAR) T-cells directed against CD19 (CART19) are effective in B-cell malignancies, but little is known about the molecular factors predicting clinical outcome of CART19 therapy. The increasingly recognized relevance of epigenetic changes in cancer immunology prompted us to determine the impact of the DNA methylation profiles of CART19 cells on the clinical course. Methods We recruited 114 patients with B-cell malignancies, comprising 77 acute lymphoblastic leukemia (ALL) and 37 non-Hodgkin lymphoma (NHL) patients, who were treated with CART19 cells. Using a comprehensive DNA methylation microarray, we determined the epigenomic changes that occur in the patient T-cells upon transduction of the CAR vector. The effects of the identified DNA methylation sites on clinical response, cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), event-free survival (EFS) and overall survival (OS) were assessed. All statistical tests were 2-sided. Results We identified 984 genomic sites with differential DNA methylation between CAR-untransduced and CAR-transduced T-cells before infusion into the patient. Eighteen of these distinct epigenetic loci were associated with complete response (CR) adjusting by multiple testing. Using the sites linked to CR, the EPICART signature was established in the initial discovery cohort (n = 79), which was associated with CR (Fisher’s exact test, P<.001) and enhanced EFS (HR = 0.36, 95% CI = 0.19 to 0.70, P=.002; log-rank P=.003) and OS (HR = 0.45, 95% CI = 0.20 to 0.99, P=.047; log-rank P=.04;). Most important the EPICART profile maintained its clinical course predictive value in the validation cohort (n = 35) where it was associated with CR (Fisher’s exact test, P<.001) and enhanced OS (HR = 0.31, 95% CI = 0.11 to 0.84, P=.02; log-rank P=.02). Conclusions We show that the DNA methylation landscape of patient CART19 cells influences the efficacy of the cellular immunotherapy treatment in patients with B-cell malignancy.
... For the treatment of EWS, there is still an urgent need for novel and effective treatments. CAR-T cell therapy is a promising immunotherapeutical approach with encouraging results for tumors of the hematologic and lymphatic system (94). In comparison to traditional adoptive T cell therapy, editable CAR-T cells do not require MHC antigen presentation and can directly bind to target cell epitope for antitumor activity. ...
Article
Full-text available
Ewing’s sarcoma (EWS) is a malignant and aggressive tumor type that predominantly occurs in children and adolescents. Traditional treatments such as surgery, radiotherapy and chemotherapy, while successful in the early disease stages, are ineffective in patients with metastases and relapses who often have poor prognosis. Therefore, new treatments for EWS are needed to improve patient’s outcomes. Chimeric antigen receptor (CAR)-T cells therapy, a novel adoptive immunotherapy, has been developing over the past few decades, and is increasingly popular in researches and treatments of various cancers. CAR-T cell therapy has been approved by the Food and Drug Administration (FDA) for the treatment of leukemia and lymphoma. Recently, this therapeutic approach has been employed for solid tumors including EWS. In this review, we summarize the safety, specificity and clinical transformation of the treatment targets of EWS, and point out the directions for further research.
... Significant clinical responses and high complete response rates have been observed in CAR-T therapy for B-cell malignancies. Based on these encouraging results, the Food and Drug Administration (FDA) recently approved two CAR-T cells targeting the CD19 protein for the treatment of acute lymphoblastic leukemia and diffuse large B-cell lymphoma [19]. Recently, researchers have also extended CAR-T therapy to solid tumors, including OS [20][21][22]. ...
Article
Full-text available
Osteosarcoma (OS) is the most common malignant bone tumor, arising mainly in children and adolescents. With the introduction of multiagent chemotherapy, the treatments of OS have remarkably improved, but the prognosis for patients with metastases is still poor, with a five-year survival rate of 20%. In addition, adverse effects brought by traditional treatments, including radical surgery and systemic chemotherapy, may seriously affect the survival quality of patients. Therefore, new treatments for OS await exploitation. As a novel immunotherapy, chimeric antigen receptor (CAR) T-cell therapy has achieved encouraging results in treating cancer in recent years, especially in leukemia and lymphoma. Furthermore, researchers have recently focused on CAR-T therapy in solid tumors, including OS. In this review, we summarize the safety, specificity, and clinical transformation of the targets in treating OS and point out the direction for further research.
... Cancer has been a leading disease target, with the treatment of B cell malignancies yielding compelling clinical outcomes, resulting in the regulatory approval of several CAR T cell therapies. 1 Concurrently, intensive research on solid tumor indications is underway. 2 Similarly, rare diseases are prominent targets for gene therapy and gene editing technologies. ...
Article
Full-text available
The emergence of new cell and gene-based therapies (CGTs) utilizing innovative technologies has recently intensified. Long-standing efforts in publicly funded biomedical research have resulted in breakthrough therapeutic approaches for patients with devastating and life-threatening diseases. Transformative gene-based therapeutic tools include human genome editing technologies, refined transposon systems, and synthetic immunoreceptors, such as chimeric antigen receptor (CAR) T cell and natural killer cell engineered immunotherapies. Cancer has been a leading disease target, with the treatment of B cell malignancies yielding compelling clinical outcomes, resulting in the regulatory approval of several CAR T cell therapies. Concurrently, intensive research on solid tumor indications is underway. Similarly, rare diseases are prominent targets for gene therapy and gene editing technologies. Founded on these scientific advances, next-generation CGTs are expected to transform into treatment options for a wider spectrum of conditions. Moreover, while these treatments, to-date, target mostly patients with advanced illnesses, future therapies may be introduced at earlier disease stages, even as primary therapeutic options. Here, we highlight some of the obstacles inherent in CGT evidence generation and research reproducibility and recommend concerted actions on how they can be overcome.