Chimeric Antigen Receptor T-Cell Access in Patients with Relapsed/Refractory Large B-Cell Lymphoma: Association of Access with Social Determinants of Health and Travel Time to Treatment Centers.

Large B-cell lymphoma (LBCL) is the most common type of non-Hodgkin lymphoma. Chimeric antigen receptor T-cell (CAR T) therapy represents a novel treatment with curative potential for relapsed or refractory (R/R) LBCL, but there are access barriers to this innovative therapy that are not well-studied. Study objectives were: (1) Assess the impact of geographic factors and social determinants of health (SDOH) on access to treatment with CAR T in a sample of patients with R/R LBCL and ≥2 prior lines of therapy (LOT). (2) Compare and contrast patient characteristics, SDOH, and travel time between patients with R/R LBCL who received CAR T and those who did not. An observational, nested case-control study of patients with R/R LBCL, ≥2 prior LOT, not in a clinical trial, identified using 100% Medicare Fee-For-Service and national multi-payer claims databases. Patients were linked to near-neighborhood SDOH using 9-digit ZIP-code address. Driving distance and time between residence and nearest CAR T treatment center (TC) was calculated. Patients were stratified based on treatments received upon third LOT initiation (Index Date) or later: (1) received CAR T and (2) did not receive CAR T. Multivariable logistic regression was used to evaluate factors associated with CAR T. 5011 patients met inclusion criteria, with 628 (12.5%) in the CAR T group. Regression models found the likelihood of receiving CAR T decreased with patient age (odds ratio [OR] = .96, P < .001), and males were 29% more likely to receive CAR T (OR = 1.29, P = .02). Likelihood of CAR T increased with Charlson Comorbidity Index (CCI; OR = 1.07, P < .001) indicating patients with more comorbidities were more likely to receive CAR T. Black patients were less than half as likely to receive CAR T than White patients (OR = .44, P = .01). Asian patients did not significantly differ from White patients (OR = 1.43, P = .24), and there was a trend for Hispanic patients to have a slightly lower likelihood of CAR T (OR = .50, P = .07). Higher household income was associated with receipt of CAR T, with the lowest income group more than 50% less likely to receive CAR T than the highest (OR = .44, P = .002), and the second lowest income group more than 30% less likely (OR = .68, P = .02). Finally, likelihood of CAR T therapy was reduced when the driving time to the nearest TC was 121 to 240 minutes (reference group: ≤30 minutes; OR = .64, P = .04). Travel times between 31 and 121 or greater than 240 minutes were not significantly different from ≤30 minutes. Payer type was collinear with age and could not be included in the regression analysis, but patients with commercial insurance were 1.5 to 3 times more likely to receive CAR T than other payers on an unadjusted basis. We identified significant disparities in access to CAR T related to demographics and SDOH. Patients who were older, female, low income, or Black were less likely to receive CAR T. The positive association of CCI with CAR T requires further research. Given the promising outcomes of CAR T, there is urgent need to address identified disparities and increase efforts to overcome access barriers.

[DESCAR-T, a nationwide registry for patient treated by CAR-T Cells in France]. / DESCAR-T, le registre national des patients traités par CAR-T Cells.

CAR-T Cells have opened new doors for cellular immunotherapies and provides new therapeutic options for patients with refractory B-cell malignancies, B-cell acute lymphoblastic leukemia and diffuse large B-cel lymphoma. CAR-T Cells have benefited from an accelerated approval procedure in many countries. Indeed, The French health authorities have approved the specialties Tisacel ® and Axicel ®, but additional data including the use of CAR-T Cells in real life were also mandatory. In regard to the scientific interest of the project, LYSA-LYSARC committed itself to prospectively and retrospectively collect information on patients eligible for CAR-T Cells as required by French health authorities. Other academic cooperating groups (GRAALL, IFM, SFCE, FILO and the scientific society SFGM-TC) were associated to this initiative which aims to build a nationwide CAR-T Cells devoted registry, so-called DESCART (Dispositif d'Enregistrement et Suivi des patients traités par CAR-T cells). DESCAR-T is a real-life multicentric registry set up in French sites qualified for CAR-T Cells treatment. DESCAR-T objective is to describe the use of CAR-T Cells in real life. All paediatric and adult patients with hematological malignancy fulfilling CAR-T Cells approval criteria and for whom a CAR-T Cells therapy has been discussed are included from 1 July 2018. Clinical data are directly collected from medical records and patients are treated according to the centers' routine practices. One of the distinctive features of DESCAR-T is its link with HTA for CAR-T Cells s reimbursement by the French public health system. DESCAR-T is the first national registry promoted by an academic group allowing centralized data collection for both academic and HTA/health authorities' purposes.

[CAR-T CELLS: How does the EBMT registry monitor European activities, identify hurdles and prepare for changes in regulations]. / CAR-T cells : comment le registre de l'EBMT monitore les activités en Europe, identifie les contraintes et prépare l'évolution des régulations.

CAR-T Cells are gene therapy medicinal products, a subcategory of Advanced Therapy Medicinal Products as defined in the EC Regulation 1394/2007. They may represent the first example of such medicinal products that are industry-manufactured and commercialized on a large scale. Their very nature, their manufacturing processes, pricing and conditions upon which they were approved by regulatory agencies, all lead the latter to require long-term follow-up after marketing approval with a view for a better definition of CAR-T Cells safety profile and efficacy profile in real world conditions. Collection and analysis of data over a 15-year period of time represents a technical and political challenge. So does the a priori definition of data to be collected for a wealth of forthcoming analyses that focus on the interests of a variety of stakeholders. EBMT has been collecting and analyzing data on hematopoietic cell transplants for decades. EBMT currently works with many interested parties to collect data on patients treated with CAR-T Cells.

Adverse Cardiovascular and Pulmonary Events Associated With Chimeric Antigen Receptor T-Cell Therapy.

BACKGROUND: Pivotal trials of chimeric antigen receptor T-cell (CAR-T) have identified common toxicities but may have been underpowered to detect cardiovascular and pulmonary adverse events (CPAEs). OBJECTIVES: This study sought to investigate CPAEs associated with commercial CD19-directed CAR-T therapy. METHODS: In this retrospective, pharmacovigilance study, the authors used the Food and Drug Administration adverse event reporting system to identify CPAEs associated with axicabtagene-ciloleucel and tisagenlecleucel. The authors evaluated disproportionate reporting by the reporting odds ratio (ROR) and the lower bound of the information component 95% credibility interval (IC025 >0 is deemed significant). Significant associations were further adjusted to age and sex (adj.ROR). RESULTS: The authors identified CAR-T reports of 2,657 patients, including 546 CPAEs (20.5%). CPAEs overlapped with cytokine release syndrome in 68.3% (373 of 546) of the reports. Compared with the full database, CAR-T was associated with overreporting of tachyarrhythmias (n = 74 [2.8%], adj.ROR = 2.78 [95% CI: 2.21-3.51]), cardiomyopathy (n = 69 [2.6%], adj.ROR = 3.51 [2.42-5.09]), pleural disorders (n = 46 [1.7%], adj.ROR = 3.91 [2.92-5.23]), and pericardial diseases (n = 11 [0.4%], adj.ROR = 2.26 [1.25-4.09], all IC025 >0). Venous thromboembolic events (VTEs) were associated only with axicabtagene-ciloleucel therapy (n = 28 [1.6%], adj.ROR = 1.80 [1.24-2.62], IC025 >0). Atrial fibrillation (n = 55) was the leading tachyarrhythmia, followed by ventricular arrhythmias (n = 14). Tachyarrhythmias and VTEs were reported more often following axicabtagene-ciloleucel than tisagenlecleucel in an age- and sex-adjusted model (adj.ROR = 1.82 [1.04-3.18] and adj.ROR = 2.86 [1.18-6.93], respectively). Finally, the fatality rate of CPAEs was 30.9%. CONCLUSIONS: In this largest post-marketing study to date, the authors identified an association between CAR-T and various CPAEs, including tachyarrhythmias, cardiomyopathy, pericardial and pleural disorders, and VTEs. These findings should be considered in the multidisciplinary assessment for and monitoring of CAR-T therapy recipients.

CAR T-cell therapy in relapsed/refractory diffuse large B-cell lymphoma: physician preferences trading off benefits, risks and time to infusion.

Aims: We evaluated physicians' willingness to trade-off benefits, risks and time to infusion for CAR T-cell therapy for relapsed or refractory diffuse large B-cell lymphoma. Materials & methods: In a discrete-choice experiment survey, 150 US oncologists/hematologists chose between two hypothetical CAR T-cell treatments defined by six attributes. Results: Decreasing time to infusion from 113 to 16 days yielded the greatest change in preference weight (1.91). Physicians were willing to accept a >20% increase in risk of severe cytokine release syndrome and 15% increase in risk of severe neurological events in exchange for an increase in the probability of overall survival at 24 months from 40 to 55%. Conclusion: Physicians value reducing time to infusion and will accept incremental increases in serious adverse event risks to gain survival improvements.

Lay abstract CAR-T therapy is a treatment option for patients with diffuse large B-cell lymphoma that has not responded to at least two other kinds of treatments. CAR-T therapies are manufactured from a patient's white blood cells, modified to attack lymphoma cells. A CAR-T therapy takes time to manufacture after these cells are collected. CAR-T therapies can result in the reduction or disappearance of lymphoma tumors and can increase the chances of survival, but also cause serious side effects for a few patients. One of these is cytokine release syndrome (CRS), in which high levels of inflammation throughout the body may cause fever, heart problems or difficulty breathing. Another is the development of temporary but serious neurological problems such as confusion, seizures and memory problems. To understand how important physicians consider certain features of CAR-T therapies to be when deciding whether to recommend them, we asked physicians to choose between two treatment options resembling CAR-T therapies in a series of questions, with the CAR-T features varying in each question. Their answers indicated whether disappearance of tumors, a patient's chances of survival after 1 and 2 years of treatment, manufacturing time, or the risk of CRS or neurological problems was the most important factor. Physicians most wanted to reduce manufacturing time from 113 to 16 days, but also were willing to accept a >20% increase in risk of severe CRS and a 15% increase in risk of severe neurological events to increase a patient's chance of survival from 40 to 55% at 2 years.

Antigen-Specific Regulatory T Cell Therapy in Autoimmune Diseases and Transplantation.

Regulatory T (Treg) cells are a heterogenous population of immunosuppressive T cells whose therapeutic potential for the treatment of autoimmune diseases and graft rejection is currently being explored. While clinical trial results thus far support the safety and efficacy of adoptive therapies using polyclonal Treg cells, some studies suggest that antigen-specific Treg cells are more potent in regulating and improving immune tolerance in a disease-specific manner. Hence, several approaches to generate and/or expand antigen-specific Treg cells in vitro or in vivo are currently under investigation. However, antigen-specific Treg cell therapies face additional challenges that require further consideration, including the identification of disease-relevant antigens as well as the in vivo stability and migratory behavior of Treg cells following transfer. In this review, we discuss these approaches and the potential limitations and describe prospective strategies to enhance the efficacy of antigen-specific Treg cell treatments in autoimmunity and transplantation.

Efficacy and Safety of CAR-T Therapy for Relapse or Refractory Multiple Myeloma: A systematic review and meta-analysis.

Background: Multiple myeloma (MM) is incurable in spite of recent treatment improvements, highlighting the development of new therapies. Chimeric antigen receptor (CAR) T-cell therapy has dramatically changed the therapeutic effectiveness in high-risk B-cell malignancies. For relapsed/refractory multiple myeloma (RRMM), preclinical evaluations of CAR-T therapy have shown promising efficacy, thus various active clinical trials are under way. Herein, we conducted this review to summarize efficacy and safety of CAR-T therapy and provide more evidence to guide clinical treatments. Method: We systematically searched literature based on databases (PubMed, EMBASE, Cochrane Central Register of Controlled Trials), and conference abstracts reported from American Society of Hematology (ASH), European Hematology Association (EHA) and American Society of Clinical Oncology (ASCO), in addition to other sources (www.clinicaltrials.gov, article citations). Data assessed efficacy and safety of CAR-T therapy in patients with RRMM were extracted and evaluated, and then systematically analyzed by Comprehensive Meta-analysis 3.0 (CMA 3.0). Results: A total of 23 studies including 350 participants from different countries, diagnosed as RRMM and treated with CAR-T therapy (containing 7 antigens targeted by CARs) were combined. In summary, we discovered the pooled overall response rate (77%), complete response rate (37%) and minimal residual disease (MRD) negativity rate within responders (78%). Furthermore, the pooled relapse rate of responders was 38% and median progression-free survival was 8 months. The pooled survival rate was 87% at last follow-up (median, 12 months). In addition, the pooled grade 3-4 rates of cytokine release syndrome (CRS) and neurologic toxicities (NT) were 14% and 13%, respectively. Conclusion: Our study suggests that CAR-T therapy has demonstrated efficacy and safety in RRMM patients. BCMA-targeted CAR-T and anti-BCMA contained regimen have shown better efficacy.

A real-world data of Immune checkpoint inhibitors in solid tumors from India.

BACKGROUND: Checkpoint inhibitors (Nivolumab and Pembrolizumab) are approved for multiple indications in solid tumors. However access to these therapies is limited in low and middle income countries. Hence we performed an audit to identify accessibility, adverse event rates, compliance, progression free survival and overall survival in solid tumors. METHODS: This was a single center retrospective analysis of prospective data base of patients with non-melanoma solid tumors who were treated with immunotherapy from August 2015 to November 2018. Adverse events during immunotherapy were documented and graded using CTCAE (Common terminology criteria for adverse events), v. 4.02. The response rates to immunotherapy, toxicities and the time to onset and resolution of toxicities were also evaluated as secondary endpoints. RESULTS: Out of 9610 patients, only 155 patients (1.61%) could receive immunotherapy. The most common malignancies included metastatic non-small cell lung cancer, metastatic renal cell carcinoma, metastatic urothelial carcinoma and relapsed/recurrent head and neck squamous cell carcinoma. Median overall survival in patients who received immunotherapy in non-melanoma solid malignancies was 5.37 months (95% CI, 3.73-9.73). Poor performance status at baseline was the only adverse prognostic factor. The median progression free survival was 2.57 months (95% CI, 1.73-3.83). Immunotherapy was well tolerated with most common side effects being fatigue 14.8% and anorexia 5.8%. The cumulative incidence of immune related adverse events like hepatitis, pneumonitis, colitis and nephritis was less than 10%. CONCLUSION: Real-world data in Indian setting confirms the benefit of immunotherapy in patients with advanced non-melanoma solid tumors.

Opportunities and challenges associated with the evaluation of chimeric antigen receptor T cells in real-life.

PURPOSE OF REVIEW: With the approval of the first chimeric antigen receptor (CAR)-T cell products on the market, the European Medicines Agency (EMA) required market authorization holders (MAHs) to monitor the long-term efficacy and safety of CAR-T cells for 15 years after administration. In 2019, the cellular therapy module of the European Society for Blood and Marrow Transplantation (EBMT) registry received a positive qualification opinion from the EMA indicating that the registry fulfills the essential needs to capture such data. We investigated its broader implication. RECENT FINDINGS: Since 2020, the cellular therapy module of the EBMT registry captures data to support postauthorization studies for MAHs and EMA. The process toward a positive qualification opinion has attracted interest from many other stakeholders, such as scientists and Health Technology Assessment bodies, and was the spin-off for a stimulating development which defined the need for a registry to comply with regulatory requirements, and also inspired ways to deal with CAR-T cell programs in terms of center qualifications and educational standards for professionals. SUMMARY: The positive qualified opinion of the EBMT registry by EMA to monitor long-term efficacy and safety of commercial CAR-T cells created opportunities and challenges and was serving as linking-pin to launch a novel CAR-T cell community.

CAR-T cells: the Chinese experience.

INTRODUCTION: Chimeric antigen receptor T (CAR-T) cells are harnessed to identify and lyse malignant cells specifically, efficiently, and independently of the major histocompatibility complex (MHC). As a result, prognoses of relapsed or refractory (R/R) B cell hematological malignancies as well as limited types of solid tumors, have been ameliorated to a great extent. In China, a rising number of clinical trials that contribute to the development of novel CAR-T therapeutic strategies have been conducted on an extensive scale. AREAS COVERED: We summarize registered clinical trials related to CAR-T therapy conducted in China by evaluating various parameters such as distribution, study phase, CAR structure, target antigen, and disease. The efficacy, toxicity, and, more importantly, the new strategies for optimization of CAR-T therapy of Chinese studies and clinical trials are elaborated in detail. EXPERT OPINION: In terms of the number of CAR-T clinical trials, China is second to the USA, registering approximately 33% of trials worldwide. China's extensive explorations and breakthroughs in the search of novel target antigens, optimization of CAR structure, cocktail CAR-T therapy, combination therapy, and extension of CAR-T cell applications, imply that we are currently on the verge of a revolution in CAR-T therapy.

A Review of Two Regulatory Approved Anti-CD19 CAR T-Cell Therapies in Diffuse Large B-Cell Lymphoma: Why Are Indirect Treatment Comparisons Not Feasible?

Anti-CD19 chimeric antigen receptor (CAR) T-cell therapies can be effective for diffuse large B-cell lymphoma (DLBCL), a cancer with limited treatment options and poor outcomes, particularly for patients with relapsed or refractory (r/r) disease. Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are CAR T-cell therapies approved by regulatory bodies for certain patients with r/r DLBCL on the basis of demonstrated treatment effects in their pivotal single-arm trials, ZUMA-1 and JULIET, respectively. In the absence of head-to-head trials, the question of whether a valid indirect treatment comparison (ITC) between axi-cel and tisa-cel could be performed using existing evidence is of interest to patients, physicians, payers, and other stakeholders. This article addresses that question by summarizing the current evidence from clinical trials and real-world studies and discussing the challenges and limitations of potential analytical approaches associated with an ITC. Two ITC approaches attempting to adjust for cross-trial heterogeneity between ZUMA-1 and JULIET, matching-adjusted indirect comparison and regression-prediction model analysis, were evaluated. After evaluating the current clinical trial data and real-world evidence, and present and prior ITC analyses of axi-cel and tisa-cel, the authors conclude that a valid comparative analysis is not currently feasible. The substantial differences (e.g., timing of leukapheresis and enrollment, use of bridging chemotherapy [90% in JULIET vs. 0% in ZUMA-1], lymphodepleting regimens) between the two trials' designs and patient populations preclude a robust and reliable ITC. No other approaches are able to account for such differences. The current real-world data are still too immature to be used for ITCs. Thus, drawing conclusions from such ITCs should be avoided to prevent misinforming treatment choices or limiting patient access to effective treatment options. Additional data from ongoing or future real-world studies with appropriate statistical analyses are needed to provide insights into the comparative effectiveness and safety of these two treatments.

How the COVID-19 pandemic changed cellular therapy at Columbia University Irving Medical Center/NewYork-Presbyterian Hospital.

New York is at the epicenter of the coronavirus disease 2019 (COVID-19) pandemic caused by the SARS-CoV-2 virus. Columbia University Irving Medical Center/NewYork-Presbyterian Hospital (CUIMC/NYPH) had to make changes to its cellular therapy operations to ensure patient, donor, and staff safety and well-being. In this article, we discuss the process changes we instituted for cellular therapy clinical care, collection, processing, and cryopreservation to cope with the rapidly evolving pandemic.

Cost-effectiveness of Anti-CD19 chimeric antigen receptor T-Cell therapy in pediatric relapsed/refractory B-cell acute lymphoblastic leukemia. A societal view.

INTRODUCTION: In several studies, the chimeric antigen receptor T-cell therapy tisagenlecleucel demonstrated encouraging rates of remission and lasting survival benefits in pediatric patients with relapsed/refractory (r/r) acute lymphoblastic leukemia (ALL). We assessed the cost-effectiveness of tisagenlecleucel (list price: 320 000 EUR) among these patients when compared to clofarabine monotherapy (Clo-M), clofarabine combination therapy (Clo-C), and blinatumomab (Blina) from both a healthcare and a societal perspective. We also assessed future medical and future non-medical consumption costs. METHODS: A three-state partitioned survival model was used to simulate a cohort of pediatric patients (12 years of age) through different disease states until the end of life (lifetime horizon). Relevant outcomes were life years, quality-adjusted life years (QALYs), healthcare costs, societal costs, and the incremental cost-effectiveness ratio (ICER). Uncertainty was explored through deterministic and probabilistic sensitivity analyses as well as through several scenario analyzes. RESULTS: Total discounted costs for tisagenlecleucel were 552 679 EUR from a societal perspective, which was much higher than the total discounted costs from a healthcare perspective (ie, 409 563 EUR). Total discounted societal costs for the comparator regimens ranged between 160 803 EUR for Clo-M and 267 259 EUR for Blina. Highest QALYs were estimated for tisagenlecleucel (11.26), followed by Blina (2.25), Clo-C (1.70) and Clo-M (0.74). Discounted societal ICERs of tisagenlecleucel ranged between 31 682 EUR/QALY for Blina and 37 531 EUR/QALY for Clo-C and were considered cost-effective with a willingness-to-pay (WTP) threshold of 80 000 EUR/QALY. None of the scenarios exceeded this threshold, and more than 98% of the iterations in the probabilistic sensitivity analysis were cost-effective. DISCUSSION: At the current price and WTP threshold, tisagenlecleucel is cost-effective from both a healthcare and a societal perspective. Nevertheless, long-term effectiveness data are needed to validate the several assumptions that were necessary for this model.

[Reporting data of patients receiving CAR T cell therapy into the EBMT registry: Guidelines of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)]. / Saisie des données des patients faisant l'objet d'un traitement par cellules CAR-T : recommandations de la Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC).

Tisagenlecleucel (Kymriah™) and axicabtagene ciloleucel (Yescarta™) are the first two approved drug products that belong to of a new class of therapies manufactured through an industrial process that includes the ex vivo genetic modification of human autologous T lymphocytes with viral vectors. Since CAR-T Cells qualify as gene therapy medicinal products, there is a requirement for long-term (15 years) follow-up of treated patients. As part of a global initiative aiming at a better use of continental registries to study the outcome of homogeneous groups of patients, EMA issued a positive opinion on the use of the EBMT registry to capture LTFU of patients treated with CAR-T Cell in EU Member states. The use of a European registry will provide a global view of this new field across EU countries and across diverse indications, and bears advantages over the use of registries dedicated to specific categories of diseases, or national registries. This is an important asset to fully measure the medical value of these innovative therapies in real-life conditions, and assess whether pricing is fully justified. To fulfill EMA requirements, as well as requirements from Pharma companies, EBMT has designed a new Cellular Therapy Med-A form that allows to capture the essential information on the administered drug product, disease and patient. Registering patients and capturing follow-up data is already possible in Promise, and will be made easier when the full migration of the EBMT database from Promise to MACRO is completed in the forthcoming weeks. Negotiations are ongoing with all interested parties including patients to define in which conditions data will be accessed and analyzed; the underlying principle is to favor rather than restrict the use of data, with a view to build cooperative projects involving relevant cooperative groups and professional associations. Here, we present practical recommendations issued by SFGM-TC to help data managers capture information related to patients treated with CAR-T Cells.

An international survey on the management of patients receiving CAR T-cell therapy for haematological malignancies on behalf of the Chronic Malignancies Working Party of EBMT.

PURPOSE OF THE STUDY: Two chimeric antigen receptor (CAR) T-cell therapies - Tisagenlecleucel (Kymriah™) and Axicabtagene ciloleucel (Yescarta™) - have been approved for commercial use. In order to inform forthcoming EBMT guidelines on the management of adults and children undergoing autologous CAR T-cell therapy, we undertook a survey of experienced clinicians. METHODS: An online survey with a dual focus on (1) 'real world' patient eligibility criteria and (2) models of care for patient follow-up was sent to experienced physicians. RESULTS: There were 41 respondents (10 countries) and 93% worked in FACT-JACIE-accredited transplant centres. Most felt that a history of malignancy (57%), prior allo-HCT for B-NHL (78%-81%) and prior treatment with anti-CD19/CD3 BiTE antibodies (76%-86%) do not constitute contra-indications to CAR T therapy. Clinicians were divided as to whether CNS involvement represented an exclusion criterion. There was agreement that patients with viral infections (HIV, Hepatitis B or Hepatitis C) are not eligible. There is no common model of care for long-term follow-up. Most respondents believed that patients should attend the hospital two (43%) to three (33%) times weekly during the first month following discharge. A majority (69%) of respondents work in centres where there is an MDT meeting with a specific focus on follow-up following CAR T Therapy. Follow-up care is currently delivered either in HCT or haematology-oncology outpatient clinics. CONCLUSION: The responses reveal wide variation in perceived patient eligibility criteria and highlight the need for consensus guidelines. The findings also illustrate the embryonic nature of current follow-up arrangements.

Estimating Long-Term Survival for Patients with Relapsed or Refractory Large B-Cell Lymphoma Treated with Chimeric Antigen Receptor Therapy: A Comparison of Standard and Mixture Cure Models.

Patients treated with anti-CD19 chimeric antigen receptor (CAR) T-cell therapies have shown either sustained remission or rapid progression. Traditional survival modeling may underestimate outcomes in these situations, by assuming the same mortality rate for all patients. To illustrate this issue, we compare standard parametric models to mixture cure models for estimating long-term overall survival in patients with relapsed or refractory large B-cell lymphoma treated with axicabtagene ciloleucel (axi-cel). Compared to standard models without cure proportions, mixture cure models have similar fit, but substantially different extrapolated survival. Standard models (Weibull and generalized gamma) estimate mean survival of 2.0 years (95% CI (1.5, 3.0)) and 3.0 years (95% CI (1.7, 5.6)), respectively, compared to 15.7 years (95% CI (9.3, 21.1)) and 17.5 yrs (12.0, 22.8) from mixture cure models (using Weibull and generalized gamme distributions). For cancer therapies where substantial fractions achieve long term remission, our results suggest that assumptions of the modeling approach should be considered. Given sufficient follow-up, mixture cure models may provide a more accurate estimate of long-term overall survival compared with standard models.

Modeling Pancreatic Cancer Dynamics with Immunotherapy.

We develop a mathematical model of pancreatic cancer that includes pancreatic cancer cells, pancreatic stellate cells, effector cells and tumor-promoting and tumor-suppressing cytokines to investigate the effects of immunotherapies on patient survival. The model is first validated using the survival data of two clinical trials. Local sensitivity analysis of the parameters indicates there exists a critical activation rate of pro-tumor cytokines beyond which the cancer can be eradicated if four adoptive transfers of immune cells are applied. Optimal control theory is explored as a potential tool for searching the best adoptive cellular immunotherapies. Combined immunotherapies between adoptive ex vivo expanded immune cells and TGF-[Formula: see text] inhibition by siRNA treatments are investigated. This study concludes that mono-immunotherapy is unlikely to control the pancreatic cancer and combined immunotherapies between anti-TGF-[Formula: see text] and adoptive transfers of immune cells can prolong patient survival. We show through numerical explorations that how these two types of immunotherapies are scheduled is important to survival. Applying TGF-[Formula: see text] inhibition first followed by adoptive immune cell transfers can yield better survival outcomes.