Point-of-care cell therapy manufacturing; it’s not for everyone

AbstractThe use of cellular therapies to treat cancer, inherited immune deficiencies, hemoglobinopathies and viral infections is growing rapidly. The increased interest in cellular therapies has led to the development of reagents and closed-system automated instruments for the production of these therapies. For cellular therapy clinical trials involving multiple sites some people are advocating a decentralized model of manufacturing where patients are treated with cells produced using automated instruments at each participating center using a single, centrally held Investigational New Drug Application (IND). Many academic centers are purchasing these automated instruments for point-of-care manufacturing and participation in decentralized multiple center clinical trials. However, multiple site manufacturing requires harmonization of product testing and manufacturing in order to interpret the clinical trial results. Decentralized manufacturing is quite challenging since all centers should use the same manufacturing protocol, the same or comparable in-process and lot release assays and the quality programs from each center must work closely together. Consequently, manufacturing cellular therapies using a decentralized model is in many ways more difficult than manufacturing cells in a single centralized facility. Before an academic center decides to establish a point-of-care cell processing laboratory, they should consider all costs associated with such a program. For many academic cell processing centers, point-of-care manufacturing may not be a good investment.

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Do eligibility criteria restrict access to clinical trials?

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.29_suppl.94 ◽

2020 ◽

Vol 38 (29_suppl) ◽

pp. 94-94

Author(s):

Nessa Stefaniak ◽

Jennifer Walker ◽

Monica L. Murphy ◽

Mishellene McKinney ◽

Lu Liu ◽

...

Keyword(s):

Clinical Trials ◽

Cellular Therapy ◽

Clinical Pathways ◽

Point Of Care ◽

Performance Status ◽

Poor Performance ◽

Cancer Center ◽

Poor Performance Status ◽

Adoptive Cellular Therapy ◽

Eligibility Criteria

94 Background: Stringent eligibility criteria may be a barrier to oncology clinical trial enrollment. We examined patients meeting basic trial eligibility criteria defined in a clinical pathway where the trial was not selected, and then performed a thorough review of full trial eligibility. Methods: Locally available trials are embedded into a pathways tool used at the point of care by medical oncologists at a tertiary cancer center. The physician can choose to have the patient fully screened for the recommended trial or bypass it. Patients where the physician bypassed the trial for eleven Phase 2 and 3 solid tumor trials from April 2018 to December 2019 were reviewed for trial eligibility. Basket trials and adoptive cellular therapy trials were excluded. Trials selected for the audit were presented for more than 20 patients and were bypassed in 80% or more cases. For each trial a random set of 20% of cases or a minimum of 15 cases minimum were reviewed. Results: Among the 184 cases reviewed, 149 (81%) were trial ineligible based upon one or more criteria. The most common reasons for patients' ineligibility were the wrong biomarker profile, prior drug treatment, and health conditions including co-morbidities, autoimmune diseases, other cancers and poor performance status. Conclusions: The majority of patients meeting basic eligibility in a clinical pathways system did not meet strict eligibility criteria. This suggests the trials may not be reflective of the needs of the cancer population being treated and may limit the applicability of trial results to the general cancer population. Use of the pathway program to define eligibility is limited by the numerous and nuanced eligibility criteria that cannot be programmed into the pathways system. Clinical trials eligibility criteria and pathway tools need to adapt to the patient population to help advance cancer research. [Table: see text]

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Perspectives of tumor-infiltrating lymphocyte treatment in solid tumors

BMC Medicine ◽

10.1186/s12916-021-02006-4 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Shuhang Wang ◽

Jingwei Sun ◽

Kun Chen ◽

Peiwen Ma ◽

Qi Lei ◽

...

Keyword(s):

Clinical Trials ◽

Solid Tumors ◽

Clinical Application ◽

Cellular Therapy ◽

Adoptive Cellular Therapy ◽

Future Directions ◽

Cellular Therapies ◽

Tumor Infiltrating Lymphocyte ◽

Tumor Homing

AbstractTumor-infiltrating lymphocyte (TIL) therapy is a type of adoptive cellular therapy by harvesting infiltrated lymphocytes from tumors, culturing and amplifying them in vitro and then infusing back to treat patients. Its diverse TCR clonality, superior tumor-homing ability, and low off-target toxicity endow TIL therapy unique advantages in treating solid tumors compared with other adoptive cellular therapies. Nevertheless, the successful application of TIL therapy currently is still limited to several types of tumors. Herein in this review, we summarize the fundamental work in the field of TIL therapy and the current landscape and advances of TIL clinical trials worldwide. Moreover, the limitations of the current TIL regimen have been discussed and the opportunities and challenges in the development of next-generation TIL are highlighted. Finally, the future directions of TIL therapy towards a broader clinical application have been proposed.

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New trends in cellular therapy

Development ◽

10.1242/dev.192567 ◽

2020 ◽

Vol 147 (18) ◽

pp. dev192567 ◽

Cited By ~ 3

Author(s):

Hideyuki Okano ◽

Doug Sipp

Keyword(s):

Stem Cells ◽

Clinical Trials ◽

Cell Therapy ◽

Pluripotent Stem Cells ◽

Clinical Studies ◽

Cellular Therapy ◽

Current Status ◽

Cellular Therapies ◽

Safety Issues ◽

Regenerative Therapies

ABSTRACTRegenerative therapies, including both gene and cellular therapies, aim to induce regeneration of cells, tissues and organs and restore their functions. In this short Spotlight, we summarize the latest advances in cellular therapies using pluripotent stem cells (PSCs), highlighting the current status of clinical trials using induced (i)PSC-derived cells. We also discuss the different cellular products that might be used in clinical studies, and consider safety issues and other challenges in iPSC-based cell therapy.

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Cellular therapies for the treatment of immune-mediated GI and liver disease

British Medical Bulletin ◽

10.1093/bmb/ldaa035 ◽

2020 ◽

Vol 136 (1) ◽

pp. 127-141

Author(s):

Sheeba Khan ◽

Reenam S Khan ◽

Philip N Newsome

Keyword(s):

Clinical Trials ◽

Liver Disease ◽

Cell Therapy ◽

Cellular Therapy ◽

Current Knowledge ◽

Unmet Need ◽

Therapeutic Effects ◽

Cellular Therapies ◽

Gastrointestinal Conditions ◽

Immune Mediated

Abstract Introduction Immune-mediated liver and gastrointestinal diseases are chronic conditions that lack curative treatments. Despite advances in the understanding and treatment of these conditions, they frequently remain refractory to treatment and represent a significant unmet need. Cellular therapies are an emerging option and hold the potential to have a major impact. Data sources A literature review was carried out using Pubmed. Keywords used for search were ‘ATMP’, ‘immune mediated’, ‘autoimmune liver disease’ and ‘immune mediated gastrointestinal conditions’, ‘cell therapy’, ‘MSC’, ‘HSCT’, ‘Regulatory T cells’, ‘GVHD’, ‘Coeliac disease’ ‘IBD’, ‘PSC’, ‘AIH’, ‘PBC’. No new data were generated or analysed in support of this review. Areas of agreement There is substantial evidence from clinical trials to support the use of cell therapies as a treatment for immune-mediated liver and gastrointestinal conditions. Cellular therapy products have the ability to ‘reset’ the dysregulated immune system and this in turn can offer a longer term remission. There are ongoing clinical trials with mesenchymal stromal cells (MSCs) and other cells to evidence their efficacy profile and fill the gaps in current knowledge. Insights gained will inform future trial designs and subsequent therapeutic applications. Areas of controversy There remains some uncertainty around the extrapolation of results from animal studies to clinical trials. Longevity of the therapeutic effects seen after the use of cell therapy needs to be scrutinized further. Heterogeneity in the selection of cells, source, methods of productions and cell administration pose challenges to the interpretation of the data. Growing points MSCs are emerging as a key therapeutic cells in immune-mediated liver and gastrointestinal conditions. Ongoing trials with these cells will provide new insights and a better understanding thus informing future larger scale studies. Areas timely for developing research Larger scale clinical trials to build on the evidence from small studies regarding safety and efficacy of cellular therapy are still needed before cellular therapies can become off the shelf treatments. Alignment of academia and industry to standardize the processes involved in cell selection, manipulation and expansion and subsequent use in clinical trials is an important avenue to explore further.

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Antibody Therapy for the Control of Viral Diseases: An Update

Current Pharmaceutical Biotechnology ◽

10.2174/1389201020666190809112704 ◽

2019 ◽

Vol 20 (13) ◽

pp. 1108-1121 ◽

Cited By ~ 7

Author(s):

Miriam Dibo ◽

Eduardo C. Battocchio ◽

Lucas M. dos Santos Souza ◽

Matheus D. Veloso da Silva ◽

Bruna K. Banin-Hirata ◽

...

Keyword(s):

Clinical Trials ◽

Monoclonal Antibodies ◽

Viral Antigen ◽

Viral Infections ◽

Antibody Therapy ◽

Therapeutic Strategies ◽

Viral Diseases ◽

Specific Antibodies ◽

The Status ◽

Epidemiological Impact

The epidemiological impact of viral diseases, combined with the emergence and reemergence of some viruses, and the difficulties in identifying effective therapies, have encouraged several studies to develop new therapeutic strategies for viral infections. In this context, the use of immunotherapy for the treatment of viral diseases is increasing. One of the strategies of immunotherapy is the use of antibodies, particularly the monoclonal antibodies (mAbs) and multi-specific antibodies, which bind directly to the viral antigen and bring about activation of the immune system. With current advancements in science and technology, several such antibodies are being tested, and some are already approved and are undergoing clinical trials. The present work aims to review the status of mAb development for the treatment of viral diseases.

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COVID-19: Role of Nutrition and Supplementation

Nutrients ◽

10.3390/nu13030976 ◽

2021 ◽

Vol 13 (3) ◽

pp. 976

Author(s):

Fiorenzo Moscatelli ◽

Francesco Sessa ◽

Anna Valenzano ◽

Rita Polito ◽

Vincenzo Monda ◽

...

Keyword(s):

Clinical Trials ◽

Randomized Clinical Trials ◽

Viral Infections ◽

Overweight And Obesity ◽

Shortness Of Breath ◽

Nutritional Interventions ◽

The World ◽

Diet Regimen ◽

Specific Diet

At the end of 2019, a new coronavirus (COVID-19) appeared on the world scene, which mainly affects the respiratory system, causing pneumonia and multi-organ failure, and, although it starts with common symptoms such as shortness of breath and fever, in about 2–3% of cases it leads to death. Unfortunately, to date, no specific treatments have been found for the cure of this virus and, therefore, it is advisable to implement all possible strategies in order to prevent infection. In this context, it is important to better define the role of all behaviors, in particular nutrition, in order to establish whether these can both prevent infection and improve the outcome of the disease in patients with COVID-19. In the literature, it is widely shown that states of malnutrition, overweight, and obesity negatively affect the immune system, leading to viral infections, and several studies have shown that nutritional interventions can act as immunostimulators, helping to prevent viral infections. Even if several measures, such as the assumption of a specific diet regimen, the use of dietary supplements, and other similar interventions, are promising for the prevention, management, and recovery of COVID-19 patients, it is important to highlight that strong data from randomized clinical trials are needed to support any such assumption. Considering this particular scenario, we present a literature review addressing several important aspects related to diet and SARS-CoV-2 infection, in order to highlight the importance of diet and supplementation in prevention and management of, as well as recovery from COVID-19.

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Navigating dilemmas in treatment choice: Our approach of supplemental apheresis prior to enrollment in early phase cellular therapy clinical trials

Transplantation and Cellular Therapy ◽

10.1016/j.jtct.2020.12.004 ◽

2020 ◽

Author(s):

Peter A. Riedell ◽

Justin P. Kline ◽

Jacklyn M. Gideon ◽

Amittha Wickrema ◽

Michael R. Bishop

Keyword(s):

Clinical Trials ◽

Early Phase ◽

Cellular Therapy ◽

Treatment Choice

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Methods of Respiratory Virus Detection: Advances towards Point-of-Care for Early Intervention

Micromachines ◽

10.3390/mi12060697 ◽

2021 ◽

Vol 12 (6) ◽

pp. 697

Author(s):

Siming Lu ◽

Sha Lin ◽

Hongrui Zhang ◽

Liguo Liang ◽

Shien Shen

Keyword(s):

Viral Load ◽

Respiratory Virus ◽

Viral Infections ◽

Point Of Care ◽

Human Life ◽

Low Cost ◽

Virus Detection ◽

Frequent Monitoring ◽

User Friendly ◽

New Strategies

Respiratory viral infections threaten human life and inflict an enormous healthcare burden worldwide. Frequent monitoring of viral antibodies and viral load can effectively help to control the spread of the virus and make timely interventions. However, current methods for detecting viral load require dedicated personnel and are time-consuming. Additionally, COVID-19 detection is generally relied on an automated PCR analyzer, which is highly instrument-dependent and expensive. As such, emerging technologies in the development of respiratory viral load assays for point-of-care (POC) testing are urgently needed for viral screening. Recent advances in loop-mediated isothermal amplification (LAMP), biosensors, nanotechnology-based paper strips and microfluidics offer new strategies to develop a rapid, low-cost, and user-friendly respiratory viral monitoring platform. In this review, we summarized the traditional methods in respiratory virus detection and present the state-of-art technologies in the monitoring of respiratory virus at POC.

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Respiratory viral infections in the elderly

Therapeutic Advances in Respiratory Disease ◽

10.1177/1753466621995050 ◽

2021 ◽

Vol 15 ◽

pp. 175346662199505

Author(s):

Alastair Watson ◽

Tom M. A. Wilkinson

Keyword(s):

Immune System ◽

Viral Infections ◽

Point Of Care ◽

The Elderly ◽

Respiratory Viruses ◽

Morbidity And Mortality ◽

Detection Methods ◽

Respiratory Viral Infections ◽

Tract Infections ◽

Prolonged Hospital

With the global over 60-year-old population predicted to more than double over the next 35 years, caring for this aging population has become a major global healthcare challenge. In 2016 there were over 1 million deaths in >70 year olds due to lower respiratory tract infections; 13–31% of these have been reported to be caused by viruses. Since then, there has been a global COVID-19 pandemic, which has caused over 2.3 million deaths so far; increased age has been shown to be the biggest risk factor for morbidity and mortality. Thus, the burden of respiratory viral infections in the elderly is becoming an increasing unmet clinical need. Particular challenges are faced due to the interplay of a variety of factors including complex multimorbidities, decreased physiological reserve and an aging immune system. Moreover, their atypical presentation of symptoms may lead to delayed necessary care, prescription of additional drugs and prolonged hospital stay. This leads to morbidity and mortality and further nosocomial spread. Clinicians currently have limited access to sensitive detection methods. Furthermore, a lack of effective antiviral treatments means there is little incentive to diagnose and record specific non-COVID-19 viral infections. To meet this unmet clinical need, it is first essential to fully understand the burden of respiratory viruses in the elderly. Doing this through prospective screening research studies for all respiratory viruses will help guide preventative policies and clinical trials for emerging therapeutics. The implementation of multiplex point-of-care diagnostics as a mainstay in all healthcare settings will be essential to understand the burden of respiratory viruses, diagnose patients and monitor outbreaks. The further development of novel targeted vaccinations as well as anti-viral therapeutics and new ways to augment the aging immune system is now also essential. The reviews of this paper are available via the supplemental material section.

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