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Finding specific solutions to overcome uncertainty has led to the evolution of a new clinical trial research environment.
Cellular therapies are a therapeutic option for thousands of people with cancer, genetic, and degenerative diseases. Immense resources are being invested into this therapeutic area as hundreds of academic research groups, biotech companies, and top pharmaceutical companies are working on cell therapies in their development pipelines.
Cellular products can show therapeutic effects based on innate cellular capabilities, although many gene-modified cellular products are being developed to enhance, change, or add new functions to cells. The current most successful technology for cell engineering is chimeric antigen receptor (CAR) expression on the patients’ T lymphocytes. This artificial receptor enhances the capacity of T cells to detect tumor cells, kill them, and activate the whole immune system.
The CAR-T trials show impressive response rates and survival outcomes in relapsed and refractory patients with B-cell malignancies and multiple myeloma, leading to growing new approvals by FDA and the European Medicines Agency each day. Recently, clinical trials showed the benefit of CAR-T in second-line therapy for lymphoma. Soon, multiple myeloma patients at early stages of the disease will be enrolled for trials with CAR-T targeting B-cell maturation antigen.
There has been tremendous improvement in the safety profile of CAR-T therapies because of increased knowledge of early side effects and because of international consensus guidelines for clinical management. Real-world data and well-designed follow-up methodology show similar anti-tumor efficacy and survival outcomes in the long term and a good safety profile without new toxicities in the long term. The clinical and technological progress that represents CAR-T has been made possible by the close link among companies, regulatory agencies, patients, investigators, and sites.
Contract research organizations (CROs) have been the glue to coordinate such strategic partnerships, supporting all the stakeholders and equilibrating their genuine interests. Furthermore, the global resources of CROs have given access to patients and companies across different countries. Adaptability is a critical advantage to working with CROs and contract manufacturing organizations, as is having access to a multidisciplinary expert group of people and resources that provide options when selecting the specific services needed at any point throughout the cell therapy development pathway. Having experienced and expertise in conducting clinical trials and the desire to support state-of-the-art therapies can overcome the main challenges seen today in cell therapy product development.
The primary challenge in cellular therapy is building trust in patients, advocacy groups, and investigators. Biotech companies and enterprises must show solid preclinical data and strong support throughout the trial. The design of a protocol is also crucial. The protocol should fit patients’ reality and have safety, tolerability, and quality of life at the frontline.
Many characteristics of cellular therapy, such as supply chain, apheresis, and infusion, impact the recruitment of patients in clinical trials. The Foundation for the Accreditation of Cellular Therapy, the Joint Accreditation Committee of the International Society of Cellular Therapy, and the European Society for Blood and Marrow Transplantation have created standard quality guidelines for appropriate clinical management of patients involved in cell and gene therapy (CGT) trials or treated with approved therapies. These standards include a guide for donor evaluation, apheresis procedure, and handling of cellular products. The centers accredited by these committees show multidisciplinary experience teams and blood bank resources. The number of CGT trials opened exceeds the number of accredited centers, however. As these institutions are large academic reference centers, they sometimes lack resources due to health necessities, as has happened with the COVID pandemic. On the other hand, many candidates enrolled in CGT trials are treated and then have follow-up appointments in middle-sized community centers with limited experience, resources, and access to CGT trials. The partnership among different health resources will be critical in recruitment and accessibility in clinical trials.
Cellular therapies are also studied outside of oncology and hematology, such as neurology and cardiology, from regenerative medicine with pluripotent cells to the anti-inflammatory effects of mesenchymal stromal cells. The local delivery of the cells is sometimes needed to improve these products’ efficacy, which is challenging for a clinical trial. The product is not only a bag or vial with cells but a part of a complex translational platform. The investigator and site need specific training on delivery tools because this approach can cause related toxicity added to the cellular product itself. This issue should be considered when designing the product maximizing the option for easy delivery and fast learning requirements and thinking in the post-commercialization period.
The quality of the trial design in terms of monitoring the patients and establishing reliable data management is paramount in cellular therapy clinical trials. The lack of deep characterization tools and methods often does not reveal rare but critical safety concerns and can caused regulatory holds to clinical trials.The mandatory long-term follow-up in clinical trials with retroviral-based cell therapy is 15 years. Furthermore, long-term safety and efficacy assessment trials are mandatory after the product´s authorization to protect patients and collect data for further therapy development. The plan to maintain contact with patients and community sites is crucial. Decentralized trial methods preserve the quality of patient follow-up and data collection improving the quality of life of patients.
Cell therapy is an exciting therapeutic area, rapidly evolving with clinical and manufacturing challenges. CAR-Ts’ clinical success has driven companies to develop more effective, safe, and persistent cellular therapies using other cell types, such as natural killer (NK) cells and macrophages, to treat other cancers, including solid tumors. The current use of retroviral vectors to insert genetic information within cells can cause oncogenic genetic changes. The advent of genome editing technologies such as clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 has enabled alternative strategies to improve genetically modified cells’ safety, efficacy, and manufacturing.
Autologous CAR-T implementation has demonstrated to the industry and the world how fast a transforming therapy can become part of the standard of care for the unmet needs of patients. It is time to design the path from small-scale treatment to large-scale allogeneic therapies that can impact a broader patient population. Allogeneic cell sources, “off-the-shelf” therapy, from healthy donors or pluripotent stem cells (PSC), are still in early phases but are open to patients, encouraging investigators, and simplifying operational challenges. The waiting time during the manufacturing process of three to four weeks is a severe limitation of autologous CAR-T cell therapy products that have currently been approved. Cells from induced PSC, in comparison, can be manufactured without limits from a single clonal cell bank, replicated, and expanded, resulting in a consistent and well-characterized product.
Some companies contract external manufacturing services at the beginning of development to have access to fast, adaptable technology until finding positive results in terms of feasibility and safety from early clinical trials. In the late stages of clinical development, the internally manufactured product may make more sense to control production and costs. Other CGT developers only get part of their starting material—cells or viral vectors—from specialized manufacturing laboratories. So, a “make vs. buy” approach can change through time, with the available data from clinical trials and the resources or partnerships that the company can develop through the clinical development path.
Decentralized manufacturing will be another approach to scalability, thanks to technology becoming increasingly portable and increasing experience in this field. There are also projects to develop CAR-Ts in vivo, for example, using viral vectors or nanoparticles, transfecting patients’ lymphocytes directly in the body, and avoiding the need to collect cells and manipulate them in the laboratory.
The manufacturing complexity of cellular therapies is unique, mainly in cell therapies containing viral vectors. Companies need to demonstrate a strong understanding of their product and the target population and have a purposeful plan to analyze therapy performance through clinical studies. The regulatory agencies are very active in developing new guidelines about the quality of cellular products.An expert clinical, chemistry, manufacturing, and controls, and regulatory consultant is likely to benefit patients and cellular products, easing the translation of the product to clinical application with proper safety testing and traceability documentation.
The challenge is to standardize assays on individual products, and companies are often forced to identify the most fit-for-purpose methodology and present it to regulators for approval. The possibility of designing a standard manufacturing approach could accelerate cell therapy manufacturing, ensure homogeneity and quality, and make the regulatory pathway easier.
Society is impressed with what science and human tenacity can achieve. Cell products are a considerable change in the therapeutic paradigm and require a new insight into the research structure and the relationship between stakeholders. The human resources, infrastructure, and investment needed to bring these therapies to market must be coordinated so that the knowledge and capabilities of pharma companies, CROs, investigators, and patients are all brought to bear to address challenges in development. The goal should be to conduct more adaptative clinical trials, resist uncertainty, and create efficient strategies for fast scale-up to make cell therapy accessible as the standard of care. The regulatory agencies also support recommendations on collecting patient-reported outcomes, tailoring operational plans, and manufacturing high-quality products. Expectations for these therapeutics are high, and it is time to make cell therapies a real option for patients.
A new approach is critical for patients with malignant and chronic diseases looking for a curative and safer therapies that can offer a better quality of life.
Izaskun Elorza, MD, is the senior medical director for cell and gene therapy at Parexel.
Vol. 35, No. 7
Pages: 16–17, 24
When referring to this article, please cite it as I. Elorza, “Evolution to a New Clinical Research Environment for Cellular Therapies,” BioPharm International 35 (7) 16–17, 24 (2022).