During the last decade the field of cancer immunotherapy has witnessed impressive progress. Highly effective immunotherapies such as immune checkpoint inhibition, and T-cell engaging therapies like bispecific T-cell engaging (BiTE) single-chain antibody constructs and chimeric antigen receptor (CAR) T cells have shown remarkable efficacy in clinical trials and some of these agents have already received regulatory approval. However, along with growing experience in the clinical application of these potent immunotherapeutic agents comes the increasing awareness of their inherent and potentially fatal adverse effects, most notably the cytokine release syndrome (CRS). This review provides a comprehensive overview of the mechanisms underlying CRS pathophysiology, risk factors, clinical presentation, differential diagnoses, and prognostic factors. In addition, based on the current evidence we give practical guidance to the management of the cytokine release syndrome.

https://jitc.bmj.com/content/jitc/6/1/56.full.pdf

Cytokine release syndrome

Background - The presence of tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment is associated with an improved prognosis and a better response to therapy in different types of cancer. In this systematic review and meta-analysis, we investigated the prognostic value of T cells in head and neck squamous cell carcinoma (HNSCC). Methods - In a systematic review, Pubmed and Embase were searched for publications that investigated the prognostic value of T cells in HNSCC. A meta-analysis was performed including all studies assessing the association between CD3+, CD4+, CD8+, and FoxP3+ TILs and overall survival (OS), disease-free survival (DFS), or locoregional control (LRC). Results - A pooled analysis indicated a favorable, prognostic role for CD3+ TILs (HR 0.64 (95%CI 0.47-0.85) for OS, HR 0.63 (95%CI 0.49-0.82) for DFS) and CD8+ TILs (HR 0.67 (95%CI 0.58-0.79) for OS, HR 0.50 (95%CI 0.37-0.68) for DFS, and HR 0.82 (95%CI 0.70-0.96) for LRC) in the clinical outcome of HNSCC. FoxP3+ TILs were also associated with better OS (HR 0.80 (95%CI 0.70-0.92)). Conclusion - This systematic review and meta-analysis confirmed the favorable, prognostic role of CD3+ and CD8+ T cell infiltration in HNSCC patients and found an association between FoxP3+ TILs and improved overall survival. Future studies using homogeneous patient cohorts with regard to tumor subsite, stage and treatment are necessary to provide more insight in the predictive value of TILs in HNSCC.

https://www.tandfonline.com/doi/pdf/10.1080/2162402X.2017.1356148

The prognostic role of tumor infiltrating T-lymphocytes in squamous cell carcinoma of the head and neck: A systematic review and meta-analysis

The approved gene therapy drugs worldwide: from 1998 to 2019

Systemic chemotherapy remains the backbone of many cancer treatments. Due to its untargeted nature and the severe side effects it can cause, numerous nanomedicine approaches have been developed to overcome these issues. However, targeted delivery of therapeutics remains challenging. Engineering microrobots is increasingly receiving attention in this regard. Their functionalities, particularly their motility, allow microrobots to penetrate tissues and reach cancers more efficiently. Here, we highlight how different microrobots, ranging from tailor-made motile bacteria and tiny bubble-propelled microengines to hybrid spermbots, can be engineered to integrate sophisticated features optimised for precision-targeting of a wide range of cancers. Towards this, we highlight the importance of integrating clinicians, the public and cancer patients early on in the development of these novel technologies.

/pdf/engineering-microrobots-for-targeted-cancer-therapies-from-a-imodv8s6jv.pdf

Engineering microrobots for targeted cancer therapies from a medical perspective

Cellular senescence is an essentially irreversible arrest of cell proliferation coupled to a complex senescence-associated secretory phenotype (SASP). The senescence arrest prevents the development of cancer, and the SASP can promote tissue repair. Recent data suggest that the prolonged presence of senescent cells, and especially the SASP, could be deleterious, and their beneficial effects early in life can become maladaptive such that they drive aging phenotypes and pathologies late in life. It is therefore important to develop strategies to eliminate senescent cells. There are currently under development or approved several immune cell-based therapies for cancer, which could be redesigned to target senescent cells. This review focuses on this possible use of immune cells and discusses how current cell-based therapies could be used for senescent cell removal.

/pdf/role-of-immune-cells-in-the-removal-of-deleterious-senescent-3gw54pf5yx.pdf

Role of immune cells in the removal of deleterious senescent cells.

Tumours use many strategies to evade the host immune response, including downregulation or weak immunogenicity of target antigens and creation of an immune-suppressive tumour environment. T cells play a key role in cell-mediated immunity and, recently, strategies to genetically modify T cells either through altering the specificity of the T cell receptor (TCR) or through introducing antibody-like recognition in chimeric antigen receptors (CARs) have made substantial advances. The potential of these approaches has been demonstrated in particular by the successful use of genetically modified T cells to treat B cell haematological malignancies in clinical trials. This clinical success is reflected in the growing number of strategic partnerships in this area that have attracted a high level of investment and involve large pharmaceutical organisations. Although our understanding of the factors that influence the safety and efficacy of these therapies has increased, challenges for bringing genetically modified T-cell immunotherapy to many patients with different tumour types remain. These challenges range from the selection of antigen targets and dealing with regulatory and safety issues to successfully navigating the routes to commercial development. However, the encouraging clinical data, the progress in the scientific understanding of tumour immunology and the improvements in the manufacture of cell products are all advancing the clinical translation of these important cellular immunotherapies.

/pdf/genetically-modified-t-cells-in-cancer-therapy-opportunities-mzqqglkuxs.pdf

Genetically modified T cells in cancer therapy: opportunities and challenges.

Cell therapies offer the promise of treating and altering the course of diseases which cannot be addressed adequately by existing pharmaceuticals. Cell therapies are a diverse group across cell types and therapeutic indications and have been an active area of research for many years but are now strongly emerging through translation and towards successful commercial development and patient access. In this article, we present a description of a classification of cell therapies on the basis of their underlying technologies rather than the more commonly used classification by cell type because the regulatory path and manufacturing solutions are often similar within a technology area due to the nature of the methods used. We analyse the progress of new cell therapies towards clinical translation, examine how they are addressing the clinical, regulatory, manufacturing and reimbursement requirements, describe some of the remaining challenges and provide perspectives on how the field may progress for the future.

/pdf/cell-based-therapy-technology-classifications-and-lb7yrvwitf.pdf

Cell-based therapy technology classifications and translational challenges.

Regenerative medicine is a rapidly evolving field that faces novel scientific and regulatory challenges. In September 2013, the International Workshop on Regulatory Pathways for Cell Therapies was convened to discuss the nature of these challenges and potential solutions and to highlight opportunities for potential convergence between different regulatory bodies that might assist the field's development. The workshop discussions generated potentially actionable steps in five main areas that could mitigate cell therapy development pathway risk and accelerate moving promising therapies to patients. These included the need for convergence of regulatory guidelines on donor eligibility and suitability of lines for use in clinical trials and subsequent commercialization for cell therapies to move forward on a global basis; the need to challenge and encourage investigators in the regenerative medicine field to share information and provide examples of comparability studies related to master cell banks; the need for convergence of guidelines across regulatory jurisdictions on requirements for tumorigenicity studies, based on particular cell types and on biodistribution studies; the need to increase transparency in sharing clinical trial information more broadly and disseminating results more rapidly; and the need to establish a forum for sharing the experiences of various approaches being developed to expedite regulatory approvals and access for patients to innovative cell and regenerative therapies in the different regulatory jurisdictions and to assess their potential strengths and weaknesses.

https://stemcellsjournals.onlinelibrary.wiley.com/doi/pdf/10.5966/sctm.2014-0122

Proceedings: International Regulatory Considerations on Development Pathways for Cell Therapies

Cell Therapy Clinical Trial and Preclinical Research databases have been established by the Cell Therapy Catapult to document current and future cell therapy clinical trials in the UK. We identified 41 ongoing trials in April 2014, an increase of seven trials from April 2013. In addition, we identified 45 late-stage preclinical research projects. The majority of the clinical trials are early phase, primarily led by academic groups. The leading therapeutic areas are cancer, cardiology and neurology. The trends in the UK are also seen globally. As the field matures, more later phase and commercial studies will emerge and the challenges will likely evolve into how to manufacture sufficient cell quantities, manage complex logistics for multi-center trials and control cost.

Landscape of current and emerging cell therapy clinical trials in the UK: current status, comparison to global trends and future perspectives.

Mesenchymal stromal cell (MSC)-based therapies have potential in a range of disease indications, and both MSC therapies themselves as well as the applicable global regulatory frameworks governing their use are evolving. MSC therapies are making the transition from experimental and unlicensed therapies for use in named patients to medicinal products that must be granted a marketing authorization to be placed on the global pharmaceutical markets for the benefit of larger patient populations. Medicinal product legislation requires the demonstration of quality, safety, and efficacy through defined strategies around manufacturing, nonclinical studies, and clinical trials. This chapter discusses in particular the medicinal product legislation applicable to MSC-based products being developed for commercialization and provides an overview of key considerations in the different regulatory jurisdictions globally.

Natalie Mount

Papers

Genetically modified T cells in cancer therapy: opportunities and challenges.

Cell-based therapy technology classifications and translational challenges.

Proceedings: International Regulatory Considerations on Development Pathways for Cell Therapies

Landscape of current and emerging cell therapy clinical trials in the UK: current status, comparison to global trends and future perspectives.

Global Regulatory Perspective for MSCs