Second Generation Cell and Gene-Based Therapies

Biological Advances, Clinical Outcomes and Strategies for Capitalisation

Alain Vertes, Nathan J. Dowden, Devyn Smith, Nasib Qureshi

• Publisher: Academic Press
• Year: 2020
• Print ISBN: 9780128120347
• eBook ISBN: 9780128120330
• Topic: Ciencias biológicas
• Subtopic: Teoría, práctica y referencia médicas

Second Generation Cell and Gene-Based Therapies: Biological Advances, Clinical Outcomes, and Strategies for Capitalisation serves as the only volume to the market to bridge basic science, clinical therapy, technology development, and business in the field of cellular therapy/cytotherapy. After more than two decades of painstaking fundamental research, the concept of therapeutic cells (stem cells, genes, etc.), beyond the concept of vaccines, is reaching clinical trial, with mounting confidence in the safety and efficacy of these products. Nonetheless, numerous incremental technical advances remain to be achieved. Thus, this volume highlights the possible R&D paths, which will ultimately facilitate clinical delivery of cutting edge curative products.The next waves of innovation are reviewed in depth for hematopoietic stem cells, mesenchymal stem cells, tissue engineering, CAR-T cells, and cells of the immune system, as well as for enabling technologies such as gene and genome editing. Additionally, deep dives in product fundamentals, history of science, pathobiology of diseases, scientific and technological bases, and financing and technology adoption constraints are taken to unravel what will shape the cytotherapy industry to the horizon 2025 and beyond. The outcome is not simply a scientific book, but a global perspective on the nascent field combining science, business, and strategic fundamentals.- Helps readers learn about the most current trends in cell-based therapy, their overall effectiveness from a clinical prospective, and how the industry is moving therapies forward for capitalization- "Perspectives" section at the end of each chapter summarizes key learnings, hypotheses, and objectives highlighted and combines scientific and business insights- Edited and authored by scientists representing both basic and clinical research and industry, presenting a complete story of the current state and future promise of cellular therapies

Part 1

Science

Outline

Chapter 1. Innovation S-Curves in Living Drugs Development and Their Commercialisation

Chapter 2. Development and Deployment of Gene Therapies: An ADA-SCID Case Study

Chapter 3. Therapeutic Potential of Cells of the Immune System

Chapter 4. T-Cell Engineering and the Rise of CAR-T Cell Therapies

Chapter 5. Harnessing Natural Killer Cells’ Killing Function in Cancer

Chapter 6. Pluripotent Stem Cell–Derived Islet Replacement Therapy for Diabetes

Chapter 7. Harnessing in Silico Technologies to Develop and Augment Second-Generation Cell-Based Therapies

Chapter 8. Second Generation Genome Editing Technologies in Drug Discovery

Chapter 9. The Next Wave: Tissue Replacement and Organ Replacement

Chapter 10. Combining Stem Cells and Materials for Nerve Tissue Regeneration

Chapter 1

Innovation S-Curves in Living Drugs Development and Their Commercialisation

Alain A. Vertès Sloan Fellow, London Business School, London, United Kingdom

Abstract

With the approval in recent years of several first-in-class gene- and cell-based therapies by the European or American regulatory agencies, including Kymriah, Yescarta, Luxturna, Glybera and Strimvelis, as well as the approval of products under the Sakigake designation by the Japanese regulatory agency, the field of regenerative medicine has at long last moved from the realm of R&D to the reality of clinical practice in the major pharmaceutical market jurisdictions as we are approaching the end of the second decade of the 21st century. The beginning of this journey in the arena of market access has already proven to be a rocky one, from big pharma U-turns to product withdrawals on commercial or strategic grounds. History teaches us that such beginnings for the development and commercialisation of any game-changing innovation are to be expected, a phenomenon that is perhaps best exemplified in the pharmaceutical industry by the slow emergence and adoption of the technology of monoclonal antibodies in the 1990–2000 decade. The first two defining moments of the biotechnology economy occurred with the creation of Cetus in 1971 and Genentech in 1976 following the discovery of restriction enzymes and ligases, and the subsequent development of genetic engineering techniques. A second transformational milestone was reached in 1997 with the approval of MabThera, further reinforced in 2005 with the global market of this life-saving anticancer antibody drug reaching a critical blockbuster commercial milestone with a global market in excess of $4 billion. One of the critical success factors for disruptive innovation products to be truly successful is to unambiguously provide game-changing benefits that conventional products cannot deliver. The S-curve shaped process at play in the development of regenerative medicine products that deliver disease-modifying or curative benefits is detailed here, and its implications in the future development of major innovation chunks is discussed through a predictive practical analysis of the innovation pattern of CAR-T cells.

Keywords

CAR-T cells; Cell-based therapeutics; Endogenous stem cells; Gene-based therapeutics; Genetic engineering; HSCs; MSCs; Pluripotent stem cells; Radical innovation; Regenerative medicine; S-curve; Technology adoption

Introduction

Innovation proceeds in S-curves (Vertès and Dowden, 2015). S-curves can be defined as polynomials with an initial period of slow growth, starting, for example (if measuring innovation over time), when a breakthrough discovery is made until an inflection point around which dramatic improvements are made, thanks to accelerating returns, after which follows a period of diminishing returns in R&D efforts that occurs until an upper asymptote is reached, which signals that the technology maturity is itself reached. Exponential mathematical entities are typically extremely difficult to appreciate intuitively (Kurzweil, 2010); hence, due to this cognition bias, decision-making on exponential phenomena is extremely difficult. In mathematics and physics, the logarithmic scale that linearises exponential phenomena is a very useful tool to circumvent this cognitive limitation. Intuitively understanding the impact of exponential phenomena on R&D advances, certainly best exemplified by Moore’s law for semiconductor electronics (Moore, 1965), remains challenging in conditions of decision-making on a new radical innovation, especially when the said radical innovation may require sustained investments of significant sizes under conditions of high uncertainty, a task further complexified by the need for the decision-maker to understand the corresponding opportunity costs of the new investment. Formal frameworks have been proposed to circumvent these cognitive limitations in business decision-making. These frameworks rely on an evaluation flowchart that comprises steps to (1) determine a technical domain of interest, (2) perform competition analyses to identify potential target technologies, (3) define the appropriate metrics for performance, (4) estimate or measure future technical improvement curves, (5) integrate a sensitivity analyses on the time variable and (6) iterate to further refine the assessment (Benson and Magee, 2018). Furthermore, other methods implementing, for example, a correlated geometric random walk with drift have been proposed to predict the pace of technological progress (Farmer and Lafond, 2016).

S-Curve Patterns in Industrial Product Emergence

S-curve patterns are well-documented in historic accounts of the emergence of technology platform-to-products companies in virtually all industries, including biotechnology companies. In the arena of monoclonal antibodies, these companies comprise Genentech (South San Francisco, CA, USA) (now a Hoffman–La Roche, Basel, Switzerland, group company), Amgen (Thousand Oaks, CA, USA), Centocor Biotech Inc. (Philadelphia, PA, USA) (now Janssen Biotech Inc.), a Johnson & Johnson (New Brunswick, NJ, USA, group company) or Biogen (Cambridge, MA, USA), to name only a few; the main technology S-curves are progressing from murine antibodies (1980s) to chimeric antibodies (late 1980s), fully human antibodies (2000s), antibody fragments (late 1990s–2000s) and further on to multivalent antibodies, immunotoxins and synthetic antibodies (2010s and beyond) (Vertès and Dowden, 2015). Integrated, these discrete S-curves, or ‘innovation chunks’, constitute the 3-decade long aggregate innovation S-curve that took place in the field of monoclonal antibodies. The tipping point here was the capacity to ‘humanise’ the antibodies to overcome antiidiotypic foreign body HAMA (human antimurine antibody) responses. Despite the technology of cell therapeutics still being in its infancy (not discussed here are conventional vaccines), several elemental technology S-curves that will mark the technological revolution of cell-based therapies can already be identified based on technological compa...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• List of Contributors
• Foreword
• Preface
• Part 1. Science
• Part 2. Translation
• Part 3. The Next Frontier
• Part 4. Perspectives
• Index