By Maria Aspioti and Paolo Siciliano, PA Consulting
The world of advanced therapeutics medicinal products (ATMPs) and, in particular, the cell and gene therapies (C>) space has been experiencing outstanding growth over the last few years, with a number of therapies transitioning from clinical research into regular clinical practice. In recent years, new cell types and new technologies have been used to overcome challenges posed by current treatments and by the nature of the targeted diseases, thus enabling us to treat, and in some cases potentially cure, severe disorders. The scientific and R&D efforts led to the discovery of new ways to engineer cells, enabling some of the most outstanding hurdles in complex disease areas such as oncology, cardiovascular, neurologic, and metabolic disorders to be addressed.
While these technology and scientific advancements are all positive and are promising signs of a growing and thriving sector, the other side of the coin shows a highly fragmented market, with very high levels of uncertainty on what type(s) of approaches will be successful in providing patients with a true alternative and which approaches will quickly become obsolete due to technical or commercial limitations. So, how do companies and investors in the CGT space hedge their bets in a fast-evolving and highly uncertain market?
In this article, we review the main cell technologies currently being developed in clinical research for oncology and other therapeutic areas, including examples of studies being conducted, developers, modes of action, and benefits of the different types of cell therapies, and share insight on how to avoid pitfalls and prepare for rapid market and technological directional changes.
An Overview Of CAR-T In The CGT World
Chimeric antigen receptor (CAR) T cells have been dominating the C> field for years, resulting in the approval and commercialization of Kymriah, the first therapy of this kind, in 2017.
Since then, CAR-T therapies have been the most researched type of cell therapy globally and five more products based on this technology have been approved for the treatment of various types of blood cancers worldwide (Yescarta, Abecma, Tecartus, Breyanzi, and Carvykti).
The current commercially available CAR T cell therapies (which are all autologous) have shown efficacy in the treatment of hematologic cancers such as acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), diffuse large B cell lymphoma (DLBCL), and other B cell malignancies. Given the increasing number of clinical studies utilizing CAR T cell therapies and the already successful application in cancer patients, this class of biotherapeutics is likely to dominate the C> market and R&D space for the next few years. This is also shown by the predicted CAGR of 30.6% over the period 2021-2031, which should lead to a total CAR T cell therapy market size of $23.2 billion in the next decade.
At present, there are 750 active CAR-T therapies in development across the globe (375 in clinical phases and 378 in preclinical stage). This represents over a 50% increase from 2019, when approximately 245 CAR-T therapies were in clinical development. Currently, CAR-T therapies still represent 31% of the clinical pipeline in C> (375 out of 1,191 active trials) The vast majority of these are in the early clinical development stage (predominantly Phase 1), with oncology counting for over 95% of the active CAR-T trials.
While still the predominant realm in C>, CAR-T therapies present some limitations.
- First, the use of CAR-T therapies is mostly limited to the field of oncology. While oncology is still the main area of focus for C>, this therapeutic area represents only ~51% of the current activity collectively in the C> space.
- Second, within the oncology field, CAR-T therapies show limitations in the treatment of certain types of cancer, particularly with regard to solid tumors.
- Last, a major limitation of the current CAR-T therapies resides in their autologous nature. While autologous cell therapies present advantages, they also pose considerable challenges, mainly with regard to their manufacturing, supply chain, and scaling issues.
Allogeneic Alternatives To CAR-T Leveraging CAR Technologies
Numerous allogeneic alternatives are being investigated to overcome some of the challenges faced by CAR-T therapies in oncology. In the field of adoptive cell immunotherapy for oncology, we are seeing an increasing exploitation of alternative cell sources with a high therapeutic potential that aim to evolve toward universal allogeneic alternatives to classic CAR-T therapies. Some examples include (further investigative product examples are shown in Table 1 [below]):
- CAR-γδ cells: These are a type of T cells that do not rely on the expression of the major histocompatibility complex (MHC) patient-specific antigens, thus reducing rejection effects and making these cell types particularly valuable for an allogeneic approach. These therapies are currently being investigated in Phase 1 clinical trials by various companies as shown in Table 1 below. Big Pharma is also starting to show an interest in this space, as shown by the recent announcement of Takeda’s acquisition of GammaDelta Therapeutics.
- CAR-NK cells: Primary NK cells engineered with CAR (CAR-NK cells) are being investigated at the clinical level in relation to their cytotoxic and cytokine-producing properties, which provides them with the ability to kill malignant and virally transformed cells. Currently, there are limited clinical studies using NK primary cells, including those conducted by the M.D. Anderson Cancer Center, the Third Affiliated Hospital of Guangzhou Medical, and PersonGen BioTherapeutics.
- CAR-M cells: Adenovirus-transduced CAR macrophage (CAR-M) therapies are under investigation thanks to their high therapeutic potential against solid tumors. The field of CAR-M therapeutics is still relatively unexplored and the leading company in this sector is Carisma Therapeutics, which is currently recruiting for a first-in-human open label Phase 1 study.
Beyond CAR Technologies
In addition to CAR-based technologies, the market is also seeing an increasing number of preclinical and clinical studies focusing on CAR-free cell therapy alternatives to cure cancer. The list of cell types is continuously growing, but we see five main categories that are showing promising results (investigative product examples are shown in Table 1):
Induced Pluripotent Stem Cells (iPSCs): iPSCs are a type of pluripotent stem cells that are generated ex vivo by treating nearly any human fully differentiated (somatic) cell (e.g., keratinocytes, fibroblasts, etc.) with the cocktail of small molecules described by the 2012 Nobel Laureate Shynia Yamanaka. iPSCs display several advantages over primary cells, including their virtually infinite proliferation capacity and amenability for genetic manipulation. Several T and NK cells derived from iPSC lines (iT and iNK, respectively) are currently under investigation, primarily for B cell lymphoma and advanced solid tumors. An example is represented by Shoreline Biosciences, which is developing a pipeline of iPSC-derived natural killer cell (iNK) and macrophage (iMACs) cellular immunotherapy candidates for the treatment of different types of cancers.
Mesenchymal Stem Cells (MSCs): MSCs are multipotent stem cells capable of self-renewal that are commonly found in the bone marrow but also in the umbilical cord, adipose tissue, and peripheral blood. In clinical trials, MSCs are used in cancer treatment either via direct transplantation (often used to support chemotherapy or radiotherapy), as genetically modified cell therapy, or as a carrier of anti-tumor agents like interferon β, interleukins, bone morphogenic protein 4, and many others. At the end of 2021, 31 clinical trials concerning MSC-based therapies for cancer were registered on ClinicalTrials.gov. The majority of these studies focus on the direct infusion or transplantation of MSCs to treat cancer, while the remaining trials use engineered MSCs as vehicles of therapeutic agents such as cytokines or oncolytic viruses. MSCs are also being investigated for a wide range of non-oncology applications, including cardiovascular conditions as well as neurodegenerative disorders such as Alzheimer’s, multiple sclerosis, and amyotrophic lateral sclerosis. Brainstorm Cell Therapeutics is currently in the process of finalizing the regulatory filing for NurOwn (autologous MSC-NTF cells produced from autologous, bone marrow-derived mesenchymal stem cells) for the treatment of ALS.
Dendritic Cells: Dendritic cells (DCs) are antigen-presenting cells (APCs) that represent another valuable alternative to CAR-T therapies. In clinical settings, DCs find applications as vaccines owing to their ability to prepare the adaptive and innate immune system against specific tumors via presenting cancer-specific antigens. To date, the only FDA-approved DC-based vaccine is Provenge (sipuleucel-T, Dendreon), which targets patients with metastatic castration-resistant prostate cancer. Another DC-based medicinal product named Apceden, developed by Apac Biotech, was approved in India by the Central Drugs Standard Control organization in 2017. Currently, there are five Phase 1, 10 Phase 2, and five Phase 3 clinical trials ongoing that demonstrate the excitement around this cell therapy type.
Tumor Infiltrating Lymphocytes (TILs): TILs are immune cells that can infiltrate tumor masses and currently present an alternative therapeutic solution that has mainly been researched for the treatment of advanced solid tumor indications. Currently, TIL cell therapies are being explored at the clinical setting, predominantly for the treatment of melanoma with a number of other cancer indications also being under investigation. Two key players in this space are Achilles Therapeutics and Iovance Biotherapeutics, both of which are developing TIL-based therapies (Phase 2 trials) for the treatment of different types of cancer.
Regulatory T Cells (Tregs): Similar to TILs, biotherapeutics based on Tregs are also being investigated as a form of cell therapy for multiple indications. Treg-cell therapies are currently in early infancy with multiple opportunities being explored across a spectrum of indications such as type 1 diabetes, rheumatoid arthritis, multiple sclerosis, and others. Quell Therapeutics, GentiBio, and Sonoma (among others) are developing Treg-based therapies to address a number of autoimmune and alloimmune conditions.
The Role Of C> Beyond Oncology
Oncology is the field where the majority of C>s are commercially available currently. As described above, a number of biotherapeutics have been approved by the FDA and other regulatory agencies, including CAR T cell therapies as well as other immunotherapies such as talimogene laherparepvec (Imlygicby Amgen Inc.) and sipuleucel-T (Provenge by Dendreon Corp.).
While oncology has been driving R&D in C> since the beginning of the new wave of therapeutic innovation, the interest of academic groups, biotechnology firms, and large pharmaceutical companies in different disease areas for ATMPs is rapidly expanding. This is particularly the case for in vivo gene therapies, where we have recently seen the approval of products for the treatment of spinal muscular atrophy (Zolgensma by Novartis) and mutation-specific retinal dystrophy (Luxturna by Spark Therapeutics), as well as an increasing number of trials across a large spectrum of non-oncology applications, including several rare genetic disorders.
For cell therapies, in the last few years, a number of therapies have been launched on the market for non-oncology applications. These include Rethymic by Enzyvant Therapeutics (congenital athymia), Stratagraft (deep partial-thickness burns), Gintuit (epithelial damage), and Maci (cartilage damage). Several non-oncological biotherapeutics received approval for use in unrelated donor hematopoietic progenitor cell transplantation (Allocord, Clevecord, Ducord, Hemacord).
As indicated in our Cell & Gene Therapy 2040 Report, which looks at the future of the C> industry, the clinical development of C>s is predominantly aimed at cardiovascular, metabolic, neurological, inflammatory/autoimmune, and musculoskeletal disorders, with a particular focus on rare genetic conditions. Currently, oncology-unrelated Phase 3 trials focus on more than 20 different indications with over 25 lead companies involved.
Among the indications with the highest number of clinical studies, it is worth noting hemophilia A, for which Pfizer, Roche, and BioMarin Pharmaceutical developed similar C>s targeting coagulation factor VIII. BioMarin Pharmaceutical retains a slight commercial advantage as their asset also targets a different coagulation factor and is expected to reach approval by the end of 2022 both in Europe and the U.S. (approvals are expected for Pfizer in 2023 and Roche in 2024, both in the U.S. only).
Other indications that are seeing a surge in late-phase clinical trials include Duchenne muscular dystrophy and Crohn’s disease. For the former indication, Pfizer and Sarepta Therapeutics are currently recruiting patients for the virus-mediated administration of the gene encoding for microdystrophin to help rescue the muscle architecture. In Crohn’s disease, Takeda Pharmaceutical and Mesoblast Ltd. are the two front-runners. Notably, both are developing MSC-based therapies for this indication, with Takeda having already shown positive results (ClinicalTrials.gov Identifier: NCT03706456) and currently recruiting for two additional Phase 3 studies.
How To Hedge Your Bets In A Fast-evolving And Highly Uncertain CGT Market
The field of C> is fast-growing and booming with novel technologies, new companies, and growing investment, with more and more positive results in treating, and even curing, life-threatening diseases. But how can organizations hedge their bets in such a fast-evolving and highly uncertain market?
Here are some tips on how different players in the CGT space can avoid pitfalls and better position themselves to succeed in this space:
- Constant monitoring of market dynamics and new developments
Being aware of the C> landscape and how it is changing becomes paramount for developers. A clear view of the market and its evolution will enable developers to:
- keep up with the fast pace of innovation in this space,
- be competitive and adapt to the market needs,
- make the right considerations for portfolio management and strategy, and
- prepare in advance the engagement with payers and regulatory bodies.
In addition, understanding the nature of the new biotherapeutics developed and how they are delivered is vital for C> manufacturers, healthcare professionals, and patients to enable a facilitated clinical application while reducing the overall costs of these transformative therapies.
- Define strategies to reduce time to market
Time to market is key to avoid a technology becoming obsolete in a fast-evolving market. The complexity of developing and launching new products in the C> market (these being therapies or technologies involved in their manufacturing) requires a level of investment, competencies, and capabilities that rarely are available in a single organization. Hence, innovators in this space should invest time and resources in identifying the right partners to support their product development, access the right technologies to manufacture their therapies, embrace digital tools early on to support the launch of their products, as well as work with experts to speed up the transition from R&D to clinical and commercial scale.
- Build diversity in the portfolio
Focus is usually key in bringing new products and services to market in highly innovative sectors. However, to mitigate risk in a highly uncertain market, established pharma and biotech companies developing biotherapeutics should look at diversifying their portfolio through the development and/or acquisition of multiple C> platforms across different therapeutic areas. Similarly, equipment manufacturers should also look at how their current products and innovation portfolios can support the needs of different product lines, as certain technologies might quickly become obsolete if a specific set of therapies becomes predominant in the market.
Overall, the advent of C> therapies has the potential to revolutionize healthcare by providing therapies for rare, complex, and life-threatening diseases. Successful positioning of players in this flourishing market will require careful consideration of the evolving market dynamics coupled with successful go-to-market and risk mitigation strategies.
About The Authors:
Maria Aspioti is a healthcare and life sciences expert at PA Consulting. She has several years of professional experience in product innovation for medical devices and a diverse academic background in life sciences. She has worked extensively with early-stage R&D teams as a biology specialist on technology landscaping, technology evaluation, and scientific diligence. She is the co-inventor of several patents in the field of advanced wound therapies. In addition, she has helped establish and managed preclinical research programs for concept evaluation in various areas, including wound care and regenerative medicine while working with clinical groups and commercial teams to support clinical evidence and business case generation. Aspioti holds a BSc (Hons) in molecular & cellular biology from the University of Glasgow and a MSc in regenerative medicine from the University of Bath.
Paolo Siciliano is an associate partner and life sciences expert at PA Consulting, and he leads PA’s work in C> globally. He has several years of experience in supporting major pharma, biotech, and medtech companies to identify, develop, and leverage new technologies to solve business needs, as well as improve their innovation and product development processes. His main areas of expertise range from technology and commercial strategy to technology development, across a number of therapeutic areas. He obtained a Ph.D. in molecular biology and worked as a senior research scientist in biotech companies in the U.K.