2022 Cell Gene Therapy Track: How to Accelerate Technological Iteration

Say goodbye to the ugly cow and welcome the Yin tiger
.

Many recent articles have predicted the development direction of cell gene therapy in the future.

01 Universal CAR-NK

01 Universal CAR-NK

This track feels like it will be rolled in soon after it comes out.
In addition to a large number of Nasdaq-listed companies in the United States such as Fate, Cellectis, Allogene, etc.
, which are already eyeing, domestic companies such as Xing Yiang, BeiGene, Jiakesi, etc.
have begun to deploy and developing similar products
.

The cell sources and technology platforms used are also varied

The main problems that need to be solved in the future development of such products: stable cell sources, currently the main sources are PBMCs of healthy adults, umbilical cord blood CBMCs and iPS
.

The first is the potential risk of cell mutation and the source stability that may require multiple apheresis; the limited number of cells in the middle source poses a great challenge to the amplification technology; whether the last iPS source is ethical, and whether the library construction process is Compliance with GMP standards, whether the differentiation technology is reliable,

02Combination therapy

02Combination therapy

Many different combinations of combination therapy have been advanced to the clinical trial stage.
Currently, the most used combinations are cell therapy (CAR-T) and oncolytic virus, cell therapy and targeted drugs, different cell therapies (such as CAR-T and HSCT)
etc.

The first one is currently the most popular, and both domestic and foreign companies are cooperating in joint development, especially in the field of solid tumors; the last one has already carried out a series of clinical trials in ALL and other diseases that have a high response rate to cell therapy but are prone to relapse.

The first challenge for combination therapy in the future is to clarify the meaning of the combination, that is, the biology or MOA of the combination therapy must be clear, so that the combination can produce clinical efficacy, rather than combination for the sake of combination
.

Second, further exploration is needed in terms of the order of administration, dose and patient population selection, and the best combined treatment method and process have been found

03In vivo production of CAR-T

03In vivo production of CAR-T

After the emergence of this technology, the industry generally feels that it is very fansy and one of the revolutionary technologies, and it feels a bit too good to be ture
.

The technical advantages are very prominent, which not only solves the problem of cell expansion and reduces the cost of in vitro expansion, but also provides an off-the-shelf solution

However, the challenges are not small, mainly how to directionally identify T cells to stably implant transcription factors into cells, and at the same time consider the safety of cell expansion in vivo and the risk of mutation
.

In the United States, companies such as Sana and Mustangbio are planning to conduct clinical trials, while domestic companies such as Reindeer are promoting the clinical development of related products through cooperation with Sana

The speed of technological update and iteration of cell gene therapy is getting faster and faster, and it is more and more difficult to keep up with or even surpass.
With the encouragement and support of the drug regulatory reform policy in 2017, China's cell gene therapy has shown a thriving development trend.
Especially in 2021, from the perspective of IND application, differentiated development ideas and products have emerged, and innovation and cooperation have increasingly become the consensus and direction of efforts of the entire industry
.

Finally, everyone is welcome to join the Tongxieyi Cell Gene Therapy Club to promote the sustainable and healthy development of China's cell gene therapy industry, so that the revolutionary treatment technology can benefit the majority of patients as soon as possible
.

Dr.
Zhang Yu, Secretary General of Tongxieyi Cell Gene Therapy Club

▼

Attachment: ZS Outlook: 3 Predictions for the Future of Cell and Gene Therapy

Attachment: ZS Outlook: 3 Predictions for the Future of Cell and Gene Therapy

Ben Hohn

Ben Hohn

The field of cell and gene therapy (C>s) has seen a nascent renaissance, with first-generation commercial products such as Kymriah, Yescarta and Luxturna setting the stage for an upcoming wave of potentially transformative cell-based gene therapies designed to address diverse Disease areas
.

Some potential opportunities will accompany this change, and we discuss three predictions below

Allogeneic natural killer (NK) cells have the potential to replace current tumor cell therapies if ultimately proven to be durable
.

Allogeneic natural killer (NK) cells have the potential to replace current tumor cell therapies if ultimately proven to be durable
.

Although in early development, allogeneic NK has been shown to be a novel therapeutic modality in oncology
.
The question of the persistence of the effects of allogeneic therapy remains an unknown
.
Fate Therapeutics' recent Phase 1 data for FT516 showed relatively faster relapse in patients compared to the already approved autologous CAR-T
.

However, other manufacturers, such as Allogene's allogeneic CAR-T therapy ALLO-501A, are exploring new approaches to lymphatic clearance to improve the persistence of allogeneic cells
.
Nonetheless, allogeneic NK exhibits a stronger value proposition relative to its T cells, as it has so far had similar effects with the added advantage of a significantly safer side effect profile in terms of safety
.

Specifically, to date, allogeneic NK cells have little risk of developing graft-versus-host disease (GvHD), cytotoxic factor release syndrome (CRS), and neurotoxicity (NT) (Figure 1)
.
Additionally, the ability to utilize an allogeneic cell source gives way to operational advantages, as off-the-shelf products offer improved turnaround time (TAT), scalability, and potentially cost-reducing advantages
.

Currently, NKs are being developed with traditional CAR-Ts in various overlapping hematological oncology indications, and the question is to what extent they will replace current cell therapies
.

Figure 1: Efficacy and safety data for autologous versus allogeneic cell therapies in development
.
The sample n size for each point is set to N:x[1]
.

In vivo gene therapy (compared to traditional cell therapy) may be the more prominent cellular gene technology in solid tumors
.

In vivo gene therapy (compared to traditional cell therapy) may be the more prominent cellular gene technology in solid tumors
.

An increasing number of in vivo gene therapies are progressing into clinical trials in solid tumors (Figure 2)
.
Gene therapy promises to deepen solid tumor therapy through several unique mechanisms of action (MOAs) through which in vivo gene therapy can target cancer, activate tumor cell apoptosis, recruit immune cells, and directly act on oncolysis
.

Although gene therapy in many solid tumors works in a more pertinent manner, often by recruiting other tumor-killing cells, cell-based therapies face difficulties in overcoming the immunosuppressive tumor microenvironment (TME) of solid cancers
.

In vivo gene therapy is more suitable for managing TME and is more advantageous as an "off the shelf" option than autologous cell therapy
.
Although still in the early stages of development, the broad pipeline and possible mechanisms of action make in vivo gene therapy a potentially attractive technological approach in the future treatment of solid tumors
.

Figure 2: Solid tumor technologies for Ph II+ C> and the number of unique assets by treatment type [1]
.

While the first waves of cell and gene therapy were single drugs, the future trend is likely to be combination therapy
.

While the first waves of cell and gene therapy were single drugs, the future trend is likely to be combination therapy
.

Manufacturers are beginning to consider combinatorial approaches, leveraging the strengths of various technologies, with the promise of revolutionary therapeutic outcomes in much-needed disease areas
.
Checkpoint inhibitor and CAR-T combinations are already in development, while many other cell and gene therapy approaches are in progress, which can also be functionally complementary (Figure 3)
.

However, patient benefit and risk need to be weighed, as combining these potent therapies may exacerbate potentially even fatal adverse events (AEs) such as cytotoxic release syndrome (CRS) and neurotoxicity (NT)
.
The search for novel cell-gene therapy combinations will continue to grow, with early identification of patient subgroups more likely to cause severe AE responses or at higher risk to better inform treatment decisions
.

Figure 3: Overview of cell gene therapy trials to date comparing monotherapy versus combination therapy, nearly 30% of cell and gene therapies are being studied in combination with various therapies, including immunorheumatoid therapy, chemotherapy, targeted therapy, radiation therapy, in vivo therapy gene therapy and other cell therapies[1]
.

The cell and gene therapy (C>) landscape is rapidly opening

The cell and gene therapy (C>) landscape is rapidly opening

In the short period from March 2021 to November 2021, the cell gene therapy products entering/exiting clinical trials experienced large fluctuations
.
Seventy-three cell (61) and gene (12) therapy trials have been suspended or terminated, while 68 new cell (62) and gene (6) trials have been identified
.
Navigating this changing C> environment requires a comprehensive understanding of C> and how the field will continue to change from manufacturing and supply chain logistics to pricing strategies and access issues
.

references:

References: References:

[1] Endpoints news/ZS Perspective: 3 Predictions on the Future of Cell & Gene Therapies

[1] Endpoints news/ZS Perspective: 3 Predictions on the Future of Cell & Gene Therapies