Looking at the future of ready-to-use cell therapy from the latest clinical results of NK cell therapy...

A few days ago, the cutting-edge company Fate Therapeutics announced the latest clinical results of natural killer (NK) cell therapy FT516 and CAR-NK cell therapy FT596 based on the differentiation of induced pluripotent stem cells (iPSC)

In the phase 1 clinical trial, patients with relapsed/refractory B-cell lymphoma received a single dose of FT596, or a single dose of FT596 combined with a single dose of anti-CD20 antibody rituximab

The results of the trial showed that of the 14 patients who received FT596 doses of more than 90 million cells, 10 (71%) patients achieved objective remission, and 7 (50%) achieved complete remission

▲Interim results of Phase 1 clinical trial of FT596 (Image source: Fate Therapeutics official website)

In addition, FT596 therapy showed good tolerability.

It is worth mentioning that this CAR-NK cell is not an autologous cell therapy generated by genetic engineering in vitro by obtaining NK cells from cancer patients

Advantages of allogeneic cell therapy

The production method of allogeneic cell therapy is to obtain T cells or other cell types from healthy donors, genetically engineer and expand them in vitro, and freeze the stock after quality testing

Because these cells can be produced in advance and frozen in inventory, patients who need to be treated only need to thaw the inventory of therapies to receive treatment immediately, eliminating the delay in the manufacturing process of autologous CAR-T therapy

Moreover, usually cancer patients cannot receive multiple CAR-T treatments due to the limitation of their own T cell number

Other companies' allogeneic cell therapy goes a step further, using iPSC cells obtained from healthy donors

At present, cutting-edge companies such as Allogene Therapeutics, Shoreline Biosciences, and the aforementioned Fate Therapeutics are all developing "ready-to-use" cell therapies based on iPSC cell differentiation

▲Fate Therapeutics' ready-to-use NK cell and T cell production process (picture source: reference [4])

The persistence of the efficacy of allogeneic cell therapy is a challenge to be solved

Although allogeneic cell therapy has many advantages over autologous cell therapy, they also need to face unique challenges

Take the latest results of Fate Therapeutics' NK cell therapy FT516 as an example.

▲Interim results of the Phase 1 clinical trial of FT516 (picture source: Fate Therapeutics official website)

Strategies to improve the durability of allogeneic cell therapy

Aiming at the problem of reduced efficacy or durability of allogeneic cell therapy due to the patient’s immune rejection, the current solution strategies in this field follow the following directions:

A more effective means of removing lymphocytes

Existing studies have shown that in order for the infused cell therapy to proliferate in the patient, it is necessary to use chemotherapy and other means to clear the existing lymphocytes in the patient before the infused cell therapy, thereby providing space for the infused cell therapy to proliferate

One method currently under research is to make allogeneic cell therapies resistant to drugs that remove T cells through gene editing, so these cells will not be affected by drugs that remove T cells

▲Strategy to improve the persistence of CAR-T by inhibiting the expression of CD52 protein in CAR-T cells (Image source: Allogene official website)

Gene editing can also make allogeneic cell therapies resistant to chemotherapeutic drugs that clear T cells, allowing them to work normally in an environment that inhibits the growth of T cells

Decrease the immunogenicity of allogeneic cells

The experience of organ transplantation and hematopoietic stem cell transplantation shows that if the donor's main human leukocyte antigen (HLA) phenotype is similar to the host's HLA phenotype, the immune rejection of the transplant can be greatly reduced

Because Class 1 HLA protein is a key molecule that mediates immune rejection factors
.
Another strategy is to use genetic engineering to eliminate Class 1 HLA proteins expressed on the surface of allogeneic cells
.
The expression of HLA on the cell surface requires a subunit called β2-microglobulin.
Knockout of β2-microglobulin through genetic engineering can prevent the expression of HLA protein on the cell surface, thereby reducing the immunogenicity of these cells
.

▲HLA structure (picture source: User atropos235 on en.
wikipedia [CC BY-SA (http://creativecommons.
org/licenses/by-sa/3.
0/)])

Improve the health and durability of allogeneic cells

In addition to reducing the immunogenicity of allogeneic cells, many cutting-edge companies are also adopting different strategies to improve the health and durability of cell therapy itself
.
For example, Wugen, which recently received US$172 million in Series B financing, uses its unique cell culture method to generate cell therapies called "memory NK cells", which have enhanced tumors compared with traditional NK cells.
Killing function and durability in the body
.

▲Mechanism of universal memory NK cell platform (picture source: Wugen company official website)

Shoreline Biosciences, which recently reached a collaboration with Kite, uses gene editing technology to knock out the expression of CISH genes in NK cells to improve cell durability
.
CRISPR gene editing technology has the potential to make multiple modifications to the genome of cell therapy at one time
.

▲Shoreline Company uses gene editing to improve the function and persistence of NK cells (Image source: Shoreline Company official website)

The future of allogeneic cell therapy

Many people believe that allogeneic cell therapy can solve the pain points of autologous therapy that is difficult to prepare and the long production cycle, bringing new hope for treatment to more patients around the world
.
At the 2020 WuXi AppTec Global Forum, Dr.
Patrick Hwu, head of the Cancer Medicine Division of the University of Texas MD Anderson Cancer Center, said that in some sensitive cancers such as B-cell lymphoma, T cells do not need to be in the tumor.
Staying nearby for a long time, "ready-to-use" cell therapy can bring rapid relief without worrying too much about rejection
.

Moreover, the feature that the ready-to-use therapy can be repeatedly administered can also make up for its durability problem to a certain extent
.

However, Dr.
Rick Klausner, the founder and CEO of Lyell Immunopharma, pointed out that one of the current driving forces for the development of "ready-to-use" cell therapies lies in the current bottlenecks in the production of autologous CAR-T therapies
.
However, we need to realize that the current technology for manufacturing CAR-T therapy is far from mature
.
In 5-10 years, the research and development and manufacturing of cell therapy will inevitably be very different from now
.

In the future, if we can isolate the subgroups of T cells that are truly curative, we can significantly reduce the number of cells needed to treat cancer
.
This can greatly reduce the number of cells we need to cultivate and shorten the production time of cell therapy from a few weeks to just a few days
.

In the end, we have to know that allogeneic and autologous cell therapy are not opposing choices
.
Many current researches used to improve the effect of cell therapy, whether it is to seek more effective cell types, or use gene editing to modify the cell's genome to improve the durability of therapy, can have a positive effect on the development of both types of cell therapy
.

Dr.
Richard Klausner once said, "Scientific development is endless and we need to recognize the beauty of innovation
.
At present, we don't know much about cell therapy
.
In the future, cell therapy will definitely be different .
"

Reference materials:

[1] Fate Therapeutics Announces Positive Interim Clinical Data from its FT596 and FT516 Off-the-shelf, iPSC-derived NK Cell Programs for B-cell Lymphoma.
Retrieved August 20, 2021, from https://ir.
fatetherapeutics.
com/ news-releases/news-release-details/fate-therapeutics-announces-positive-interim-clinical-data-its

[2] Caldwell et al.
, (2021).
Allogeneic CAR Cell Therapy—More Than a Pipe Dream.
Front Immunol.
, doi: 10.
3389/fimmu.
2020.
618427

[3] Fate delivers, up to a point.
Retrieved August 20, 2021, from https:// Fate Therapeutics Corporate Presentation.
Retrieved August 20, 2021, from https://ir.
fatetherapeutics.
com/static-files/726ecee3-28ab-4276-a7dd-885544972a16

[5] Vivier et al.
, (2008).
Functions of natural killer cells.
Nature Immunology, https://doi.
org/10.
1038/ni1582