Yang Lin Comments | A rising star in cancer immunotherapy-γδ T cells

On March 25, 2021, Dutch biotech startup Lava Therapeutics listed on the Nasdaq with an initial public offering (IPO) of US$100.

immunity

The emerging γδ T cell therapy Immune T cells are the main targets of cancer immunotherapy.

Source: Lava Therapeutics official website

Source: Lava Therapeutics official website Source: Lava Therapeutics official website

γδ T cells and αβ T cells have many things in common, for example, they can exert cytotoxic effect and produce pro-inflammatory cytokines.

cholesterol

Compared with αβ T cells, γδ T cells have several advantages: First of all, as mentioned above, γδ T cells recognize their target cells in a manner independent of MHC, thereby reducing allogeneic reactions and grafts.

Secondly, γδ T cells infiltrate a variety of tissues, which can quickly respond to targets and release effector cytokines.

Third, the recognition and killing of tumors by γδ T cells does not depend on the expression of a single antigen.

Tumor immune CAR-T

Lava Therapeutics, a leader in γδ T cell therapy, was established in 2016, focusing on translating the expertise of the bispecific γδ T cell adaptor into cancer therapy.

Before the IPO on March 25, Lava had completed 3 rounds of financing and received a total of approximately US$100 million.

The bispecific antibody developed by Lava, which binds to tumor cells on one side and γδ T cells on the other, can redirect the patient's own γδ T cells and other immune cells (such as natural killer cells) to tumor targets.

LAVA's bispecific γδ T cell adaptor (bsTCE) directly induces effective killing of tumor cells through its unique targeting of Vγ9Vδ2 T cells and tumor-associated antigen (TAA).

(Source: LAVA official website) (Source: LAVA official website)

Lava’s leading project LAVA-051 is a unique humanized bispecific γδ T cell adaptor (γδ bsTCE) that attracts immune cells (including γδ T cells) to an antigen called CD1d.

Lava Therapeutics pipeline (source: company website)

Lava Therapeutics pipeline (source: company website) Lava Therapeutics pipeline (source: company website)

In addition to LAVA-051, Lava has also completed the preclinical proof of concept of another γδ bsTCE LAVA-1207 that targets prostate-specific membrane antigen (PSMA).

In addition, Lava is also advancing a collaborative research.

Part of the company that develops γδ T cell therapy

Some companies that develop γδ T cell therapies Some companies that develop γδ T cell therapies

Source: References [5]

Source: Reference Materials [5] Source: Reference Materials [5]

Unlike the αβ T cells commonly used in CAR-T therapy, γδ T cells play a role in the innate immune response of the immune system's first faster line of defense.

Michael Leek, CEO of TC Biopharm said: “Because γδ T cells are part of the innate immune system, they have been pre-programmed to locate and destroy cells that are subject to cancer-related transformational stress.

Source: The company's official website.

Outlook

Outlook outlook

Barts and Neil McCarthy, Lecturer in Immunology at the London Medical College, said: "We have long known that γδ T cells have powerful antimicrobial and tumor-killing functions, but they have very different rules of the game with other major types of lymphocytes in human blood and tissues.
It is very different, so the use of these characteristics for patient treatment has always been a very challenging problem.
What is exciting is that in recent years, our understanding of the molecules and mechanisms that control the activity of γδ T cells has progressed very rapidly, so now it is more It is suitable to use this biological knowledge to achieve potential therapeutic purposes.
" However, the use of γδ T cells to develop cancer immunotherapy still faces many challenges.
This includes how to allow these cells to circulate in the blood long enough to maximize contact with blood cancer target cells.
In addition, how to ensure that these therapies will not cause problematic inflammation in organs including skin, lungs and intestines (γδ T cells are mainly found in epithelial and mucosal tissues, such as skin, intestine, etc.
) also need to be considered.
However, in contrast, γδ T cells may have great potential in the treatment of infectious or inflammatory diseases in the future .
McCarthy said: "As we continue to develop better tools that can modify γδ T cells in a more targeted way, I am optimistic that these methods will bring effective new therapies for a series of major diseases.
" Experts

infection

Reviews

Reviews

Professor Yang Lin, Chairman of Boshengji

Berson Professor Dong Shichang Ji Yang Lin Berson Professor Dong Shichang Ji Yang Lin

Medical Rubik's Cube Pro: What is the current stage of the development of γδ T cell therapy? What are your impressive developments?

Medical Rubik's Cube Pro: What is the current stage of the development of γδ T cell therapy? What are your impressive developments? Medical Rubik's Cube Pro: What is the current stage of the development of γδ T cell therapy? What are your impressive developments?

Yang Lin: Since the discovery of γδ T cells in 1984, with the continuous in-depth research of researchers, people have gradually realized that γδ T cells also play a very important role in human tumor immunity.
First, the researchers discovered that γδ T cells themselves carry a variety of receptors that can recognize cancer or abnormal cells (for example: γδ TCR and NKG2D, etc.
).
In 2015, a study published in the journal Nature Medicine further showed that the amount of γδ T cell infiltration in tumors is the best positive predictor of patient prognosis.
In addition, the study also found that after allogeneic transplantation, the level of γδ T cells is closely related to the prognosis.
These results fully confirmed the anti-tumor relevance of γδ T cells.
The recognition of γδ T cells for tumor cells mostly does not depend on the antigen presentation mechanism of MHC molecules, so it is not easy to produce allogeneic rejection.
Another advantage of γδ T cells is that they are safe, even if high doses are used for killing experiments, they will not cause damage to normal tissue cells.
Combining the above advantages, γδ T cells have become one of the sources of natural immune cells suitable for the production of allogeneic cell therapy products, without the need for gene editing, avoiding the potential risks that may be introduced by gene editing.

So far, many international clinical trials have used γδ T cell-related therapies to treat cancer.
However, according to the published data, the overall efficacy is still not as good as traditional CAR-T cell therapy.
Most of these clinical trials use γδ T cells expanded in vivo or cultured in vitro, and have not been engineered.
However, the reason why cancer cells can multiply and expand in patients is mainly because cancer cells have developed a set of mechanisms that can prevent immune cells from recognizing and reduce the effects of immune cells, resulting in the killing effect of γδ T cells on tumors in the body.
limited.
Therefore, I think it is very necessary to engineer γδ T cells to further enhance the recognition and killing of tumors by γδ T cells.

Regarding engineered γδ T cells, especially CAR-γδ T cells, the company that has made rapid progress in international research and development should be Adicet Bio in the United States.
The company’s CD20-CAR-γδ T cells (ADI-001) are in In October 2020, it officially obtained the IND approval from the US FDA .
According to the published data so far, ADI-001 can harvest up to 1,000 doses of cells per batch, and pre-clinical data also shows excellent tumor clearance effects, so I am looking forward to seeing this product in clinical practice.
The safety and effectiveness data were demonstrated in the test.

FDA

Medical Rubik's Cube Pro: What challenges still need to be overcome in the development of cancer immunotherapy based on γδ T cells?

Medical Rubik's Cube Pro: What challenges still need to be overcome in the development of cancer immunotherapy based on γδ T cells? Medical Rubik's Cube Pro: What challenges still need to be overcome in the development of cancer immunotherapy based on γδ T cells?

Yang Lin: Regarding the bottleneck in the development of CAR-γδ T cell products, I think there are two main aspects: 1) the in vitro expansion and culture process of γδ T cells, and 2) the cell engineering transformation (that is, the CAR genetic modification) program.
First of all, the number of γδ T cells in the human body is relatively small, accounting for only about 0.
5%–5% of all T cells.
Therefore, how to expand these very few cells to a dose sufficient for many people is a development.
The first challenge that γδ T cell products must face.
In addition to the number of cells, how to avoid cell depletion due to excessive proliferation, and how to maintain the cell purity of the final product (too many αβ T cells may cause the risk of immune rejection), all test the cell culture process of each company.
Another major challenge in developing γδ T cell products is how to engineer γδ T cells.
Regarding the engineering of immune cells, the most common method is generally to use lentivirus or retroviral transfection.
However, compared with ordinary αβ T cells, due to the natural antiviral properties of γδ T cells, it is difficult to γδ T cells.
Virus transfection of cells is extremely difficult.
Not only is virus transfection extremely low, but also the CAR gene is easily lost during cell culture.
Therefore, Lava Therapeutics' development of bispecific antibodies against γδ T cells, bypassing the obstacles of γδ T cell engineering, is also a smarter approach.

Medical Rubik's Cube Pro: When did Boshengji start to deploy UCAR-γδ T cell therapy? What progress has been made so far?

Medical Rubik's Cube Pro: When did Boshengji start to deploy UCAR-γδ T cell therapy? What progress has been made so far? Medical Rubik's Cube Pro: When did Boshengji start to deploy UCAR-γδ T cell therapy? What progress has been made so far?

Yang Lin: Our company first started to develop UCAR-γδ T cell products in 2017.
So far, we have developed a total of two cell culture expansion platforms, one is the preparation method of Vγ9Vδ2 T cells; the other is more An expansion platform for clonal γδ T cells.
Vγ9Vδ2 T cells are mainly distributed in peripheral blood, which is less difficult to prepare and may be more suitable for the treatment of hematological tumors.
However, Vγ9Vδ2 T cells have the defects of poor persistence in vivo and relatively unsatisfactory anti-tumor activity.
On the other hand, polyclonal γδ T cells mainly composed of Vδ1 cells are considered to be the most promising therapeutic γδ T cells due to their strong in vivo persistence and superior solid tissue infiltration ability.
For example, in an article just published in the journal Science Translational Medicine in January 2021, researchers found that a large number of γδ T cells infiltrated in solid tumor samples of primary ovarian cancer , and these γδ T cells have a high degree of TCR.
Diversity, and the proportion of Vγ9Vδ2 T cells is relatively small.
These findings further confirm that polyclonal γδ T cells have more advantages and potential in the treatment of solid tumors.
However, the preparation process of polyclonal γδ T cells is more challenging.
Our company has spent a considerable amount of time and energy over the years, testing a variety of processes and combinations, and repeatedly optimizing and verifying our cell expansion method.

Ovarian cancer

So far, the two cell culture platforms can amplify γδ T cells by more than 1,000 times, and the final product has almost no αβ T cells remaining, and both exhibit extremely high killing activity in in vitro tumor cell killing tests.
In particular, we have reached a relatively advanced level in the preparation process of polyclonal γδT cells.
On the other hand, regarding the engineering modification of γδ T cells, our R&D team has been continuously researching and testing for many years, and finally successfully developed the best γδ T modification technology.
When our cell products are harvested, the ratio of CAR+ cells can reach between 50% and 80%, successfully solving the bottleneck of γδ T cell engineering.
More importantly, these CAR-modified γδ T cells showed very strong specific killing to target-positive tumors; on the contrary, there were almost no target-positive primary normal cells.
The experimental results are impressive.
Uplifting.
Currently, we have a number of UCAR-γδ T cell products under development for different targets (such as CD7, BCMA, CD19, and solid tumor targets, etc.
).
It is expected that UCAR-γδ T cell confirmatory clinical trials will be launched in the near future test.

Medical Rubik's Cube Pro: In general, how do you see the prospects of γδ T cell therapy? In your opinion, what breakthroughs will be made in this field in the next 3 to 5 years?

Medical Rubik's Cube Pro: In general, how do you see the prospects of γδ T cell therapy? In your opinion, what breakthroughs will be made in this field in the next 3 to 5 years? Medical Rubik's Cube Pro: In general, how do you see the prospects of γδ T cell therapy? In your opinion, what breakthroughs will be made in this field in the next 3 to 5 years?

Yang Lin: In recent years, immune cell therapy represented by CAR-T cells has set off a wave of craze in the field of tumor treatment.
CAR-T therapy has also made some major breakthroughs in certain tumor indications (especially hematological tumors).
However, under this wave of enthusiasm, the potential problems of this method of preparing products from patients' own immune cells have gradually been exposed.
These problems mainly include: patient cell quality is relatively unstable, cell preparation time is long and cannot be prepared in advance, and the cost of cell single batch production is high.
In order to make up for the above problems, many international companies and research units have invested capital and manpower to develop allogeneic universal immune cell therapy products derived from healthy donors .
Commonly used are UCAR-T cells, UCAR-NK cells and UCAR-γδT cells.
Wait.

Yang Lin: Immune Cell Therapy

As the raw material for allogeneic universal cell products, γδ T cells are born with the following advantages: 1) The cell itself has many anti-tumor mechanisms and is a natural tumor killer; 2) It is not limited to the presentation mechanism of MHC molecules.
The safety of tumor clinical treatment has been verified many times; 3) Unlike UCAR-T, UCAR-γδ T cells do not need to use gene editing technology to knock out the TCR gene to reduce immune rejection, so it can avoid many risks such as off-target; 4) Many studies so far have shown that γδ T cells have good tumor infiltration ability and have extremely high potential for overcoming the solid tumor barriers of general CAR-T therapy (such as TME).

In addition to the advantages of the above-mentioned γδ T cells, according to the known preclinical data of UCAR-γδ T cells, whether from our company or other companies at home and abroad, they have demonstrated the good tumor-specific killing of UCAR-γδ T cells.
active.
Therefore, I am personally very optimistic about the prospects of γδ T cell therapy.
I boldly guess that in the next three to five years, several UCAR-γδ T cells should enter the key clinical phase II, and even be approved for marketing.

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